Deciphering STAT3 signaling potential in hepatocellular carcinoma: tumorigenesis, treatment resistance, and pharmacological significance
Cellular & Molecular Biology Letters volume 28, Article number: 33 (2023)
Hepatocellular carcinoma (HCC) is considered one of the greatest challenges to human life and is the most common form of liver cancer. Treatment of HCC depends on chemotherapy, radiotherapy, surgery, and immunotherapy, all of which have their own drawbacks, and patients may develop resistance to these therapies due to the aggressive behavior of HCC cells. New and effective therapies for HCC can be developed by targeting molecular signaling pathways. The expression of signal transducer and activator of transcription 3 (STAT3) in human cancer cells changes, and during cancer progression, the expression tends to increase. After induction of STAT3 signaling by growth factors and cytokines, STAT3 is phosphorylated and translocated to the nucleus to regulate cancer progression. The concept of the current review revolves around the expression and phosphorylation status of STAT3 in HCC, and studies show that the expression of STAT3 is high during the progression of HCC. This review addresses the function of STAT3 as an oncogenic factor in HCC, as STAT3 is able to prevent apoptosis and thus promote the progression of HCC. Moreover, STAT3 regulates both survival- and death-inducing autophagy in HCC and promotes cancer metastasis by inducing the epithelial–mesenchymal transition (EMT). In addition, upregulation of STAT3 is associated with the occurrence of chemoresistance and radioresistance in HCC. Specifically, non-protein-coding transcripts regulate STAT3 signaling in HCC, and their inhibition by antitumor agents may affect tumor progression. In this review, all these topics are discussed in detail to provide further insight into the role of STAT3 in tumorigenesis, treatment resistance, and pharmacological regulation of HCC.
Liver cancer is the fifth most common tumor worldwide and the second leading cause of death . In 2012 alone, a total of 14.1 million cases of liver cancer were diagnosed, which were responsible for 745,500 deaths . The mortality rate of liver cancer differs between men and women. It is the second leading cause of death in men and the sixth leading cause of death in women. The most common form of liver cancer is hepatocellular carcinoma (HCC), which can be caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, aflatoxin contamination in food, alcohol consumption, obesity, type 2 diabetes, liver cirrhosis, and smoking, among other factors [2, 3]. Due to the synergy between these additional factors, the risk of developing HCC in the community and individuals has increased significantly [4,5,6,7]. Up to 70–85% of HCC cases are caused by HBV and HCV . According to studies, 50% of HCC cases are due to HBV, while HCV is responsible for the development of 25% of HCC cases [8, 9]. Treatment strategies for HCC vary and include chemotherapy, radiotherapy, surgery, and immunotherapy. Clinical studies have shown that chemotherapy can improve the prognosis of patients with HCC. For example, a combination of atezolizumab and bevacizumab can increase the survival rate of patients with HCC, and its therapeutic potential is better than that of sorafenib . In addition, a combination of oxaliplatin and fluorouracil shows a better effect in improving the prognosis of patients with HCC compared with sorafenib . Basic research has shown that the function of chemotherapy in the treatment of HCC may be affected by the development of drug resistance [12, 13]. Moreover, there is a possibility that the response of HCC cells to radiotherapy may be altered. For example, high expression of METTL1 leads to DNA repair and prevents the radiosensitivity of HCC cells . In addition, dysbiosis in the gut microbiota is responsible for the impairment of the antitumor immune response by radiotherapy and may enhance HCC progression . Some genetic modulations may also increase the efficacy of immunotherapy in the treatment of HCC. For example, silencing of MCT4 increases T cell infiltration and promotes immunotherapeutic potential in suppressing HCC . GDF1 is involved in the upregulation of CTA by downregulating LSD1 to improve the immunotherapy of HCC . However, much progress still needs to be made in the treatment of patients with HCC. Therefore, one area for developing new therapeutics is to focus on factors that mediate the progression of HCC. The cellular and molecular interactions determine the progression of HCC cells via molecular signaling pathways [18,19,20]. Disruption of the intrahepatic microbiota leads to stimulation of hepatic stellate cells and their senescence, to direct liver cirrhosis toward HCC development . Moreover, SNORAD17 inactivates p53 by binding to NPM1 and MYBBP1A in the nucleus to promote HCC progression . Inhibition of IRF8 impairs HCC cell progression, which is important for increasing the potential of anti-PD-1 therapy . The extracellular vesicles derived from hepatic stellate cells are able to secrete HK1 to increase the malignancy of HCC by stimulating glycolysis . Even more interestingly, dysregulation of molecular signaling pathways may lead to drug resistance in HCC . The upregulation of ROBO1 is considered to be a factor for the increase of HCC progression and its downregulation by miR-152-3p affects the malignancy of HCC . In addition, inflammation is considered a factor in the pathogenesis of HCC, and the upregulation of signal transducer and activator of transcription 3 (STAT3) by GNAS creates such a condition . Therapeutic targeting of UCK2 and its downregulation may lead to an increase in cancer immunity in HCC . Since molecular interactions play a key role in HCC progression [29, 30], the current review was dedicated to understanding the function of STAT3 signaling in HCC tumorigenesis.
There are also a number of reviews on the STAT3 pathway in HCC [31,32,33,34,35]. However, their structure is not comprehensive, and the novelty of the current work is that it has focused in different sections and subsections on the role of STAT3 in growth, invasion, drug resistance, radioresistance, molecular pathways regulating STAT3, and its targeting by anticancer agents. These topics have not been fully investigated in previous reviews. As science continues to advance, an up-to-date review of STAT3 is needed for HCC. Therefore, most references in this article are new and updated.
STAT3 signaling: an overview
Structure and mechanism of activation
The STAT family comprises seven transcription factors: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6. Their interaction with cytokines, growth proteins, and polypeptide ligands is critical for controlling important biological events in cells [36,37,38]. STAT3 is the best known member of the STAT family. This transcription factor has the ability to bind to DNA and its expression can be induced by cytokines, growth factors, inflammation, interleukin-6 (IL-6), and others . Structurally, STAT3 has a unique shape and the presence of different domains in this protein leads to its specific functions in cells. The N-terminal, coiled-coil, DNA-binding, Src homology 2 (SH2), and C-terminal transactivation domains make up STAT3 [37, 38, 40]. Each of these domains is responsible for a specific function of STAT3. For example, dimer–dimer interactions are mediated by the N-terminal domain and the formation of the DNA–protein complex in STAT3 is mediated by the DNA-binding domain. The SH2 domain is involved in increasing the stability of STAT3 and transcriptional activation is mediated by the C-terminal domain . STAT3 was first discovered in 1996, when researchers investigated the intracellular transduction of epidermal growth factor (EGF) and IL-6, and STAT3 was believed to be involved in the regulation of cell growth and inflammatory responses [41, 42]. As a downstream target of inflammatory factors and growth factors, STAT3 is able to regulate important biological mechanisms in cells such as proliferation, differentiation, migration, and others [43,44,45,46]. In cells, there are endogenous inhibitors of STAT3 signaling, including PIAS, SOCS, and protein tyrosine phosphatases, as well as ubiquitin enzymes that can suppress this pathway . Stimulation of STAT3 signaling in cells is mediated by phosphorylation at tyrosine (705) and serine (727) residues induced by JAK proteins, tyrosine kinases, cytokines, and nonreceptor tyrosine kinases such as SRC and ABL. After phosphorylation of STAT3 and formation of homo- or heterodimers, STAT3 migrates to the nucleus to regulate gene expression . Figure 1 illustrates STAT3 signaling in cells.
STAT3 signaling in cancer
The field of oncology is rapidly evolving thanks to the development of various therapeutics. A major limitation of current treatment strategies is that there are few therapies based on targeting of molecular signaling pathways that regulate cancer progression. Therefore, due to the development of precision medicine and improvements in the biological field, it is strongly recommended to develop novel therapies based on molecular signaling pathways that are mainly involved in cancer development. There is increasing evidence that STAT3 regulation is important in cancer and promotes cancer progression. Exosomal S100A4 stimulates STAT3 signaling to mediate resistance of lung tumor cells to the immune system [49, 50]. Moreover, high expression of STAT3 mediated by IL-6 can promote invasion and metastasis of gastric cancer cells . The presence of a high-fat diet due to cyclophilin B is significant in inducing STAT3 signaling to increase PVT1 expression. Moreover, there is a positive feedback loop between STAT3 and PVT1 that may promote the progression of colorectal tumor cells . When STAT3 expression increases, it induces YAP signaling to promote lung tumor cell metastasis . Nuclear translocation of STAT3 has been reported to be critical for the induction of the epithelial–mesenchymal transition (EMT) and increasing metastasis of bladder cancer, and this is mediated via SENP3 as a regulatory factor . Circ-BGN and circ-RPPH1 are able to stimulate STAT3 signaling to promote gastric and lung tumor cell progression, respectively [55, 56]. Due to the important function of STAT3 in oncogenesis, studies have focused on the use of antitumor agents targeting this molecular signaling pathway to suppress it and impair tumorigenesis . Fangchinoline increases oxidative stress to suppress STAT3 signaling to reduce myeloma progression . Moreover, epigallocatechin-3-gallate decreases STAT3 expression by impairing colon tumor cell invasion and metastasis . According to these descriptions, the function of STAT3 signaling in cancer is oncogenic and its suppression may therefore introduce new therapeutics for tumor therapy. The aim of the current review is to understand the function of STAT3 signaling in HCC, which will be discussed in detail in the next sections.
A summary of STAT3 inhibitors
Repurposed drugs and natural products can be considered as important STAT3 inhibitors in cancer therapy . In addition, medicinal chemistry has emerged as a new field for STAT3 suppression and cancer therapy . The variety of natural products is large and they have shown high potential for modulating the STAT3 signaling pathway in cancer therapy. Betulinic acid, curcumin, plumbagin, diosgenin, caffeic acid, honokiol, and thymoquinone are among the phytochemicals that suppress STAT3 . However, since natural products have poor bioavailability, the development of effective small molecule inhibitors of STAT3 has been proposed. These inhibitors are able to regulate upstream modulators of STAT3 such as JAK or Src, or they can directly interfere with the phosphorylation of STAT3 . Most STAT3 inhibitors bind to the SH2 domain of STAT3 to interfere with its tyrosine phosphorylation . Interestingly, different types of small molecules such as AG490, LS-104, INCB018424, and CEP-701 have been used in preclinical models and clinical trials . However, since there are similarities between the SH2 domain of STAT3 and other members of the family, it is recommended that SH2 domain regulators be used with more caution in clinical trials.
STAT3 in HCC apoptosis
One of the programmed cell death mechanisms important for cancer therapy is apoptosis. This cell death mechanism involves intrinsic and extrinsic pathways, with the intrinsic pathway involving mitochondria, while the extrinsic pathway involves death receptors . In both pathways, the caspase cascade is upregulated to stimulate apoptosis. However, one of the drawbacks in cancer therapy is the development of apoptosis resistance, in which tumor cells do not respond to this form of cell death, leading to chemoresistance [67,68,69,70]. The interplay of oncogenic molecular signaling pathways and their upregulation may lead to the development of apoptosis resistance in HCC cells and inhibition of this intracellular mechanism. High expression of AKR1C3 suppresses apoptosis in HCC cells, and its silencing promotes apoptosis. To this end, AKR1C3 increases the expression of STAT3 via IL-6, and there is also a positive feedback loop in which overexpressed STAT3 promotes AKR1C3 expression in inhibiting apoptosis in HCC cells . When apoptosis is inhibited, cancer cells gain more potential to proliferate and increase their population . The upregulation of TRIM52 increases the growth rate of HCC cells, and to this end, TRIM52 stimulates STAT3 signaling as an oncogenic factor to prevent apoptosis in tumor cells . Indeed, the function of STAT3 signaling is to protect HCC cells from apoptosis and to provide optimal conditions for tumor cell growth. However, stimulation of STAT3 signaling in HCC cells is complicated and requires interactions between different molecular signaling pathways. For example, circRNA-9119 is involved in protecting HCC cells from apoptosis. Upregulation of circRNA-9119 in HCC cells leads to inhibition of miR-26a to stimulate the JAK1/STAT3 axis to prevent apoptosis in tumor cells . In chemotherapy, the main goal is to stimulate apoptosis to reduce HCC cell viability and progression. Doxorubicin (DOX) is commonly used in the treatment of HCC, and the goal of its administration is to induce apoptosis in tumor cells. The high expression level of CKLF1 can suppress apoptosis in DOX-exposed HCC cells, which is due to the activation of the IL-6/STAT3 axis .
Inhibition of apoptosis following upregulation of STAT3 may also lead to the development of radioresistance. Therefore, researchers have sought to understand apoptosis regulation after targeting STAT3 signaling in HCC therapy. XL888 is a selective inhibitor of HSP90 that can reduce the expression of STAT3 to stimulate apoptosis after inadequate radiotherapy in the treatment of HCC . The factors targeting STAT3 signaling in HCC may affect tumorigenesis. miR-383 is an inducer of apoptosis in HCC cells. The expression of miR-383 decreases in HCC cells, while IL-17 shows an increase in expression. miR-383 downregulates the expression of IL-17, inhibiting STAT3 signaling in triggering apoptosis in HCC cells . Another important factor regulating cancer cell progression is PDIA3, the upregulation of which leads to an unfavorable prognosis . Inhibition of PDIA3 is important for suppressing growth and metastasis in multidrug-resistant tumor cells . Low expression of PDIA3 leads to apoptosis in HCC cells, and after its inhibition, suppression of STAT3 phosphorylation occurs to stimulate apoptosis . According to these studies, inhibition of apoptosis occurs frequently in HCC, and upregulation of STAT3 increases tumorigenesis and prevents apoptosis in tumor cells.
STAT3 in HCC autophagy
In the previous section, the role of STAT3 in regulating apoptosis as a form of programmed cell death was explained. Another important mechanism is autophagy, which can have both oncogenic and oncosuppressive functions, and whose function is important in HCC. AMPK, Beclin-1, LC3, PI3K, and ATGs are important regulators of autophagy, which is a multistep mechanism involving initiation, elongation, maturation, and fusion steps. Therefore, targeting autophagy is of great importance in cancer therapy. One of the most important challenges is the dual function of autophagy as a pro-survival or pro-death mechanism [81,82,83]. Recent studies have shown that autophagy regulates the progression of HCC cells [84, 85]. Hepatocytic p62 impairs tumor progression and carcinogenesis via mTORC1 induction and defective autophagy . Downregulation of SPTBN1 promotes the expression of YAP and inhibits autophagy in promoting HCC progression . This section focuses on the role of STAT3 signaling in modulating autophagy in HCC. Capsaicin promotes the formation of reactive oxygen species (ROS), to increase STAT3 expression and induce autophagy. Notably, suppression of ROS /STAT3/autophagy enhances the ability of capsaicin to stimulate apoptosis in HCC cells . Moreover, Zingiberensis newsaponin reduces the expression of AKR1C to suppress the Janus kinase 2 (JAK2)/STAT3 axis, thereby inhibiting autophagy and reducing the malignancy of HCC cells .
Under these circumstances, autophagy has an oncosuppressor function to inhibit cancer progression, and induction of autophagy is crucial to reduce HCC cell progression. Bufothionine decreases the serum level of IL-6 to inhibit the JAK2/STAT3 axis and increase the expression of ATG5, ATG7, and LC3II in autophagy induction and prevent the progression of HCC . However, the function of autophagy in cancer can always be pro-survival, even after stimulation by agents and drugs. Myricetin increases MARCH1 levels to induce STAT3 signaling in mediating autophagy. Moreover, inhibition of autophagy increases the potential of myricetin to induce cell cycle arrest, demonstrating the function of autophagy as a mechanism promoting survival . Dimethyl fumarate impairs HCC cell progression by suppressing growth, angiogenesis, and autophagy by increasing SOCS3 expression, thereby inhibiting the JAK1/STAT3 axis .
Oxaliplatin is one of the chemotherapeutic agents commonly used in cancer treatment, although its efficacy may be determined and regulated by the autophagy mechanism. Stimulation of apoptosis and autophagy by 6-shogaol enhances the potential of oxaliplatin in cancer therapy . Moreover, wogonin stimulates autophagy and increases the cytotoxicity of oxaliplatin . However, induction of survival-promoting autophagy may lead to oxaliplatin resistance in HCC cells. Upregulation of STAT3 stimulates autophagy, whereas inhibition of the JAK2/STAT3 axis inhibits autophagy, promoting oxaliplatin-mediated apoptosis in HCC cells . According to these studies, the interplay between STAT3 and autophagy not only determines the progression and survival rate of HCC cells, but also influences the response to chemotherapy. When autophagy has a tumor suppressive function, its induction is followed, and when it has a pro-survival function, its inhibition can promote apoptosis in HCC cells (Fig. 2 and Table 1).
STAT3/EMT axis in HCC
The previous sections have shown that STAT3 signaling is able to increase proliferation and survival of HCC cells via inhibition of apoptosis and modulation of autophagy (the function of autophagy can be pro-survival or pro-death). Although proliferation is an important hallmark of HCC cells, abnormal metastasis of these tumor cells may also adversely affect patient survival and prognosis. According to clinical and experimental reports, interfering with STAT3 signaling is a therapeutic approach to prevent HCC cell metastasis. On the other hand, the best-known mechanism for cancer invasion and metastasis is the epithelial–mesenchymal transition (EMT), which converts epithelial cells into mesenchymal cells and is associated with downregulation of E-cadherin and upregulation of N-cadherin and vimentin [96, 97]. The increase in metastasis and the development of chemoresistance may be due to the induction of EMT in tumor cells [98,99,100]. This section focuses on the function of STAT3 signaling in regulating the EMT mechanism in HCC. First of all, two important aspects should be considered regarding the role of STAT3 signaling in the regulation of HCC metastasis. In the initial phase, STAT3 signaling may be involved in the increased invasion and progression of HCC cells, either alone or by targeting related factors of EMT. For example, high expression of STAT3 leads to upregulation of transforming growth factor-beta (TGF-β1) to stimulate the EMT mechanism and enhance tumor metastasis . In the next phase, the cooperation of STAT3 signaling with other molecular signaling pathways is required for EMT induction in HCC. DYRK1A may be involved in increasing metastasis of HCC cells via EMT induction. To this end, DYRK1A promotes the expression of STAT3 and accelerates its nuclear translocation; DYRK1A also interacts with TSC1 to phosphorylate the Smad2/Smad3 complex. Subsequently, it translocates to the nucleus, and the interaction of the Smad2/Smad3 complex with STAT3 signaling induces EMT and enhances metastasis of HCC cells . Moreover, STAT3 can create positive feedback loops with upstream mediators that facilitate HCC cell metastasis and invasion. High levels of DDR1 lead to poor prognosis and low survival in HCC. DDR1 increases phosphorylation of STAT3, and overexpressed STAT3 in turn increases DDR1 expression. These interactions lead to EMT induction, which promotes HCC invasion . Regarding the oncogenic function of STAT3 in increasing metastasis of HCC cells, the upstream factors that suppress STAT3 signaling may impair tumorigenesis. PIRK4 is considered an inhibitor of HCC invasion. In this way, PIRK4 impairs the phosphorylation of STAT3, suppressing EMT and metastasis in HCC .
PRN2 is a new emerging target in the field of cancer therapy because its downregulation impairs growth and metastasis and promotes apoptosis in cancer cells . Moreover, PRN2 interacts with EGFR to promote cancer growth . STAT3 is strongly regulated by PRN2, and its upregulation leads to radioresistance . PRN2 promotes the expression of STAT3 in HCC and increases its nuclear translocation to induce EMT in HCC invasion and metastasis . More importantly, endoplasmic reticulum (ER) stress may lead to malignancy of HCC cells via affecting STAT3 signaling. Hepatitis B virus small surface antigen leads to ER stress in HCC cells. Subsequently, ATF4 is upregulated to upregulate FGF19. The secreted FGF19 binds to the FGFR4 receptor on the cell surface to activate the JAK2/STAT3 pathway. Subsequently, nuclear translocation of STAT3 signaling occurs, increasing the levels of Slug, Snail, ZEB1, and Twist upon EMT induction and promoting tumor metastasis . Due to advances in the field of biology, key molecular signaling pathways regulating STAT3 have become increasingly well understood, revealing both oncogenic and oncosuppressive properties. For example, EFTUD2 stimulates NF-κB to mediate inflammation and colitis-induced carcinogenesis [110, 111]. In HCC, high levels of EFTUD2 are indicative of poor tumor cell prognosis . Mechanistically, EFTUD2 upregulates STAT3 expression, which is important for inducing EMT and facilitating metastasis and invasion of HCC .
Akt is another important factor in HCC, in which its overexpression and interaction with various molecular signaling pathways are responsible for the increase in HCC progression, malignancy, and development of drug resistance [114,115,116]. Interfering with Akt signaling is important for the treatment of HCC. Euphorbia factor L2 (EFL2) suppresses TGF-β-induced EMT in HCC cells. To this end, EFL2 reduces Akt expression and suppresses STAT3 signaling, which impairs tumor cell progression and metastasis . Moreover, high expression of SHC4 has been associated with upregulation of STAT3 and subsequent induction of EMT in HCC cells . According to these studies, STAT3 is a positive regulator of EMT in HCC, and therefore, suppression of STAT3 signaling may impair tumor progression by reducing EMT (Table 2 and Fig. 3) [119,120,121,122].
STAT3 in HCC drug resistance
The process of drug resistance in HCC is complicated and subject to the control of different molecular pathways in tumor cells. The process of drug resistance in HCC is favored by the upregulation of ribosomal RACK1, which increases tumor cell proliferation and viability . PBK/TOPK expression increases in chemoresistant HCC cells and mediates oxaliplatin resistance via downregulation of PTEN expression . In addition, high levels of CPEB1 decrease the stemness of HCC cells and are critical for suppressing drug resistance . LINC01234 is able to promote the expression of MAGEA3 via miR-31-5p sponging to increase the proliferation rate of tumor cells and mediate drug resistance in HCC . When the TRIM37 level is increased in HCC cells, it promotes Akt signaling to mediate chemoresistance . Moreover, ID-1 is involved in triggering oxaliplatin resistance in HCC by inducing the pentose phosphate pathway . Therefore, aberrant expression of proteins and genes can lead to the development of chemoresistance in HCC cells [129, 130], and this part of the text is focused on understanding the role of STAT3 signaling in the development of HCC drug resistance. The STAT3 pathway contributes to the development of drug resistance in HCC, and its expression level can be modulated by upstream mediators. The expression of DNMT3B is increased in HCC and shows a positive association with Oct4, which in turn increases the expression of IL-6 to induce STAT3 signaling in the development of sorafenib resistance in HCC and mediate an unfavorable prognosis in tumor cells . As mentioned previously, the oncogenic function of STAT3 may be related to the inhibition of apoptosis in HCC cells. When dovitinib is administered, it suppresses STAT3 signaling in a SHP-1-dependent manner to prevent apoptosis and develop sorafenib resistance in HCC . In the same way, dovitinib also increases the sensitivity of HCC cells to TRAIL and tigatuzumab. To this end, dovitinib inhibits STAT3 signaling in a SHP-1 manner to prevent tumor cell progression . The function of STAT3 in the development of chemoresistance in HCC was confirmed by the finding of increased sensitivity of HCC cells to sorafenib after suppression of STAT3 signaling by pharmacological compounds or genetic tools . Although studies have shown that activation of STAT3 signaling can lead to the development of sorafenib resistance in HCC, it has been shown that STAT3 expression is also regulated by sorafenib. Based on this finding, sorafenib administration downregulates STAT3 to prevent the development of TRAIL resistance in HCC . In addition, the inhibition of STAT3 signaling by sorafenib is important for increasing the radiosensitivity of HCC cells .
High excretion of drugs can also lead to the development of chemoresistance, and drug efflux transporters may contribute to this condition . ABCB1, also known as P-glycoprotein (P-gp), is a member of the ABC protein family and is located on the cell membrane [137, 138]. The substrates with a molecular weight of 250–1250 Da, including phospholipids, sterols, cholic acids, peptides, metabolites, and drugs, can be transported out of cells by ABCB1 . In particular, STAT3 shows some interactions with ABCB1 in HCC cells. High expression of ABCB1 may lead to exocytosis of envatinib from HCC cells and thus development of drug resistance. Overexpression of EGFR in HCC cells induces STAT3 signaling to increase ABCB1 expression in the development of chemoresistance . As mentioned earlier, the discovery of STAT3 is related to inflammatory processes. Now, the question arises whether inflammation in the liver can trigger STAT3 signaling and whether there is a link with the development of chemoresistance? The answer is yes. In a fibrotic liver, the presence of inflammation can lead to the induction of STAT3 signaling, which promotes the progression (proliferation and invasion) of HCC cells and mediates sorafenib resistance .
One of the important regulators of STAT3 signaling in HCC is RFX-1, which upregulates SHP-1 expression to suppress STAT3-mediated HCC progression . SC-2001 is involved in disrupting HCC progression and promotes RFX-1 expression to upregulate SHP-1 in inhibiting STAT3 signaling and suppressing sorafenib resistance in tumor cells . Even antitumor agents increase the level of SHP-1 in affecting the malignancy of HCC. Phloretin is a regulator of molecular signaling pathways in cancer  and can stimulate apoptosis to reduce tumor progression . Phloretin suppresses the progression of HCC and promotes the expression of SHP-1 to suppress STAT3 signaling, leading to sorafenib sensitivity in tumor cells . Moreover, inhibition of STAT3 signaling is important for the sensitivity of HCC cells to TRAIL-mediated apoptosis . These studies suggest that high expression of STAT3 promotes drug resistance in HCC cells. Therefore, therapeutic targeting of this molecular pathway may impair tumorigenesis and promote chemosensitivity. In addition, regulators of STAT3 signaling may indirectly target STAT3 expression to modulate drug sensitivity in HCCs. Table 3 summarizes the role of STAT3 signaling in the development of drug resistance in HCC.
STAT3 in HCC radio-resistance
Radiotherapy is considered minimally invasive in the treatment of cancer, and is preferred to chemotherapy and surgery in some cases . In addition, the development of stereotactic body irradiation and heavy ion therapy has greatly improved the potential of radiotherapy [148,149,150]. Although radiotherapy has brought many improvements in the treatment of patients with HCC, its potential may be threatened by the development of resistance. Molecular interactions have been reported to play an important role in the development of radiation resistance in HCC. Upregulation of NEAT1 may lead to radiation resistance in HCC due to stimulation of the PINK1/Parkin axis . Furthermore, loss of CPS1 may lead to deubiquitination of c-Myc, triggering radioresistance in HCC . Thus, when the expression level of oncosuppressor factors such as PTEN decreases and/or when oncogenic factors such as long noncoding RNA regulator of reprogramming (lncRNA ROR) increase, the likelihood of developing radioresistance in HCC is quite high [148, 153]. The role of STAT3 in the development of radioresistance in HCC has been investigated. High expression of mucin 1 may lead to radioresistance in HCC. Mechanistically, mucin 1 stimulates the JAK2/STAT3 axis to prevent apoptosis during radiation exposure in HCC cells . Stattic, a small-molecule inhibitor of STAT3, is considered an inhibitor of radioresistance in HCC as it decreases STAT3 levels to suppress the radiation-mediated increase in metastasis of HCC cells . However, the role of STAT3 signaling in regulating the response to radiotherapy in HCC needs further discussion (Fig. 4).
Non-coding RNAs regulating STAT3 in HCC
Noncoding RNAs (ncRNAs) play a rather crucial role in the process of tumorigenesis and microRNAs (miRNAs) are endogenous short noncoding RNAs that modulate gene expression by binding to the 3′-untranslated region (UTR) of target genes [156,157,158]. The role of miRNAs in HCC has been investigated and suggests a regulatory role of miRNAs in the progression and therapeutic response in HCC [159, 160]. Therefore, miRNAs are potential therapeutic targets in HCC. Moreover, miRNAs are able to regulate STAT3 signaling in various cancers [161, 162]. This section focuses on the role of miRNAs in STAT3 regulation in HCC. The progression of HCC cells can be suppressed by miR-637. Exogenous leukemia inhibitory factors (LIF) can induce STAT3 signaling and thus enhance HCC progression. On the other hand, miR-637 reduces the expression of LIF, to suppress STAT3 signaling . miR-124 is another factor mainly responsible for reducing the progression of HCC cells. Of note, miR-124 downregulates STAT3 expression, and restoration of STAT3 expression impairs the efficacy of miR-124 in suppressing HCC cell proliferation and progression . Two important references should be mentioned: First, upstream regulators of STAT3 can be modulated by miRNAs, and second, the goal of miRNAs in STAT3 targeting is to affect their downstream targets. For example, miR-340 reduces the expression of JAK1 to suppress STAT3 signaling and decreases the expression of Bcl-2, cyclin D1, and MMP-2 . In addition, the level of miRNAs can be affected by STAT3 in HCC. Stimulation of STAT3 signaling leads to upregulation of Snail and Twist1 in facilitating metastasis of HCC cells. However, miR-370-3p binds to the 3′-UTR of Snail and Twist1, suppressing HCC metastasis. On the other hand, IL-8 stimulates STAT3 signaling to reduce miR-370-3p expression in mediating tumorigenesis . Moreover, STAT3 increases the level of miR-23a to prevent gluconeogenesis in HCC . miR-26a is a suppressor of HCC with attenuated expression in tumor cells . miR-26a is able to reduce the expression of ERα to suppress the progression and proliferation of hepatomas mediated by E2 . Moreover, miR-26a is involved in reducing DNMT3B expression in alleviating HCC progression . Thus, miR-26a is an important tumor suppressor factor. miR-26a is able to decrease the levels of IL-6 by inhibiting STAT3 signaling and reducing the progression of HCC . Apoptosis, proliferation, and invasion of HCC cells are tightly regulated by STAT3 signaling. High levels of STAT3 can lead to acceleration of proliferation through upregulation of c-Myc, an increase in migration through upregulation of MMP-9, and decreased apoptosis of cells through downregulation of Bax and caspase-3. However, miR-378a-3p is able to suppress STAT3 signaling and thus disrupt HCC progression . Even the regulation of STAT3 by miRNAs can affect the response of HCC cells to therapy. miR-539 inhibits STAT3 signaling to stimulate apoptosis and promote the sensitivity of HCC cells to arsenic trioxide therapy . Thus, STAT3 is strongly regulated by miRNAs in HCC cells.
Long noncoding RNAs
Long noncoding RNAs (lncRNAs) are RNA transcripts that have gained much interest in recent years and regulate muscle differentiation , pluripotent stem cell reprogramming , apoptosis, and migration . lncRNAs are responsible for aberrant expression of genes in tumors and may influence colony formation, metastasis, and malignancy of cancer cells [177,178,179,180]. Interestingly, lncRNAs have shown their potential in regulating STAT3 signaling in HCC. To this end, the lncRNA TPTEP1 reduces the phosphorylation of STAT3, which has a positive effect on HCC cell progression . On the other hand, the lncRNA TINCR is able to enhance the progression of HCC. TINCR interacts and binds with TCPTP to stimulate STAT3 signaling, which is critical for enhancing tumor cell proliferation and metastasis . Similar to miRNAs, the expression levels of which can be regulated by STAT3, STAT3 is able to bind to the promoter of lncRNAs to modulate their expression levels. STAT3 increases the level of lncRNA HOXD-AS1, which downregulates the level of miR-130a-3p by acting as competing endogenous (ce)RNA. Then, it induces SOX4 expression to upregulate EZH2 and MMP-2 to promote carcinogenesis in HCC . In addition, infection with HBV can affect the expression level of lncRNAs in HCC. For example, in tissues infected with HBV, upregulation of lncRNA 01,152 is observed to increase the level of IL-23, inducing STAT3 signaling and promoting HCC progression .
The lncRNA 00,364 was reported to suppress the progression of HCC cells. Of note, lncRNA 00,364 suppresses STAT3 phosphorylation, paving the way for increased levels of IFIT2, leading to induction of apoptosis, cell cycle arrest in G1/S phase, and inhibition of proliferation . However, most studies have focused on the function of oncogenic lncRNAs and their ability to induce STAT3 signaling. The lncRNA TUG1 is another factor whose overexpression has been observed in HCC and can relieve miR-144. This stimulates the JAK2/STAT3 axis, which promotes the growth and metastasis of HCC cells and the carcinogenesis process . These studies have highlighted the fact that lncRNAs can modulate STAT3 signaling in HCC and their interaction is mainly based on influencing miRNAs . It is proposed that small interfering (si)RNA, small hairpin (sh)RNA, and CRISPR/Cas9 can be used as powerful genetic tools to target lncRNAs in the treatment of HCC and suppress tumorigenesis.
Circular RNAs (circRNAs) are another member of the family of ncRNAs that do not code for proteins and develop a loop structure without 5′-3′ polarity, and with no polyadenylated tail in their structure [188, 189]. An abnormal amount of circRNAs is responsible for the process of tumorigenesis . Moreover, circRNAs play a key role in HCC. For example, circ-0008934 sponges miR-1305 to increase TMTC3 expression, promoting HCC progression . Moreover, circ-HIPK3 reduces the levels of miR-124 and miR-506 to increase PDK2 expression, thereby accelerating HCC progression . Therefore, understanding the function of circRNAs is important for HCC therapy . The malignancy of HCC cells is increased by the function of circ-0006916. It has been reported that circ-0006916 stimulates STAT3 signaling via downregulating miR-337-3p to increase the malignancy of HCC and mediate poor prognosis . Circ-0072088 has an oncogenic function in cancers, and by decreasing miR-377 expression, circ-0072088 increases the progression of esophageal cancer cells . Moreover, circ-0072088 increases NOVA2 expression via downregulating miR-377-5p, accelerating the progression of lung tumor cells . In HCC, circ-0072088 shows a similar function and promotes tumorigenesis. A high level of circ-0072088 is associated with upregulation of STAT3, and this is achieved by downregulation of miR-375 to increase proliferation and metastasis of HCC cells and mediate EMT . On the other hand, there are circRNAs that can inhibit the progression of HCC. Circ-0004913 is an inhibitor of HCC progression and for this purpose, it reduces the expression of miR-184 to increase HAMP expression. When the expression level of HAMP increases in response to circ-0004913, it can suppress proliferation, invasion, and glycolysis in HCC cells . Table 4 and Fig. 5 provide an overview of the ncRNAs that regulate STAT3 signaling in HCC.
Pharmacological regulation of STAT3 in HCC
The use of novel antitumor agents for the treatment of HCC has received much attention recently. There are a number of reasons for this. The first is that conventional drugs and compounds such as chemotherapeutics are no longer very effective in treating cancer due to resistance. Therefore, when new types of therapeutics are introduced for HCC, the prognosis and survival of patients can be greatly improved. Due to the emergence of the field of precision medicine, studies have focused on targeting specific molecular pathways in cancer therapy. Because the STAT3 pathway is oncogenic and promotes progression of HCC cells, studies have focused on using antitumor agents that target the STAT3 pathway in cancer therapy. One of the new agents that has been extensively used to treat HCC in recent years is quercetin, which inhibits Akt signaling and suppresses HCC invasion . In addition, quercetin shows a synergistic effect with oncolytic adenoviruses, which upregulate TRAIL in apoptosis induction . JAK /STAT signaling can be regulated by quercetin in HCC therapy . Quercetin suppresses the progression of HCC both in vitro and in vivo. Specifically, quercetin stimulates apoptosis and autophagy, and suppresses metastasis and proliferation of HCC cells. These anticancer activities of quercetin are mediated by inhibition of JAK2/STAT3 signaling . Another antitumor agent currently used in cancer therapy is curcumin, which stimulates apoptosis and cell cycle arrest, impairs metastasis, and increases chemosensitivity [203,204,205]. In HCC, curcumin impairs tumor cell progression by affecting molecular signaling pathways, and its efficacy can be enhanced by nanoparticle delivery [206,207,208]. Trichloroethylene can induce EMT to promote HCC cell progression and metastasis. However, curcumin suppresses the IL-6R/STAT3 axis to inhibit EMT-mediated metastasis in HCC and reduce tumor cell malignancy . In the context of the current review, STAT3 signaling promotes both growth and metastasis in HCC cells. Therefore, a novel therapeutic approach targeting STAT3 signaling in the treatment of HCC should affect two important hallmarks of HCC cells. For example, administration of (−)-oleocanthal may suppress STAT3 signaling to impair HCC metastasis and proliferation . However, most studies have focused on these two hallmarks. Since chemoresistance is common in HCC [211,212,213], the development of novel therapies to inhibit STAT3 signaling should help reverse drug resistance in HCC.
Polydatin, another reagent used in the treatment of HCC, has been shown to be efficient in apoptosis induction to suppress tumor cell proliferation and metastasis . The antitumor activity of polydatin appears to be related to the inhibition of STAT3 signaling in HCC. Administration of polydatin reduces Akt expression to suppress STAT3 signaling as a downstream target. Subsequently, it is observed that overexpression of FOXO1 stimulates apoptosis and G2/8 M cycle arrest and reduces cancer cell metastasis . In addition, regulation of STAT3 signaling by anticancer drugs is important to improve the response of HCC cells to radiotherapy. Since radioresistance is also common in HCC [216, 217], inhibition of radiosensitivity through STAT3 signaling can greatly enhance the therapeutic potential in HCC. Lenvatinib reduces the expression of Src to downregulate STAT3. It then inhibits NF-κB signaling to impair EMT and increase the radiosensitivity of HCC cells . An important regulator of HCC progression is RECK, whose methylation by LINC01419 can increase tumor malignancy . Moreover, GAS5 increases the expression of RECK in HCC suppression , indicating an anticancer effect of this factor. Salvianolic acid decreases mortalin levels to upregulate RECK. Subsequently, STAT3 signaling is inhibited to downregulate MMP-9 to delay HCC cell invasion and metastasis . According to these studies, antitumor agents targeting STAT3 signaling may be very useful in the treatment and suppression of HCC (Table 5 and Fig. 6).
Conclusion and remarks
Thanks to advances in the field of cancer biology, the progression of cancer has been significantly affected. Nowadays, researchers increasingly understand the molecular mechanisms involved in the development of cancer cells. With a better knowledge of their interaction with other signaling networks, unique targeted therapies can be developed. One of the best known molecular signaling pathways involved in cancer development and progression is the STAT3 pathway. Although upregulation of STAT3 has been mentioned in several human cancers, its overexpression in HCC is unique because a number of biological behaviors are controlled by STAT3 signaling in HCC cells. HCC is the most common form of liver cancer, and its treatment is a major challenge for physicians around the world. STAT3 levels increase in HCC, and high STAT3 expression is associated with poor prognosis and malignant behavior of cancer cells. The biological aspect of STAT3 goes beyond a single molecular pathway, as STAT3 can interact with other signaling pathways such as EZH2. Nevertheless, ncRNAs are the most prominent modulators of STAT3 signaling in HCC. Upregulation of STAT3 is frequently observed during the progression of HCC and the interesting thing is that STAT3 can support tumor cells against apoptosis. The interaction of STAT3 with autophagy is complicated because autophagy has both oncogenic and oncosuppressive properties, and thus therapeutic interventions in autophagy should be undertaken with caution. The major mechanism promoting HCC invasion and metastasis is EMT, and it is noteworthy that EMT is activated by STAT3, leading to enhanced HCC progression. Moreover, high STAT3 levels may also lead to the development of radio- and chemoresistance in HCC. Therapeutic suppression of STAT3 signaling may impair progression and increase tumor cell sensitivity to therapy. Atorvastatin and brusatol are among the antitumor agents that target STAT3 signaling and can suppress the progression of HCC. In addition, ncRNAs create new molecular pathways in the regulation of STAT3. Future studies should focus on the clinical translation of experimental advances in ncRNAs.
The most important aspect of this review is to highlight both the underlying interactions of STAT3 with other molecular signaling pathways in HCC and the development of strategies to target it. The question now arises as to which part of the treatment of patients with HCC will be more important in the future. If there is a plan for developing effective therapeutics for HCC in the near future, it is better to focus on both parts. In fact, treatment strategies mainly use anticancer agents targeting STAT3 in HCC. Since combination therapy is a priority in HCC, it is proposed to use antitumor agents together with genetic tools targeting STAT3 and its downstream targets in HCC therapy.
One challenge physicians face in treating HCC in the clinical setting is that patients with HCC are diagnosed at an advanced stage. At this stage, tumor cells spread rapidly in the body and upregulation of STAT3 is one of the reasons for this. Therefore, STAT3 can be targeted by safe products in the treatment of HCC. One of the most important applications of STAT3 in patients with HCC is its function as a biomarker. Therefore, the expression of STAT3 may affect the prognosis of patients and also the response to therapy to prevent treatment failure.
In this comprehensive review article, the role of STAT3 in the progression of HCC has been discussed in detail. However, it is better to provide an overview of the function of STAT3 in HCC. First, STAT3 determines growth, metastasis, drug resistance, and radioresistance in HCC. Second, STAT3 interacts with upstream mediators in HCC, which include Akt, IL-6, PRN2, non-coding RNAs, TRIM52, and CKLF1. In addition, STAT3 can also regulate downstream signaling pathways, including TGF-β, ZEB1, Slug, and Twist, as well as matrix metalloproteinases (MMPs) and others. Interestingly, STAT3 can regulate important molecular mechanisms in HCC, including apoptosis, autophagy, and EMT, and can determine the response of HCC to chemotherapy and radiotherapy.
This paper has demonstrated that STAT3 has a versatile function in HCC due to its interaction with various networks and molecular signaling pathways. However, there are some limitations that should be considered for the future. The regulation of STAT3 in HCC has been clearly demonstrated. Moreover, its influence on downstream targets has been studied in great detail. However, one of the drawbacks of the current studies is that not enough attention has been paid to the role of STAT3 in the development of radioresistance. Moreover, one of the pathways for the transfer of STAT3 to HCC is its incorporation into exosomes, and this has been somewhat ignored in HCC. In addition, many clinical trials should be conducted worldwide in the future to investigate STAT3 serum levels and its association with prognosis and overall survival of patients. Another important aspect is that the anticancer drugs used to suppress STAT3 are mainly phytochemicals. Since STAT3 has binding sites, the discovery of drugs can be used to modulate STAT3 expression, and its suppression by small molecules can pave the way for the treatment of cancer patients.
Availability of data and materials
Three prime untranslated region
ATP-binding cassette subfamily B member 1
Epidermal growth factor
Hepatitis B virus
Hepatitis C virus
Janus kinase 2
Long noncoding RNAs
Src homology 2
Signal transducer and activator of transcription 3
Transforming growth factor-beta
Wang X, Xiang L, Li H, Chen P, Feng Y, Zhang J, et al. The role of HMGB1 signaling pathway in the development and progression of hepatocellular carcinoma: a review. Int J Mol Sci. 2015;16(9):22527–40.
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal AJ. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.
Paskeh MDA, Mirzaei S, Ashrafizadeh M, Zarrabi A, Sethi GJ. Wnt/β-catenin signaling as a driver of hepatocellular carcinoma progression: an emphasis on molecular pathways. J Hepatocell Carcinoma. 2021;8:1415.
Saalim M, Resham S, Manzoor S, Ahmad H, Jaleel S, Ashraf J, et al. IL-22: a promising candidate to inhibit viral-induced liver disease progression and hepatocellular carcinoma. Tumour Biol. 2016;37(1):105–14.
Hassan MM, Hwang L-Y, Hatten CJ, Swaim M, Li D, Abbruzzese JL, et al. Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology. 2002;36(5):1206–13.
Marrero JA, Fontana RJ, Fu S, Conjeevaram HS, Su GL, Lok AS. Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma. J Hepatol. 2005;42(2):218–24.
Cougot D, Neuveut C, Buendia MA. HBV induced carcinogenesis. J Hepatol. 2005;34:S75–8.
Anthony PJH. Hepatocellular carcinoma: an overview. Pediatr Dev Pathol. 2001;39(2):109–18.
Block TM, Mehta AS, Fimmel CJ, Jordan RJO. Molecular viral oncology of hepatocellular carcinoma. Oncogene. 2003;22(33):5093–107.
Cheng AL, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022;76(4):862–73.
Lyu N, Wang X, Li JB, Lai JF, Chen QF, Li SL, et al. Arterial chemotherapy of oxaliplatin plus fluorouracil versus sorafenib in advanced hepatocellular carcinoma: a biomolecular exploratory, randomized, phase III trial (FOHAIC-1). J Clin Oncol. 2022;40(5):468–80.
Zhou Y, Tang W, Zhuo H, Zhu D, Rong D, Sun J, et al. Cancer-associated fibroblast exosomes promote chemoresistance to cisplatin in hepatocellular carcinoma through circZFR targeting signal transducers and activators of transcription (STAT3)/nuclear factor-kappa B (NF-κB) pathway. Bioengineered. 2022;13(3):4786–97.
Yang D, Zhang P, Yang Z, Hou G, Yang Z. miR-4461 inhibits liver cancer stem cells expansion and chemoresistance via regulating SIRT1. Carcinogenesis. 2022. https://doi.org/10.1093/carcin/bgac093.
Liao J, Yi Y, Yue X, Wu X, Zhu M, Chen Y, et al. Methyltransferase 1 is required for nonhomologous end-joining repair and renders hepatocellular carcinoma resistant to radiotherapy. Hepatology. 2022. https://doi.org/10.1002/hep.32615.
Li Z, Zhang Y, Hong W, Wang B, Chen Y, Yang P, et al. Gut microbiota modulate radiotherapy-associated antitumor immune responses against hepatocellular carcinoma via STING signaling. Gut Microbes. 2022;14(1):2119055.
Fang Y, Liu W, Tang Z, Ji X, Zhou Y, Song S, et al. Monocarboxylate transporter 4 inhibition potentiates hepatocellular carcinoma immunotherapy through enhancing T cell infiltration and immune attack. Hepatology. 2022. https://doi.org/10.1002/hep.32348.
Cheng W, Li HL, Xi SY, Zhang XF, Zhu Y, Le X, et al. Growth differentiation factor 1-induced tumour plasticity provides a therapeutic window for immunotherapy in hepatocellular carcinoma. Nat Commun. 2021;12(1):7142.
Yu M, Chen Z, Zhou Q, Zhang B, Huang J, Jin L, et al. PARG inhibition limits HCC progression and potentiates the efficacy of immune checkpoint therapy. J Hepatol. 2022;77(1):140–51.
Nguyen PHD, Wasser M, Tan CT, Lim CJ, Lai HLH, Seow JJW, et al. Trajectory of immune evasion and cancer progression in hepatocellular carcinoma. Nat Commun. 2022;13(1):1441.
Yang Y, Ren P, Liu X, Sun X, Zhang C, Du X, et al. PPP1R26 drives hepatocellular carcinoma progression by controlling glycolysis and epithelial-mesenchymal transition. J Exp Clin Cancer Res. 2022;41(1):101.
Liu B, Zhou Z, Jin Y, Lu J, Feng D, Peng R, et al. Hepatic stellate cell activation and senescence induced by intrahepatic microbiota disturbances drive progression of liver cirrhosis toward hepatocellular carcinoma. J Immunother Cancer. 2022. https://doi.org/10.1136/jitc-2021-003069.
Liang J, Li G, Liao J, Huang Z, Wen J, Wang Y, et al. Non-coding small nucleolar RNA SNORD17 promotes the progression of hepatocellular carcinoma through a positive feedback loop upon p53 inactivation. Cell Death Differ. 2022;29(5):988–1003.
Wu H, Li Y, Shi G, Du S, Wang X, Ye W, et al. Hepatic interferon regulatory factor 8 expression suppresses hepatocellular carcinoma progression and enhances the response to anti-programmed cell death protein-1 therapy. Hepatology (Baltimore, MD). 2022;76(6):1602–16.
Chen QT, Zhang ZY, Huang QL, Chen HZ, Hong WB, Lin T, et al. HK1 from hepatic stellate cell-derived extracellular vesicles promotes progression of hepatocellular carcinoma. Nat Metab. 2022;4(10):1306–21.
Li P, Song R, Yin F, Liu M, Liu H, Ma S, et al. circMRPS35 promotes malignant progression and cisplatin resistance in hepatocellular carcinoma. Mol Ther. 2022;30(1):431–47.
Yin T, Zhao H. miR-152-3p impedes the malignant phenotypes of hepatocellular carcinoma by repressing roundabout guidance receptor 1. Cell Mol Biol Lett. 2022;27(1):22.
Ding H, Zhang X, Su Y, Jia C, Dai C. GNAS promotes inflammation-related hepatocellular carcinoma progression by promoting STAT3 activation. Cell Mol Biol Lett. 2020;25(1):8.
Wu D, Zhang C, Liao G, Leng K, Dong B, Yu Y, et al. Targeting uridine–cytidine kinase 2 induced cell cycle arrest through dual mechanism and could improve the immune response of hepatocellular carcinoma. Cell Mol Biol Lett. 2022;27(1):105.
Dai Y-Z, Liu Y-D, Li J, Chen M-T, Huang M, Wang F, et al. METTL16 promotes hepatocellular carcinoma progression through downregulating RAB11B-AS1 in an m6A-dependent manner. Cell Mol Biol Lett. 2022;27(1):41.
Wang L, Yi X, Xiao X, Zheng Q, Ma L, Li B. Exosomal miR-628-5p from M1 polarized macrophages hinders m6A modification of circFUT8 to suppress hepatocellular carcinoma progression. Cell Mol Biol Lett. 2022;27(1):106.
Galoczova M, Coates P, Vojtesek B. STAT3, stem cells, cancer stem cells and p63. Cell Mol Biol Lett. 2018;23(1):12.
Svinka J, Mikulits W, Eferl R. STAT3 in hepatocellular carcinoma: new perspectives. Hepat Oncol. 2014;1(1):107–20.
Lee C, Cheung ST. STAT3: an emerging therapeutic target for hepatocellular carcinoma. Cancers. 2019;11(11):1646.
Tang JJH, Thng DKH, Lim JJ, Toh TB. JAK/STAT signaling in hepatocellular carcinoma. Hepat Oncol. 2020;7(1):HEP18.
Xu J, Lin H, Wu G, Zhu M, Li M. IL-6/STAT3 Is a promising therapeutic target for hepatocellular carcinoma. Front Oncol. 2021. https://doi.org/10.3389/fonc.2021.760971.
Kanna R, Choudhary G, Ramachandra N, Steidl U, Verma A, Shastri AJL, et al. STAT3 inhibition as a therapeutic strategy for leukemia. Leuk Lymphoma. 2018;59(9):2068–74.
Yue P, Turkson J. Targeting STAT3 in cancer: how successful are we? Expert Opin Investig Drugs. 2009;18(1):45–56.
Fagard R, Metelev V, Souissi I, Baran-Marszak FJ. STAT3 inhibitors for cancer therapy: have all roads been explored? JAKSTAT. 2013;2(1):e22882.
Levy DE, Lee C-K. What does Stat3 do? J Clin Invest. 2002;109(9):1143–8.
Al Zaid Siddiquee K, Turkson J. STAT3 as a target for inducing apoptosis in solid and hematological tumors. Cell Res. 2008;18(2):254–67.
Li J, Yin Z, Huang B, Xu K, Su JJ. Stat3 signaling pathway: a future therapeutic target for bone-related diseases. Front Pharmacol. 2022. https://doi.org/10.3389/fphar.2022.897539.
Zhong Z, Wen Z, Darnell JE Jr. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science (New York, NY). 1994;264(5155):95–8.
Zou S, Tong Q, Liu B, Huang W, Tian Y, Fu X. Targeting STAT3 in cancer immunotherapy. Mol Cancer. 2020;19(1):145.
Ashrafizadeh M, Gholami MH, Mirzaei S, Zabolian A, Haddadi A, Farahani MV, et al. Dual relationship between long non-coding RNAs and STAT3 signaling in different cancers: new insight to proliferation and metastasis. Life Sci. 2021;270:119006.
Mirzaei S, Gholami MH, Mahabady MK, Nabavi N, Zabolian A, Banihashemi SM, et al. Pre-clinical investigation of STAT3 pathway in bladder cancer: paving the way for clinical translation. Biomed Pharmacother. 2021;133:111077.
Ashrafizadeh M, Zarrabi A, Orouei S, Zarrin V, Rahmani Moghadam E, Zabolian A, et al. STAT3 pathway in gastric cancer: signaling, therapeutic targeting and future prospects. Biology. 2020;9(6):126.
Johnson DE, O’Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol. 2018;15(4):234–48.
Sgrignani J, Garofalo M, Matkovic M, Merulla J, Catapano CV, Cavalli A. Structural biology of STAT3 and its implications for anticancer therapies development. Int J Mol Sci. 2018;19(6):1591.
Wu X, Zhang H, Jiang G, Peng M, Li C, Lu J, et al. Exosome-transmitted S100A4 induces immunosuppression and non-small cell lung cancer development by activating STAT3. Clin Exp Immunol. 2022. https://doi.org/10.1093/cei/uxac102.
Paskeh MDA, Entezari M, Mirzaei S, Zabolian A, Saleki H, Naghdi MJ, et al. Emerging role of exosomes in cancer progression and tumor microenvironment remodeling. J Hematol Oncol. 2022. https://doi.org/10.1186/s13045-022-01305-4.
Liu M, Li H, Zhang H, Zhou H, Jiao T, Feng M, et al. RBMS1 promotes gastric cancer metastasis through autocrine IL-6/JAK2/STAT3 signaling. Cell Death Dis. 2022;13(3):287.
Guo H, Zhuang K, Ding N, Hua R, Tang H, Wu Y, et al. High-fat diet induced cyclophilin B enhances STAT3/lncRNA-PVT1 feedforward loop and promotes growth and metastasis in colorectal cancer. Cell Death Dis. 2022;13(10):883.
Hsu PC, Li JM, Yang CT. Forced overexpression of signal transducer and activator of transcription 3 (STAT3) activates yes-associated protein (YAP) expression and increases the invasion and proliferation abilities of small cell lung cancer (SCLC) cells. Biomedicines. 2022;10(7):1704.
Li Z, Liu J, Fu H, Li Y, Liu Q, Song W, et al. SENP3 affects the expression of PYCR1 to promote bladder cancer proliferation and EMT transformation by deSUMOylation of STAT3. Aging. 2022;14(19):8032–45.
Xiong JW, Song SB, Xiong LM, Duan CH, Song Q, Yu DL, et al. CircRPPH1 promotes cell proliferation, migration and invasion of non-small cell lung cancer via the PI3K/AKT and JAK2/STAT3 signalling axes. J Biochem. 2022;171(2):245–52.
Li C, Peng X, Peng Z, Yan B. circBGN accelerates gastric cancer cell proliferation and invasion via activating IL6/STAT3 signaling pathway. FASEB J. 2022;36(11): e22604.
Sun Y, Sun Y, Li S, Tao X, Cai L. Zhenzhu Xiaoji decoction induces autophagy and apoptosis cell death in liver cancer cells through AKT/mTOR and JAK2/STAT3 signaling pathway. eCAM. 2022;2022:4445293.
Jung YY, Ha IJ, Um JY, Sethi G, Ahn KS. Fangchinoline diminishes STAT3 activation by stimulating oxidative stress and targeting SHP-1 protein in multiple myeloma model. J Adv Res. 2022;35:245–57.
Zhang Z, Zhu Q, Wang S, Shi C. Epigallocatechin-3-gallate inhibits the formation of neutrophil extracellular traps and suppresses the migration and invasion of colon cancer cells by regulating STAT3/CXCL8 pathway. Mol Cell Biochem. 2022. https://doi.org/10.1007/s11010-022-04550-w.
Yang L, Lin S, Xu L, Lin J, Zhao C, Huang X. Novel activators and small-molecule inhibitors of STAT3 in cancer. Cytokine Growth Factor Rev. 2019;49:10–22.
Dong J, Cheng X-D, Zhang W-D, Qin J-J. Recent update on development of small-molecule STAT3 inhibitors for cancer therapy: from phosphorylation inhibition to protein degradation. J Med Chem. 2021;64(13):8884–915.
Siveen KS, Sikka S, Surana R, Dai X, Zhang J, Kumar AP, et al. Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors. Biochim Biophys Acta. 2014;1845(2):136–54.
Iwamaru A, Szymanski S, Iwado E, Aoki H, Yokoyama T, Fokt I, et al. A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo. Oncogene. 2007;26(17):2435–44.
Siddiquee K, Zhang S, Guida WC, Blaskovich MA, Greedy B, Lawrence HR, et al. Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc Natl Acad Sci. 2007;104(18):7391–6.
Santos FPS, Kantarjian HM, Jain N, Manshouri T, Thomas DA, Garcia-Manero G, et al. Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Blood. 2010;115(6):1131–6.
Tan SC, Ankathil R. Genetic susceptibility to cervical cancer: role of common polymorphisms in apoptosis-related genes. Tumour Biol. 2015;36(9):6633–44.
Wang Z, Cui X, Hao G, He J. Aberrant expression of PI3K/AKT signaling is involved in apoptosis resistance of hepatocellular carcinoma. Open life sciences. 2021;16(1):1037–44.
Wang Q, Lu D, Fan L, Li Y, Liu Y, Yu H, et al. COX-2 induces apoptosis-resistance in hepatocellular carcinoma cells via the HIF-1α/PKM2 pathway. Int J Mol Med. 2019;43(1):475–88.
Yang JR, Ling XL, Guan QL. RAP2A promotes apoptosis resistance of hepatocellular carcinoma cells via the mTOR pathway. Clin Exp Med. 2021;21(4):545–54.
Pepper C, Hoy T, Bentley P. Elevated Bcl-2/Bax are a consistent feature of apoptosis resistance in B-cell chronic lymphocytic leukaemia and are correlated with in vivo chemoresistance. Leuk Lymphoma. 1998;28(3–4):355–61.
Zhou Q, Tian W, Jiang Z, Huang T, Ge C, Liu T, et al. A positive feedback loop of AKR1C3-mediated activation of NF-κB and STAT3 facilitates proliferation and metastasis in hepatocellular carcinoma. Can Res. 2021;81(5):1361–74.
Tan SC, Ismail MP, Duski DR, Othman NH, Ankathil R. FAS c.-671A>G polymorphism and cervical cancer risk: a case-control study and meta-analysis. Cancer Genet. 2017;211:18–25.
Pan S, Deng Y, Fu J, Zhang Y, Zhang Z, Ru X, et al. TRIM52 promotes colorectal cancer cell proliferation through the STAT3 signaling. Cancer Cell Int. 2019;19:57.
Yang L, Xue H, Sun Y, Zhang L, Xue F, Ge R. CircularRNA-9119 protects hepatocellular carcinoma cells from apoptosis by intercepting miR-26a/JAK1/STAT3 signaling. Cell Death Dis. 2020;11(7):605.
Liu Y, Liu L, Zhou Y, Zhou P, Yan Q, Chen X, et al. CKLF1 Enhances Inflammation-Mediated Carcinogenesis and Prevents Doxorubicin-Induced Apoptosis via IL6/STAT3 Signaling in HCC. Clin Cancer Res. 2019;25(13):4141–54.
Sun C, Bai M, Ke W, Wang X, Zhao X, Lu Z. The HSP90 inhibitor, XL888, enhanced cell apoptosis via downregulating STAT3 after insufficient radiofrequency ablation in hepatocellular carcinoma. Life Sci. 2021;282: 119762.
Wang J, Lu L, Luo Z, Li W, Lu Y, Tang Q, et al. miR-383 inhibits cell growth and promotes cell apoptosis in hepatocellular carcinoma by targeting IL-17 via STAT3 signaling pathway. Biomed Pharmacother. 2019;120:109551.
Gu X, Li X, Zhang X, Feng R, Zheng M, Liu L, et al. MicroRNA-mediated high expression of PDIA3 was correlated with poor prognosis of patients with LUAD. Genomics. 2022;114(4): 110417.
Song D, Guo M, Wu K, Hao J, Nie Y, Fan D. Silencing of ER-resident oxidoreductase PDIA3 inhibits malignant biological behaviors of multidrug-resistant gastric cancer. Acta Biochim Biophys Sin. 2021;53(9):1216–26.
Kondo R, Ishino K, Wada R, Takata H, Peng WX, Kudo M, et al. Downregulation of protein disulfide-isomerase A3 expression inhibits cell proliferation and induces apoptosis through STAT3 signaling in hepatocellular carcinoma. Int J Oncol. 2019;54(4):1409–21.
Ashrafizadeh M, Zarrabi A, Orouei S, Hushmandi K, Hakimi A, Zabolian A, et al. MicroRNA-mediated autophagy regulation in cancer therapy: the role in chemoresistance/chemosensitivity. Eur J Pharmacol. 2021;892:173660.
Ashrafizadeh M, Paskeh MDA, Mirzaei S, Gholami MH, Zarrabi A, Hashemi F, et al. Targeting autophagy in prostate cancer: preclinical and clinical evidence for therapeutic response. J Exp Clin Cancer Res. 2022;41(1):1–37.
Paskeh MDA, Entezari M, Clark C, Zabolian A, Ranjbar E, Farahani MV, et al. Targeted regulation of autophagy using nanoparticles: New insight into cancer therapy. Biochim Biophys Acta Mol Basis Dis. 2022;1868(3): 166326.
Shao WQ, Zhu WW, Luo MJ, Fan MH, Li Q, Wang SH, et al. Cholesterol suppresses GOLM1-dependent selective autophagy of RTKs in hepatocellular carcinoma. Cell Rep. 2022;39(3): 110712.
Zhao Z, He J, Feng C. CircCBFB is a mediator of hepatocellular carcinoma cell autophagy and proliferation through miR-424-5p/ATG14 axis. Immunol Res. 2022;70(3):341–53.
Chao X, Wang S, Fulte S, Ma X, Ahamed F, Cui W, et al. Hepatocytic p62 suppresses ductular reaction and tumorigenesis in mouse livers with mTORC1 activation and defective autophagy. J Hepatol. 2022;76(3):639–51.
Chen S, Wu H, Wang Z, Jia M, Guo J, Jin J, et al. Loss of SPTBN1 suppresses autophagy via SETD7-mediated YAP methylation in hepatocellular carcinoma initiation and development. Cell Mol Gastroenterol Hepatol. 2022;13(3):949-73.e7.
Chen X, Tan M, Xie Z, Feng B, Zhao Z, Yang K, et al. Inhibiting ROS-STAT3-dependent autophagy enhanced capsaicin-induced apoptosis in human hepatocellular carcinoma cells. Free Radical Res. 2016;50(7):744–55.
He K, Liu X, Cheng S, Zhou P. Zingiberensis newsaponin inhibits the malignant progression of hepatocellular carcinoma via suppressing autophagy moderated by the AKR1C1-mediated JAK2/STAT3 pathway. eCAM. 2021;2021:4055209.
Kong WS, Shen FX, Xie RF, Zhou G, Feng YM, Zhou X. Bufothionine induces autophagy in H22 hepatoma-bearing mice by inhibiting JAK2/STAT3 pathway, a possible anti-cancer mechanism of cinobufacini. J Ethnopharmacol. 2021;270: 113848.
Yang W, Su J, Li M, Li T, Wang X, Zhao M, et al. Myricetin Induces Autophagy and Cell Cycle Arrest of HCC by Inhibiting MARCH1-Regulated Stat3 and p38 MAPK Signaling Pathways. Front Pharmacol. 2021;12: 709526.
Liu H, Feng XD, Yang B, Tong RL, Lu YJ, Chen DY, et al. Dimethyl fumarate suppresses hepatocellular carcinoma progression via activating SOCS3/JAK1/STAT3 signaling pathway. Am J Trans Res. 2019;11(8):4713–25.
Woźniak M, Makuch S, Winograd K, Wiśniewski J, Ziółkowski P, Agrawal S. 6-Shogaol enhances the anticancer effect of 5-fluorouracil, oxaliplatin, and irinotecan via increase of apoptosis and autophagy in colon cancer cells in hypoxic/aglycemic conditions. BMC Complement Med Ther. 2020;20(1):141.
Hong ZP, Wang LG, Wang HJ, Ye WF, Wang XZ. Wogonin exacerbates the cytotoxic effect of oxaliplatin by inducing nitrosative stress and autophagy in human gastric cancer cells. Phytomedicine. 2018;39:168–75.
Wu J, Guo J, Cao Q, Wang Y, Chen J, Wang Z, et al. Autophagy impacts on oxaliplatin-induced hepatocarcinoma apoptosis via the IL-17/IL-17R-JAK2/STAT3 signaling pathway. Oncol Lett. 2017;13(2):770–6.
Ashrafizadeh M, Shahinozzaman M, Orouei S, Zarrin V, Hushmandi K, Hashemi F, et al. Crosstalk of long non-coding RNAs and EMT: Searching the missing pieces of an incomplete puzzle for lung cancer therapy. Curr Cancer Drug Targets. 2021;21(8):640–65.
Ashrafizadeh M, Hushmandi K, Hashemi M, Akbari ME, Kubatka P, Raei M, et al. Role of microRNA/epithelial-to-mesenchymal transition axis in the metastasis of bladder cancer. Biomolecules. 2020;10(8):1159.
Ashrafizadeh M, Zarrabi A, Hushmandi K, Kalantari M, Mohammadinejad R, Javaheri T, et al. Association of the epithelial–mesenchymal transition (EMT) with cisplatin resistance. Int J Mol Sci. 2020;21(11):4002.
Ashrafizadeh M, Mirzaei S, Hashemi F, Zarrabi A, Zabolian A, Saleki H, et al. New insight towards development of paclitaxel and docetaxel resistance in cancer cells: EMT as a novel molecular mechanism and therapeutic possibilities. Biomed Pharmacother. 2021;141: 111824.
Mirzaei S, Abadi AJ, Gholami MH, Hashemi F, Zabolian A, Hushmandi K, et al. The involvement of epithelial-to-mesenchymal transition in doxorubicin resistance: Possible molecular targets. Eur J Pharmacol. 2021;908: 174344.
Wang B, Liu T, Wu JC, Luo SZ, Chen R, Lu LG, et al. STAT3 aggravates TGF-β1-induced hepatic epithelial-to-mesenchymal transition and migration. Biomed Pharmacother. 2018;98:214–21.
Li YL, Zhang MM, Wu LW, Liu YH, Zhang ZY, Zeng LH, et al. DYRK1A reinforces epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma via cooperatively activating STAT3 and SMAD. J Biomed Sci. 2022;29(1):34.
Lin Y, Jin H, Wu X, Jian Z, Zou X, Huang J, et al. The cross-talk between DDR1 and STAT3 promotes the development of hepatocellular carcinoma. Aging. 2020;12(14):14391–405.
Li H, Luo D, Huttad L, Zhang M, Wang Y, Feng J, et al. RIPK4 Suppresses the Invasion and Metastasis of Hepatocellular Carcinoma by Inhibiting the Phosphorylation of STAT3. Front Mol Biosci. 2021;8: 654766.
Bi C, Jiang B. Downregulation of RPN2 induces apoptosis and inhibits migration and invasion in colon carcinoma. Oncol Rep. 2018;40(1):283–93.
Li H, Al-Japairai K, Tao Y, Xiang Z. RPN2 promotes colorectal cancer cell proliferation through modulating the glycosylation status of EGFR. Oncotarget. 2017;8(42):72633–51.
Li C, Ran H, Song S, Liu W, Zou W, Jiang B, et al. Overexpression of RPN2 suppresses radiosensitivity of glioma cells by activating STAT3 signal transduction. Mol Med (Cambridge, Mass). 2020;26(1):43.
Huang L, Jian Z, Gao Y, Zhou P, Zhang G, Jiang B, et al. RPN2 promotes metastasis of hepatocellular carcinoma cell and inhibits autophagy via STAT3 and NF-κB pathways. Aging. 2019;11(17):6674–90.
Wu S, Ye S, Lin X, Chen Y, Zhang Y, Jing Z, et al. Small hepatitis B virus surface antigen promotes malignant progression of hepatocellular carcinoma via endoplasmic reticulum stress-induced FGF19/JAK2/STAT3 signaling. Cancer Lett. 2021;499:175–87.
Lv Z, Wang Z, Luo L, Chen Y, Han G, Wang R, et al. Spliceosome protein Eftud2 promotes colitis-associated tumorigenesis by modulating inflammatory response of macrophage. Mucosal Immunol. 2019;12(5):1164–73.
Tan SC. Low penetrance genetic polymorphisms as potential biomarkers for colorectal cancer predisposition. J Gene Med. 2018;20(4): e3010.
Lv C, Li XJ, Hao LX, Zhang S, Song Z, Ji XD, et al. Over-activation of EFTUD2 correlates with tumor propagation and poor survival outcomes in hepatocellular carcinoma. Clin Trans Oncol. 2022;24(1):93–103.
Tu M, He L, You Y, Li J, Yao N, Qu C, et al. EFTUD2 maintains the survival of tumor cells and promotes hepatocellular carcinoma progression via the activation of STAT3. Cell Death Dis. 2020;11(10):830.
Xie J, Guo T, Zhong Z, Wang N, Liang Y, Zeng W, et al. ITGB1 drives hepatocellular carcinoma progression by modulating cell cycle process through PXN/YWHAZ/AKT pathways. Front Cell Dev Biol. 2021;9: 711149.
Chen T, Liu R, Niu Y, Mo H, Wang H, Lu Y, et al. HIF-1α-activated long non-coding RNA KDM4A-AS1 promotes hepatocellular carcinoma progression via the miR-411-5p/KPNA2/AKT pathway. Cell Death Dis. 2021;12(12):1152.
Paskeh MDA, Ghadyani F, Hashemi M, Abbaspour A, Zabolian A, Javanshir S, et al. Biological impact and therapeutic perspective of targeting PI3K/Akt signaling in hepatocellular carcinoma: promises and challenges. Pharmacol Res. 2023;187: 106553.
Fan L, Zhu H, Tao W, Liu L, Shan X, Zhao M, et al. Euphorbia factor L2 inhibits TGF-β-induced cell growth and migration of hepatocellular carcinoma through AKT/STAT3. Phytomedicine. 2019;62: 152931.
Zhang X, Zhang H, Liao Z, Zhang J, Liang H, Wang W, et al. SHC4 promotes tumor proliferation and metastasis by activating STAT3 signaling in hepatocellular carcinoma. Cancer Cell Int. 2022;22(1):24.
Lee S, Lee M, Kim JB, Jo A, Cho EJ, Yu SJ, et al. 17β-estradiol exerts anticancer effects in anoikis-resistant hepatocellular carcinoma cell lines by targeting IL-6/STAT3 signaling. Biochem Biophys Res Commun. 2016;473(4):1247–54.
Wu J, Zhang J, Shen B, Yin K, Xu J, Gao W, et al. Long noncoding RNA lncTCF7, induced by IL-6/STAT3 transactivation, promotes hepatocellular carcinoma aggressiveness through epithelial-mesenchymal transition. J Exp Clin Cancer Res. 2015;34:116.
Wang J, Yin D, Xie C, Zheng T, Liang Y, Hong X, et al. The iron chelator Dp44mT inhibits hepatocellular carcinoma metastasis via N-Myc downstream-regulated gene 2 (NDRG2)/gp130/STAT3 pathway. Oncotarget. 2014;5(18):8478–91.
Zhang X, Lv J, Luo H, Liu Z, Xu C, Zhou D, et al. Nucleostemin promotes hepatocellular carcinoma by regulating the function of STAT3. Exp Cell Res. 2020;387(1): 111748.
Ruan Y, Sun L, Hao Y, Wang L, Xu J, Zhang W, et al. Ribosomal RACK1 promotes chemoresistance and growth in human hepatocellular carcinoma. J Clin Investig. 2012;122(7):2554–66.
Cao H, Yang M, Yang Y, Fang J, Cui Y. PBK/TOPK promotes chemoresistance to oxaliplatin in hepatocellular carcinoma cells by regulating PTEN. Acta Biochim Biophys Sin. 2021;53(5):584–92.
Xu M, Fang S, Song J, Chen M, Zhang Q, Weng Q, et al. CPEB1 mediates hepatocellular carcinoma cancer stemness and chemoresistance. Cell Death Dis. 2018;9(10):957.
Chen Y, Zhao H, Li H, Feng X, Tang H, Qiu C, et al. LINC01234/MicroRNA-31-5p/MAGEA3 axis mediates the proliferation and chemoresistance of hepatocellular carcinoma cells. Mol Ther Nucleic acids. 2020;19:168–78.
Tan G, Xie B, Yu N, Huang J, Zhang B, Lin F, et al. TRIM37 overexpression is associated with chemoresistance in hepatocellular carcinoma via activating the AKT signaling pathway. Int J Clin Oncol. 2021;26(3):532–42.
Yin X, Tang B, Li JH, Wang Y, Zhang L, Xie XY, et al. ID1 promotes hepatocellular carcinoma proliferation and confers chemoresistance to oxaliplatin by activating pentose phosphate pathway. J Exp Clin Cancer Res. 2017;36(1):166.
Xiao J, Lv Y, Jin F, Liu Y, Ma Y, Xiong Y, et al. LncRNA HANR promotes tumorigenesis and increase of chemoresistance in hepatocellular carcinoma. Cell Physiol Biochem. 2017;43(5):1926–38.
Lin M, Lv D, Zheng Y, Wu M, Xu C, Zhang Q, et al. Downregulation of CPT2 promotes tumorigenesis and chemoresistance to cisplatin in hepatocellular carcinoma. Onco Targets Ther. 2018;11:3101–10.
Lai SC, Su YT, Chi CC, Kuo YC, Lee KF, Wu YC, et al. DNMT3b/OCT4 expression confers sorafenib resistance and poor prognosis of hepatocellular carcinoma through IL-6/STAT3 regulation. J Exp Clin Cancer Res. 2019;38(1):474.
Tai WT, Cheng AL, Shiau CW, Liu CY, Ko CH, Lin MW, et al. Dovitinib induces apoptosis and overcomes sorafenib resistance in hepatocellular carcinoma through SHP-1-mediated inhibition of STAT3. Mol Cancer Ther. 2012;11(2):452–63.
Chen KF, Chen HL, Liu CY, Tai WT, Ichikawa K, Chen PJ, et al. Dovitinib sensitizes hepatocellular carcinoma cells to TRAIL and tigatuzumab, a novel anti-DR5 antibody, through SHP-1-dependent inhibition of STAT3. Biochem Pharmacol. 2012;83(6):769–77.
Xie L, Zeng Y, Dai Z, He W, Ke H, Lin Q, et al. Chemical and genetic inhibition of STAT3 sensitizes hepatocellular carcinoma cells to sorafenib induced cell death. Int J Biol Sci. 2018;14(5):577–85.
Chen KF, Tai WT, Liu TH, Huang HP, Lin YC, Shiau CW, et al. Sorafenib overcomes TRAIL resistance of hepatocellular carcinoma cells through the inhibition of STAT3. Clin Cancer Res. 2010;16(21):5189–99.
Huang CY, Lin CS, Tai WT, Hsieh CY, Shiau CW, Cheng AL, et al. Sorafenib enhances radiation-induced apoptosis in hepatocellular carcinoma by inhibiting STAT3. Int J Radiat Oncol Biol Phys. 2013;86(3):456–62.
Gerlach JH, Kartner N, Bell D, Ling VJCS. Multidrug resistance. Cancer Surv. 1986;5(1):25–46.
Sauna ZE, Smith MM, Müller M, Kerr KM, Ambudkar SV. The mechanism of action of multidrug-resistance-linked P-glycoprotein. J Bioenerg Biomembr. 2001;33:481–91.
Robey RW, Pluchino KM, Hall MD, Fojo AT, Bates SE, Gottesman MMJNRC. Revisiting the role of ABC transporters in multidrug-resistant cancer. Nat Rev Cancer. 2018;18(7):452–64.
Hu B, Zou T, Qin W, Shen X, Su Y, Li J, et al. Inhibition of EGFR Overcomes Acquired Lenvatinib Resistance Driven by STAT3-ABCB1 Signaling in Hepatocellular Carcinoma. Can Res. 2022;82(20):3845–57.
Jiang Y, Chen P, Hu K, Dai G, Li J, Zheng D, et al. Inflammatory microenvironment of fibrotic liver promotes hepatocellular carcinoma growth, metastasis and sorafenib resistance through STAT3 activation. J Cell Mol Med. 2021;25(3):1568–82.
Su JC, Chiang HC, Tseng PH, Tai WT, Hsu CY, Li YS, et al. RFX-1-dependent activation of SHP-1 inhibits STAT3 signaling in hepatocellular carcinoma cells. Carcinogenesis. 2014;35(12):2807–14.
Su JC, Tseng PH, Wu SH, Hsu CY, Tai WT, Li YS, et al. SC-2001 overcomes STAT3-mediated sorafenib resistance through RFX-1/SHP-1 activation in hepatocellular carcinoma. Neoplasia (New York, NY). 2014;16(7):595–605.
Roy S, Mondru AK, Chakraborty T, Das A, Dasgupta S. Apple polyphenol phloretin complexed with ruthenium is capable of reprogramming the breast cancer microenvironment through modulation of PI3K/Akt/mTOR/VEGF pathways. Toxicol Appl Pharmacol. 2022;434: 115822.
Min J, Huang K, Tang H, Ding X, Qi C, Qin X, et al. Phloretin induces apoptosis of non-small cell lung carcinoma A549 cells via JNK1/2 and p38 MAPK pathways. Oncol Rep. 2015;34(6):2871–9.
Saraswati S, Alhaider A, Abdelgadir AM, Tanwer P, Korashy HM. Phloretin attenuates STAT-3 activity and overcomes sorafenib resistance targeting SHP-1-mediated inhibition of STAT3 and Akt/VEGFR2 pathway in hepatocellular carcinoma. Cell Commun Signal. 2019;17(1):127.
Carlisi D, D’Anneo A, Angileri L, Lauricella M, Emanuele S, Santulli A, et al. Parthenolide sensitizes hepatocellular carcinoma cells to TRAIL by inducing the expression of death receptors through inhibition of STAT3 activation. J Cell Physiol. 2011;226(6):1632–41.
Chen Y, Shen Z, Zhi Y, Zhou H, Zhang K, Wang T, et al. Long non-coding RNA ROR promotes radioresistance in hepatocelluar carcinoma cells by acting as a ceRNA for microRNA-145 to regulate RAD18 expression. Arch Biochem Biophys. 2018;645:117–25.
Kamimura K, Terai S. The promise of radiotherapy for hepatocellular carcinoma. Hepatol Res. 2021;51(8):837–8.
Shibuya K, Katoh H, Koyama Y, Shiba S, Okamoto M, Okazaki S, et al. Efficacy and safety of 4 fractions of carbon-ion radiation therapy for hepatocellular carcinoma: a prospective study. Liver Cancer. 2022;11(1):61–74.
Tsuchiya H, Shinonaga R, Sakaguchi H, Kitagawa Y, Yoshida K, Shiota G. NEAT1 confers radioresistance to hepatocellular carcinoma cells by inducing PINK1/parkin-mediated mitophagy. Int J Mol Sci. 2022. https://doi.org/10.3390/ijms232214397.
Zhang S, Hu Y, Wu Z, Zhou X, Wu T, Li P, et al. Deficiency of carbamoyl phosphate synthetase 1 engenders radioresistance in hepatocellular carcinoma via deubiquitinating c-Myc. Int J Radiat Oncol Biol Phys. 2022. https://doi.org/10.1016/j.ijrobp.2022.11.022.
Zhang Y, Zheng L, Ding Y, Li Q, Wang R, Liu T, et al. MiR-20a induces cell radioresistance by activating the PTEN/PI3K/Akt signaling pathway in hepatocellular carcinoma. Int J Radiat Oncol Biol Phys. 2015;92(5):1132–40.
Yi FT, Lu QP. Mucin 1 promotes radioresistance in hepatocellular carcinoma cells through activation of JAK2/STAT3 signaling. Oncol Lett. 2017;14(6):7571–6.
Xu G, Zhu L, Wang Y, Shi Y, Gong A, Wu C. Stattic enhances radiosensitivity and reduces radio-induced migration and invasion in HCC cell lines through an apoptosis pathway. Biomed Res Int. 2017;2017:1832494.
Paskeh MDA, Mirzaei S, Orouei S, Zabolian A, Saleki H, Azami N, et al. Revealing the role of miRNA-489 as a new onco-suppressor factor in different cancers based on pre-clinical and clinical evidence. Int J Biol Macromol. 2021;191:727–37.
Zia A, Sahebdel F, Farkhondeh T, Ashrafizadeh M, Zarrabi A, Hushmandi K, et al. A review study on the modulation of SIRT1 expression by miRNAs in aging and age-associated diseases. Int J Biol Macromol. 2021;188:52–61.
Tan SC, Lim PY, Fang J, Mokhtar MFM, Hanif EAM, Jamal R. Association between MIR499A rs3746444 polymorphism and breast cancer susceptibility: a meta-analysis. Sci Rep. 2020;10(1):3508.
Zhou J, Wang L, Cui Y, Tang L. miR-125a-5p-targeted regulation of TRA2β expression inhibits proliferation and metastasis of hepatocellular carcinoma cells. Am J Trans Res. 2021;13(12):14074–80.
Yang Y, Yang Z, Zhang R, Jia C, Mao R, Mahati S, et al. MiR-27a-3p enhances the cisplatin sensitivity in hepatocellular carcinoma cells through inhibiting PI3K/Akt pathway. 2021. Biosci Rep. https://doi.org/10.1042/BSR20192007.
Liu YP, Qiu ZZ, Li XH, Li EY. Propofol induces ferroptosis and inhibits malignant phenotypes of gastric cancer cells by regulating miR-125b-5p/STAT3 axis. World J Gastrointest Oncology. 2021;13(12):2114–28.
Xu L, Yao Y, Lu T, Jiang L. miR-451a targeting IL-6R activates JAK2/STAT3 pathway, thus regulates proliferation and apoptosis of multiple myeloma cells. J Musculoskelet Neuronal Interact. 2022;22(2):251–60.
Zhang JF, He ML, Fu WM, Wang H, Chen LZ, Zhu X, et al. Primate-specific microRNA-637 inhibits tumorigenesis in hepatocellular carcinoma by disrupting signal transducer and activator of transcription 3 signaling. Hepatology (Baltimore, MD). 2011;54(6):2137–48.
Lu Y, Yue X, Cui Y, Zhang J, Wang K. MicroRNA-124 suppresses growth of human hepatocellular carcinoma by targeting STAT3. Biochem Biophys Res Commun. 2013;441(4):873–9.
Yuan J, Ji H, Xiao F, Lin Z, Zhao X, Wang Z, et al. MicroRNA-340 inhibits the proliferation and invasion of hepatocellular carcinoma cells by targeting JAK1. Biochem Biophys Res Commun. 2017;483(1):578–84.
Peng S, Chen Y, Li T, Mao J, Yang P, Zou B, et al. Hsa-microRNA-370–3p targeting Snail and Twist1 suppresses IL-8/STAT3-driven hepatocellular carcinoma metastasis. Cancer Sci. 2022. https://doi.org/10.1111/cas.15571.
Wang B, Hsu SH, Frankel W, Ghoshal K, Jacob ST. Stat3-mediated activation of microRNA-23a suppresses gluconeogenesis in hepatocellular carcinoma by down-regulating glucose-6-phosphatase and peroxisome proliferator-activated receptor gamma, coactivator 1 alpha. Hepatology (Baltimore, MD). 2012;56(1):186–97.
Liang L, Zeng JH, Wang JY, He RQ, Ma J, Chen G, et al. Down-regulation of miR-26a-5p in hepatocellular carcinoma: A qRT-PCR and bioinformatics study. Pathol Res Pract. 2017;213(12):1494–509.
Chen L, Zheng J, Zhang Y, Yang L, Wang J, Ni J, et al. Tumor-specific expression of microRNA-26a suppresses human hepatocellular carcinoma growth via cyclin-dependent and -independent pathways. Mol Ther. 2011;19(8):1521–8.
Li Y, Ren M, Zhao Y, Lu X, Wang M, Hu J, et al. MicroRNA-26a inhibits proliferation and metastasis of human hepatocellular carcinoma by regulating DNMT3B-MEG3 axis. Oncol Rep. 2017;37(6):3527–35.
Yang X, Liang L, Zhang XF, Jia HL, Qin Y, Zhu XC, et al. MicroRNA-26a suppresses tumor growth and metastasis of human hepatocellular carcinoma by targeting interleukin-6-Stat3 pathway. Hepatology (Baltimore, MD). 2013;58(1):158–70.
Li Y, Zhou T, Cheng X, Li D, Zhao M, Zheng WV. microRNA-378a-3p regulates the progression of hepatocellular carcinoma by regulating PD-L1 and STAT3. Bioengineered. 2022;13(3):4730–43.
Zhu C, Zhou R, Zhou Q, Chang Y, Jiang M. microRNA-539 suppresses tumor growth and tumorigenesis and overcomes arsenic trioxide resistance in hepatocellular carcinoma. Life Sci. 2016;166:34–40.
Cesana M, Cacchiarelli D, Legnini I, Santini T, Sthandier O, Chinappi M, et al. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell. 2011;147(2):358–69.
Loewer S, Cabili MN, Guttman M, Loh Y-H, Thomas K, Park IH, et al. Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells. Nat Genet. 2010;42(12):1113–7.
Khaitan D, Dinger ME, Mazar J, Crawford J, Smith MA, Mattick JS, et al. The Melanoma-upregulated long noncoding RNA SPRY4-IT1 modulates apoptosis and invasion noncoding RNA function SPRY4-IT1 in human melanoma. Cancer Res. 2011;71(11):3852–62.
Yang H, Hu Y, Weng M, Liu X, Wan P, Hu Y, et al. Hypoxia inducible lncRNA-CBSLR modulates ferroptosis through m6A-YTHDF2-dependent modulation of CBS in gastric cancer. J Adv Res. 2022;37:91–106.
Xia A, Yuan W, Wang Q, Xu J, Gu Y, Zhang L, et al. The cancer-testis lncRNA lnc-CTHCC promotes hepatocellular carcinogenesis by binding hnRNP K and activating YAP1 transcription. Nat Cancer. 2022;3(2):203–18.
Chen F, Yang J, Fang M, Wu Y, Su D, Sheng Y. Necroptosis-related lncRNA to establish novel prognostic signature and predict the immunotherapy response in breast cancer. J Clin Lab Anal. 2022;36(4): e24302.
Najafi S, Tan SC, Raee P, Rahmati Y, Asemani Y, Lee EHC, et al. Gene regulation by antisense transcription: A focus on neurological and cancer diseases. Biomed Pharmacother. 2022;145:112265.
Ding H, Liu J, Zou R, Cheng P, Su Y. Long non-coding RNA TPTEP1 inhibits hepatocellular carcinoma progression by suppressing STAT3 phosphorylation. J Exp Clin Cancer Res. 2019;38(1):189.
Tang C, Feng W, Bao Y, Du H. Long non-coding RNA TINCR promotes hepatocellular carcinoma proliferation and invasion via STAT3 signaling by direct interacting with T-cell protein tyrosine phosphatase (TCPTP). Bioengineered. 2021;12(1):2119–31.
Wang H, Huo X, Yang XR, He J, Cheng L, Wang N, et al. STAT3-mediated upregulation of lncRNA HOXD-AS1 as a ceRNA facilitates liver cancer metastasis by regulating SOX4. Mol Cancer. 2017;16(1):136.
Chen T, Pei J, Wang J, Luo R, Liu L, Wang L, et al. HBx-related long non-coding RNA 01152 promotes cell proliferation and survival by IL-23 in hepatocellular carcinoma. Biomed Pharmacother. 2019;115:108877.
Tang WG, Hu B, Sun HX, Sun QM, Sun C, Fu PY, et al. Long non-coding RNA00364 represses hepatocellular carcinoma cell proliferation via modulating p-STAT3-IFIT2 signaling axis. Oncotarget. 2017;8(60):102006–19.
Lv J, Kong Y, Gao Z, Liu Y, Zhu P, Yu Z. LncRNA TUG1 interacting with miR-144 contributes to proliferation, migration and tumorigenesis through activating the JAK2/STAT3 pathway in hepatocellular carcinoma. Int J Biochem Cell Biol. 2018;101:19–28.
Liu Y, Feng J, Sun M, Yang G, Yuan H, Wang Y, et al. Long non-coding RNA HULC activates HBV by modulating HBx/STAT3/miR-539/APOBEC3B signaling in HBV-related hepatocellular carcinoma. Cancer Lett. 2019;454:158–70.
Qu S, Yang X, Li X, Wang J, Gao Y, Shang R, et al. Circular RNA: a new star of noncoding RNAs. Cancer Lett. 2015;365(2):141–8.
Zhao ZJ, Shen J. Circular RNA participates in the carcinogenesis and the malignant behavior of cancer. RNA Biol. 2017;14(5):514–21.
Li J, Zhang G, Liu C-G, Xiang X, Le MT, Sethi G, et al. The potential role of exosomal circRNAs in the tumor microenvironment: insights into cancer diagnosis and therapy. Theranostics. 2022;12(1):87.
Li JX, Wang JJ, Deng ZF, Zheng H, Yang CM, Yuan Y, et al. Circular RNA circ_0008934 promotes hepatocellular carcinoma growth and metastasis through modulating miR-1305/TMTC3 axis. Hum Cell. 2022;35(2):498–510.
Yu Q, Chen W, Li Y, He J, Wang Y, Yang S, et al. The novel circular RNA HIPK3 accelerates the proliferation and invasion of hepatocellular carcinoma cells by sponging the micro RNA-124 or micro RNA-506/pyruvate dehydrogenase kinase 2 axis. Bioengineered. 2022;13(3):4717–29.
Shen H, Li H, Zhou J. Circular RNA hsa_circ_0032683 inhibits the progression of hepatocellular carcinoma by sponging microRNA-338-5p. Bioengineered. 2022;13(2):2321–35.
Zhou XY, Yang H, Bai YQ, Li XL, Han SY, Zhou BX. hsa_circ_0006916 promotes hepatocellular carcinoma progression by activating the miR-337-3p/STAT3 axis. Cell Mol Biol Lett. 2020;25(1):47.
Fang N, Shi Y, Fan Y, Long T, Shu Y, Zhou J. Circ_0072088 promotes proliferation, migration, and invasion of esophageal squamous cell cancer by absorbing miR-377. Journal of oncology. 2020;2020:8967126.
Tan Z, Cao F, Jia B, Xia L. Circ_0072088 promotes the development of non-small cell lung cancer via the miR-377-5p/NOVA2 axis. Thoracic cancer. 2020;11(8):2224–36.
Li L, Xiao C, He K, Xiang G. Circ_0072088 promotes progression of hepatocellular carcinoma by activating JAK2/STAT3 signaling pathway via miR-375. IUBMB Life. 2021;73(9):1153–65.
Wu M, Sun T, Xing L. Circ_0004913 inhibits cell growth, metastasis, and glycolysis by absorbing miR-184 to regulate HAMP in hepatocellular carcinoma. Cancer Biother Radiopharm. 2020. https://doi.org/10.1089/cbr.2020.3779.
Yamada N, Matsushima-Nishiwaki R, Kozawa O. Quercetin suppresses the migration of hepatocellular carcinoma cells stimulated by hepatocyte growth factor or transforming growth factor-α: Attenuation of AKT signaling pathway. Arch Biochem Biophys. 2020;682: 108296.
Zou H, Zheng YF, Ge W, Wang SB, Mou XZ. Synergistic anti-tumour effects of quercetin and oncolytic adenovirus expressing TRAIL in human hepatocellular carcinoma. Sci Rep. 2018;8(1):2182.
Igbe I, Shen XF, Jiao W, Qiang Z, Deng T, Li S, et al. Dietary quercetin potentiates the antiproliferative effect of interferon-α in hepatocellular carcinoma cells through activation of JAK/STAT pathway signaling by inhibition of SHP2 phosphatase. Oncotarget. 2017;8(69):113734–48.
Wu L, Li J, Liu T, Li S, Feng J, Yu Q, et al. Quercetin shows anti-tumor effect in hepatocellular carcinoma LM3 cells by abrogating JAK2/STAT3 signaling pathway. Cancer Med. 2019;8(10):4806–20.
Ashrafizadeh M, Najafi M, Makvandi P, Zarrabi A, Farkhondeh T, Samarghandian S. Versatile role of curcumin and its derivatives in lung cancer therapy. J Cell Physiol. 2020;235(12):9241–68.
Ashrafizadeh M, Zarrabi A, Hashemi F, Moghadam ER, Hashemi F, Entezari M, et al. Curcumin in cancer therapy: a novel adjunct for combination chemotherapy with paclitaxel and alleviation of its adverse effects. Life Sci. 2020;256: 117984.
Abadi AJ, Mirzaei S, Mahabady MK, Hashemi F, Zabolian A, Hashemi F, et al. Curcumin and its derivatives in cancer therapy: potentiating antitumor activity of cisplatin and reducing side effects. Phytother Res. 2022;36(1):189–213.
Zheng Y, Jia R, Li J, Tian X, Qian Y. Curcumin- and resveratrol-co-loaded nanoparticles in synergistic treatment of hepatocellular carcinoma. J Nanobiotechnol. 2022;20(1):339.
Chen Q, Guo H, Zong Y, Zhao X. Curcumin restrains hepatocellular carcinoma progression depending on the regulation of the circ_0078710/miR-378b/PRIM2 axis. J Recept Signal Transduct Res. 2022;42(3):313–24.
Zhu J, Qu J, Fan Y, Zhang R, Wang X. Curcumin inhibits invasion and epithelial-mesenchymal transition in hepatocellular carcinoma cells by regulating TET1/Wnt/β-catenin signal axis. Bull Exp Biol Med. 2022;173(6):770–4.
Cao W, Zhang Y, Li A, Yu P, Song L, Liang J, et al. Curcumin reverses hepatic epithelial mesenchymal transition induced by trichloroethylene by inhibiting IL-6R/STAT3. Toxicol Mech Methods. 2021;31(8):589–99.
Pei T, Meng Q, Han J, Sun H, Li L, Song R, et al. (-)-Oleocanthal inhibits growth and metastasis by blocking activation of STAT3 in human hepatocellular carcinoma. Oncotarget. 2016;7(28):43475–91.
Xia C, Sun Y, Li Y, Ma J, Shi J. LncRNA CCAT1 enhances chemoresistance in hepatocellular carcinoma by targeting QKI-5. Sci Rep. 2022;12(1):7826.
Huang Y, Zhu Y, Yang J, Pan Q, Zhao J, Song M, et al. CMTM6 inhibits tumor growth and reverses chemoresistance by preventing ubiquitination of p21 in hepatocellular carcinoma. Cell Death Dis. 2022;13(3):251.
Zhou J, Che J, Xu L, Yang W, Li Y, Zhou W, et al. Enhancer of zeste homolog 2 promotes hepatocellular cancer progression and chemoresistance by enhancing protein kinase B activation through microRNA-381-mediated SET domain bifurcated 1. Bioengineered. 2022;13(3):5737–55.
Jiao Y, Wu Y, Du D. Polydatin inhibits cell proliferation, invasion and migration, and induces cell apoptosis in hepatocellular carcinoma. Braz J Med Biol Res. 2018;51(4):e6867.
Jiang J, Chen Y, Dong T, Yue M, Zhang Y, An T, et al. Polydatin inhibits hepatocellular carcinoma via the AKT/STAT3-FOXO1 signaling pathway. Oncol Lett. 2019;17(5):4505–13.
Sun J, Zhu Z, Li W, Shen M, Cao C, Sun Q, et al. UBE2T-regulated H2AX monoubiquitination induces hepatocellular carcinoma radioresistance by facilitating CHK1 activation. J Exp Clin Cancer Res. 2020;39(1):222.
Cheng CC, Ho AS, Peng CL, Chang J, Sie ZL, Wang CL, et al. Sorafenib suppresses radioresistance and synergizes radiotherapy-mediated CD8(+) T cell activation to eradicate hepatocellular carcinoma. Int Immunopharmacol. 2022;112: 109110.
Weng YS, Chiang IT, Tsai JJ, Liu YC, Hsu FT. Lenvatinib synergistically promotes radiation therapy in hepatocellular carcinoma by inhibiting Src/STAT3/NF-κB-mediated epithelial-mesenchymal transition and metastasis. Int J Radiat Oncol Biol Phys. 2023;115(3):719–32. https://doi.org/10.1016/j.ijrobp.2022.09.060.
Zhang G, Chen X, Ma L, Ding R, Zhao L, Ma F, et al. LINC01419 facilitates hepatocellular carcinoma growth and metastasis through targeting EZH2-regulated RECK. Aging. 2020;12(11):11071–84.
Yang L, Jiang J. GAS5 regulates RECK expression and inhibits invasion potential of HCC cells by sponging miR-135b. Biomed Res Int. 2019;2019:2973289.
Teng M, Hu C, Yang B, Xiao W, Zhou Q, Li Y, et al. Salvianolic acid B targets mortalin and inhibits the migration and invasion of hepatocellular carcinoma via the RECK/STAT3 pathway. Cancer Cell Int. 2021;21(1):654.
Yu M, Xue H, Wang Y, Shen Q, Jiang Q, Zhang X, et al. miR-345 inhibits tumor metastasis and EMT by targeting IRF1-mediated mTOR/STAT3/AKT pathway in hepatocellular carcinoma. Int J Oncol. 2017;50(3):975–83.
Yang S, Yang C, Yu F, Ding W, Hu Y, Cheng F, et al. Endoplasmic reticulum resident oxidase ERO1-Lalpha promotes hepatocellular carcinoma metastasis and angiogenesis through the S1PR1/STAT3/VEGF-A pathway. Cell Death Dis. 2018;9(11):1105.
Lin Y, Jian Z, Jin H, Wei X, Zou X, Guan R, et al. Long non-coding RNA DLGAP1-AS1 facilitates tumorigenesis and epithelial-mesenchymal transition in hepatocellular carcinoma via the feedback loop of miR-26a/b-5p/IL-6/JAK2/STAT3 and Wnt/β-catenin pathway. Cell Death Dis. 2020;11(1):34.
Lee YK, Kwon SM, Lee EB, Kim GH, Min S, Hong SM, et al. Mitochondrial respiratory defect enhances hepatoma cell invasiveness via STAT3/NFE2L1/STX12 axis. Cancers. 2020;12(9):2632.
Wang C, Dou C, Wang Y, Liu Z, Roberts L, Zheng X. TLX3 repressed SNAI1-induced epithelial-mesenchymal transition by directly constraining STAT3 phosphorylation and functionally sensitized 5-FU chemotherapy in hepatocellular carcinoma. Int J Biol Sci. 2019;15(8):1696–711.
Kang FB, Wang L, Jia HC, Li D, Li HJ, Zhang YG, et al. B7–H3 promotes aggression and invasion of hepatocellular carcinoma by targeting epithelial-to-mesenchymal transition via JAK2/STAT3/Slug signaling pathway. Cancer Cell Int. 2015;15:45.
Wang Y, Li N, Zheng Y, Wang A, Yu C, Song Z, et al. KIAA1217 promotes epithelial-mesenchymal transition and hepatocellular carcinoma metastasis by interacting with and activating STAT3. Int J Mol Sci. 2021;23(1):104.
Wang YD, Sun XJ, Yin JJ, Yin M, Wang W, Nie ZQ, et al. Long non-coding RNA FEZF1-AS1 promotes cell invasion and epithelial-mesenchymal transition through JAK2/STAT3 signaling pathway in human hepatocellular carcinoma. Biomed Pharmacother. 2018;106:134–41.
He Y, Pei JH, Li XQ, Chi G. IL-35 promotes EMT through STAT3 activation and induces MET by promoting M2 macrophage polarization in HCC. Biochem Biophys Res Commun. 2021;559:35–41.
Zhang L, Zhang Y, Shen D, Chen Y, Feng J, Wang X, et al. RNA binding motif protein 3 promotes cell metastasis and epithelial-mesenchymal transition through STAT3 signaling pathway in hepatocellular carcinoma. Journal of hepatocellular carcinoma. 2022;9:405–22.
Shi C, Yang J, Hu L, Liao B, Qiao L, Shen W, et al. Glycochenodeoxycholic acid induces stemness and chemoresistance via the STAT3 signaling pathway in hepatocellular carcinoma cells. Aging. 2020;12(15):15546–55.
Yin X, Zhang BH, Zheng SS, Gao DM, Qiu SJ, Wu WZ, et al. Coexpression of gene Oct4 and Nanog initiates stem cell characteristics in hepatocellular carcinoma and promotes epithelial-mesenchymal transition through activation of Stat3/Snail signaling. J Hematol Oncol. 2015;8:23.
Han Y, Chen M, Wang A, Fan X. STAT3-induced upregulation of lncRNA CASC11 promotes the cell migration, invasion and epithelial-mesenchymal transition in hepatocellular carcinoma by epigenetically silencing PTEN and activating PI3K/AKT signaling pathway. Biochem Biophys Res Commun. 2019;508(2):472–9.
Gai X, Zhou P, Xu M, Liu Z, Zheng X, Liu Q. Hyperactivation of IL-6/STAT3 pathway leaded to the poor prognosis of post-TACE HCCs by HIF-1α/SNAI1 axis-induced epithelial to mesenchymal transition. J Cancer. 2020;11(3):570–82.
Dong L, Cao X, Luo Y, Zhang G, Zhang D. A positive feedback loop of lncRNA DSCR8/miR-98-5p/STAT3/HIF-1α plays a role in the progression of ovarian cancer. Front Oncol. 2020;10:1713.
Zhang C, Guo F, Xu G, Ma J, Shao F. STAT3 cooperates with Twist to mediate epithelial-mesenchymal transition in human hepatocellular carcinoma cells. Oncol Rep. 2015;33(4):1872–82.
Sakamoto T, Kuboki S, Furukawa K, Takayashiki T, Takano S, Yoshizumi A, et al. TRIM27-USP7 complex promotes tumour progression via STAT3 activation in human hepatocellular carcinoma. Liver Int. 2022. https://doi.org/10.1111/liv.15346.
Zhang CH, Guo FL, Xu GL, Jia WD, Ge YS. STAT3 activation mediates epithelial-to-mesenchymal transition in human hepatocellular carcinoma cells. Hepatogastroenterology. 2014;61(132):1082–9.
Li F, Wang J, Wu N, Zhang H, Li Z, Wei N. H1, a derivative of tetrandrine, enhances the efficacy of 5-FU in Bel7402/5-FU cells via suppressing STAT3/MCL-1 and inducing PUMA. Biochem Biophys Res Commun. 2019;520(1):93–8.
Liu Y, Chen L, Yuan H, Guo S, Wu G. LncRNA DANCR promotes sorafenib resistance via activation of IL-6/STAT3 signaling in hepatocellular carcinoma cells. Onco Targets Ther. 2020;13:1145–57.
Sakurai T, Yada N, Hagiwara S, Arizumi T, Minaga K, Kamata K, et al. Gankyrin induces STAT3 activation in tumor microenvironment and sorafenib resistance in hepatocellular carcinoma. Cancer Sci. 2017;108(10):1996–2003.
Hong H, Jin Z, Qian T, Xu X, Zhu X, Fei Q, et al. Falcarindiol enhances cisplatin chemosensitivity of hepatocellular carcinoma via down-regulating the STAT3-modulated PTTG1 pathway. Front Pharmacol. 2021;12: 656697.
Lau CK, Yang ZF, Lam SP, Lam CT, Ngai P, Tam KH, et al. Inhibition of Stat3 activity by YC-1 enhances chemo-sensitivity in hepatocellular carcinoma. Cancer Biol Ther. 2007;6(12):1900–7.
Chen W, Shen X, Xia X, Xu G, Ma T, Bai X, et al. NSC 74859-mediated inhibition of STAT3 enhances the anti-proliferative activity of cetuximab in hepatocellular carcinoma. Liver Int. 2012;32(1):70–7.
Shi C, Kwong DL, Li X, Wang X, Fang X, Sun L, et al. MAEL augments cancer stemness properties and resistance to sorafenib in hepatocellular carcinoma through the PTGS2/AKT/STAT3 axis. Cancers. 2022;14(12):2880.
Long J, Jiang C, Liu B, Dai Q, Hua R, Chen C, et al. Maintenance of stemness by miR-589-5p in hepatocellular carcinoma cells promotes chemoresistance via STAT3 signaling. Cancer Lett. 2018;423:113–26.
Xue F, Liu Y, Zhang H, Wen Y, Yan L, Tang Q, et al. Let-7a enhances the sensitivity of hepatocellular carcinoma cells to cetuximab by regulating STAT3 expression. Onco Targets Ther. 2016;9:7253–61.
Ma W, Sze KM, Chan LK, Lee JM, Wei LL, Wong CM, et al. RhoE/ROCK2 regulates chemoresistance through NF-κB/IL-6/ STAT3 signaling in hepatocellular carcinoma. Oncotarget. 2016;7(27):41445–59.
Zhou JJ, Cheng D, He XY, Meng Z, Ye HL, Chen RF. Knockdown of long non-coding RNA HOTAIR sensitizes hepatocellular carcinoma cell to cisplatin by suppressing the STAT3/ABCB1 signaling pathway. Oncol Lett. 2017;14(6):7986–92.
Siddharth S, Kuppusamy P, Wu Q, Nagalingam A, Saxena NK, Sharma D. Metformin enhances the anti-cancer efficacy of sorafenib via suppressing MAPK/ERK/Stat3 axis in hepatocellular carcinoma. Int J Mol Sci. 2022. https://doi.org/10.3390/ijms23158083.
Youness RA, El-Tayebi HM, Assal RA, Hosny K, Esmat G, Abdelaziz AI. MicroRNA-486-5p enhances hepatocellular carcinoma tumor suppression through repression of IGF-1R and its downstream mTOR, STAT3 and c-Myc. Oncol Lett. 2016;12(4):2567–73.
Guo D, Gu Y, Ma D, Liu P, Chen B, Liu Z, et al. A novel microRNA miR-MTCO3P38 inhibits malignant progression via STAT3/PTTG1/MYC in hepatocellular carcinoma. Genes Dis. 2022;9(4):845–8.
Zhou P, Huang G, Zhao Y, Zhong D, Xu Z, Zeng Y, et al. MicroRNA-363-mediated downregulation of S1PR1 suppresses the proliferation of hepatocellular carcinoma cells. Cell Signal. 2014;26(6):1347–54.
Yang YM, Lee CG, Koo JH, Kim TH, Lee JM, An J, et al. Gα12 overexpressed in hepatocellular carcinoma reduces microRNA-122 expression via HNF4α inactivation, which causes c-Met induction. Oncotarget. 2015;6(22):19055–69.
Yin D, Hu ZQ, Luo CB, Wang XY, Xin HY, Sun RQ, et al. LINC01133 promotes hepatocellular carcinoma progression by sponging miR-199a-5p and activating annexin A2. Clin Transl Med. 2021;11(5): e409.
Huang H, Bu YZ, Zhang XY, Liu J, Zhu LY, Fang Y. LINC01433 promotes hepatocellular carcinoma progression via modulating the miR-1301/STAT3 axis. J Cell Physiol. 2019;234(5):6116–24.
Zuo XL, Chen ZQ, Wang JF, Wang JG, Liang LH, Cai J. miR-337-3p suppresses the proliferation and invasion of hepatocellular carcinoma cells through targeting JAK2. Am J Cancer Res. 2018;8(4):662–74.
Huang B, Huang M, Li Q. MiR-137 suppresses migration and invasion by targeting EZH2-STAT3 signaling in human hepatocellular carcinoma. Pathol Res Pract. 2018;214(12):1980–6.
Mao J, Hu X, Pang P, Zhou B, Li D, Shan H. miR-30e acts as a tumor suppressor in hepatocellular carcinoma partly via JAK1/STAT3 pathway. Oncol Rep. 2017;38(1):393–401.
Mo Y, He L, Lai Z, Wan Z, Chen Q, Pan S, et al. LINC01287/miR-298/STAT3 feedback loop regulates growth and the epithelial-to-mesenchymal transition phenotype in hepatocellular carcinoma cells. J Exp Clin Cancer Res. 2018;37(1):149.
Lin Q, Zheng H, Xu J, Zhang F, Pan H. LncRNA SNHG16 aggravates tumorigenesis and development of hepatocellular carcinoma by sponging miR-4500 and targeting STAT3. J Cell Biochem. 2019. https://doi.org/10.1002/jcb.28440.
Jiang C, Long J, Liu B, Xu M, Wang W, Xie X, et al. miR-500a-3p promotes cancer stem cells properties via STAT3 pathway in human hepatocellular carcinoma. J Exp Clin Cancer Res. 2017;36(1):99.
Sun S, Gao J, Zhou S, Li Y, Wang Y, Jin L, et al. A novel circular RNA circ-LRIG3 facilitates the malignant progression of hepatocellular carcinoma by modulating the EZH2/STAT3 signaling. J Exp Clin Cancer Res. 2020;39(1):252.
Su Z, Ye X, Shang L. MiR-506 promotes natural killer cell cytotoxicity against human hepatocellular carcinoma cells by targeting STAT3. Yonsei Med J. 2019;60(1):22–9.
Sun X, Zhang J, Hou Z, Han Q, Zhang C, Tian Z. miR-146a is directly regulated by STAT3 in human hepatocellular carcinoma cells and involved in anti-tumor immune suppression. Cell Cycle (Georgetown, Tex). 2015;14(2):243–52.
Zhang XN, Zhou J, Lu XJ. The long noncoding RNA NEAT1 contributes to hepatocellular carcinoma development by sponging miR-485 and enhancing the expression of the STAT3. J Cell Physiol. 2018;233(9):6733–41.
Liu X, Zhang A, Xiang J, Lv Y, Zhang X. miR-451 acts as a suppressor of angiogenesis in hepatocellular carcinoma by targeting the IL-6R-STAT3 pathway. Oncol Rep. 2016;36(3):1385–92.
Ni JS, Zheng H, Ou YL, Tao YP, Wang ZG, Song LH, et al. miR-515-5p suppresses HCC migration and invasion via targeting IL6/JAK/STAT3 pathway. Surg Oncol. 2020;34:113–20.
Van Renne N, Roca Suarez AA, Duong FHT, Gondeau C, Calabrese D, Fontaine N, et al. miR-135a-5p-mediated downregulation of protein tyrosine phosphatase receptor delta is a candidate driver of HCV-associated hepatocarcinogenesis. Gut. 2018;67(5):953–62.
Jie M, Zhang ZQ, Deng N, Liu QM, Wang C, Ge QY, et al. 18[Formula: see text]-glycyrrhetinic acid inhibits TGF-[Formula: see text]-induced epithelial-to-mesenchymal transition and metastasis of hepatocellular carcinoma by targeting STAT3. Am J Chin Med. 2022;50(1):313–32.
Song X, Wang J, Zheng T, Song R, Liang Y, Bhatta N, et al. LBH589 Inhibits proliferation and metastasis of hepatocellular carcinoma via inhibition of gankyrin/STAT3/Akt pathway. Mol Cancer. 2013;12(1):114.
Wang ST, Huang SW, Liu KT, Lee TY, Shieh JJ, Wu CY. Atorvastatin-induced senescence of hepatocellular carcinoma is mediated by downregulation of hTERT through the suppression of the IL-6/STAT3 pathway. Cell death discovery. 2020;6:17.
Liu K, Tian T, Zheng Y, Zhou L, Dai C, Wang M, et al. Scutellarin inhibits proliferation and invasion of hepatocellular carcinoma cells via down-regulation of JAK2/STAT3 pathway. J Cell Mol Med. 2019;23(4):3040–4.
Wang X, Gupta P, Jramne Y, Danilenko M, Liu D, Studzinski GP. Carnosic acid increases sorafenib-induced inhibition of ERK1/2 and STAT3 signaling which contributes to reduced cell proliferation and survival of hepatocellular carcinoma cells. Oncotarget. 2020;11(33):3129–43.
Coker-Gurkan A, Can E, Sahin S, Obakan-Yerlikaya P, Arisan ED. Atiprimod triggered apoptotic cell death via acting on PERK/eIF2α/ATF4/CHOP and STAT3/NF-ΚB axis in MDA-MB-231 and MDA-MB-468 breast cancer cells. Mol Biol Rep. 2021;48(6):5233–47.
Lee JH, Mohan CD, Deivasigamani A, Jung YY, Rangappa S, Basappa S, et al. Brusatol suppresses STAT3-driven metastasis by downregulating epithelial-mesenchymal transition in hepatocellular carcinoma. J Adv Res. 2020;26:83–94.
Gao Y, Li W, Liu R, Guo Q, Li J, Bao Y, et al. Norcantharidin inhibits IL-6-induced epithelial-mesenchymal transition via the JAK2/STAT3/TWIST signaling pathway in hepatocellular carcinoma cells. Oncol Rep. 2017;38(2):1224–32.
Li J, Zhou Y, Liu Y, Dai B, Zhang YH, Zhang PF, et al. Sorafenib inhibits caspase-1 expression through suppressing TLR4/stat3/SUMO1 pathway in hepatocellular carcinoma. Cancer Biol Ther. 2018;19(11):1057–64.
Huang Y, Zhou B, Luo H, Mao J, Huang Y, Zhang K, et al. ZnAs@SiO(2) nanoparticles as a potential anti-tumor drug for targeting stemness and epithelial-mesenchymal transition in hepatocellular carcinoma via SHP-1/JAK2/STAT3 signaling. Theranostics. 2019;9(15):4391–408.
Cho IJ, Kim JK, Kim EO, Park SM, Kim SC, Ki SH, et al. Hemistepsin a induces apoptosis of hepatocellular carcinoma cells by downregulating STAT3. Int J Mol Sci. 2021;22(9):4743.
Yang T, Huo J, Xu R, Su Q, Tang W, Zhang D, et al. Selenium sulfide disrupts the PLAGL2/C-MET/STAT3-induced resistance against mitochondrial apoptosis in hepatocellular carcinoma. Clin Transl Med. 2021;11(9): e536.
Seo HY, Lee SH, Lee JH, Lee JH, Jang BK, Kim MK. Kahweol induces apoptosis in hepatocellular carcinoma cells by inhibiting the Src/mTOR/STAT3 signaling pathway. Int J Mol Sci. 2021. https://doi.org/10.3390/ijms221910509.
Yang W, Feng Q, Li M, Su J, Wang P, Wang X, et al. Sinomenine suppresses development of hepatocellular carcinoma cells via inhibiting MARCH1 and AMPK/STAT3 signaling pathway. Front Mol Biosci. 2021;8: 684262.
Hu X, Jiao F, Zhang L, Jiang Y. Dihydrotanshinone Inhibits Hepatocellular Carcinoma by Suppressing the JAK2/STAT3 Pathway. Front Pharmacol. 2021;12: 654986.
Wang JR, Luo YH, Piao XJ, Zhang Y, Feng YC, Li JQ, et al. Mechanisms underlying isoliquiritigenin-induced apoptosis and cell cycle arrest via ROS-mediated MAPK/STAT3/NF-κB pathways in human hepatocellular carcinoma cells. Drug Dev Res. 2019;80(4):461–70.
Lu X, Xu C, Dong J, Zuo S, Zhang H, Jiang C, et al. Liraglutide activates nature killer cell-mediated antitumor responses by inhibiting IL-6/STAT3 signaling in hepatocellular carcinoma. Trans Oncol. 2021;14(1): 100872.
Fang XY, Zhang H, Zhao L, Tan S, Ren QC, Wang L, et al. A new xanthatin analogue 1β-hydroxyl-5α-chloro-8-epi-xanthatin induces apoptosis through ROS-mediated ERK/p38 MAPK activation and JAK2/STAT3 inhibition in human hepatocellular carcinoma. Biochimie. 2018;152:43–52.
Research in S.C.T.’s laboratory is supported by the Fundamental Research Grant Scheme of the Ministry of Higher Education, Malaysia (no. FRGS/1/2019/SKK08/UKM/02/9) and the Research University Grant of Universiti Kebangsaan Malaysia (no. GUP-2020-076).
Open access funding enabled and organized by Projekt DEAL. The funders have no role in the design of the study and collection, analysis, and interpretation of data or in writing the manuscript.
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Hashemi, M., Sabouni, E., Rahmanian, P. et al. Deciphering STAT3 signaling potential in hepatocellular carcinoma: tumorigenesis, treatment resistance, and pharmacological significance. Cell Mol Biol Lett 28, 33 (2023). https://doi.org/10.1186/s11658-023-00438-9