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Analysis of the role of the integrin signaling pathway in hepatocytes during rat liver regeneration

Cellular & Molecular Biology Letters volume 17, pages 274–288 (2012)Cite this article

Abstract

To explore the role of the integrin signaling pathway in hepatocytes during rat liver regeneration, the integrin signaling pathway-related gene expression profile in hepatocytes of regenerative liver was detected using Rat Genome 230 2.0 array. The chip data showed that 265 genes of the integrin signaling pathway were included by Rat Genome 230 2.0 array and 132 genes showed significant expression changes in hepatocytes of regenerative liver. The numbers of up-, down- and up/down-regulated genes were 110, 15 and 7 respectively. In addition, bioinformatics and systems biology methods were used to analyze the role of the integrin signaling pathway in hepatocytes. The analysis of gene synergy value indicated that paths 1, 8, 12, and 15 promoted hepatocyte proliferation at the priming phase of liver regeneration; paths 1, 3, 8, and 12–15 enhanced hepatocyte proliferation at the progressing phase; paths 11 and 14 promoted hepatocyte proliferation, while paths 12 and 13 reduced hepatocyte proliferation at the terminal phase. Additionally, the other 8 paths (2, 4, 5–7, 9–10, and 16) were not found to be related to liver regeneration. In conclusion, 132 genes and 8 cascades of the integrin signaling pathway participated in regulating hepatocyte proliferation during rat liver regeneration.

Abbreviations

AC:

adenyl cyclase

Akt:

v-Akt murine thymoma viral oncogene

ECM:

extracellular matrix

ERK:

extracellular regulated protein kinases

FAK:

focal adhesion kinase

GSK3:

glycogen synthase kinase-3

ILK:

integrin-linked kinase

JNK:

c-Jun NH2-terminal kinase

MAPK:

mitogen-activated protein kinase

mTOR:

mammalian target of rapamycin

PAK-p21:

activated kinase

PH:

partial hepatectomy

PI3K:

phosphoinositide 3-kinase

PKA:

protein kinase-A

PKB:

protein kinase B

PKC:

protein kinase C

ROCK:

Rho-associated kinase

References

  1. Yokoyama, Y., Nagino, M. and Nimura, Y. Mechanisms of hepatic regeneration following portal vein embolization and partial hepatectomy: a review. World J. Surg. 31 (2007) 367–374.

    Article  PubMed  CAS  Google Scholar 

  2. Michalopoulos, G.K. Liver regeneration. J. Cell Physiol. 213 (2007) 286–300.

    Article  PubMed  CAS  Google Scholar 

  3. Vondran, F.W., Katenz, E., Schwartlander, R., Morgul, R.S., Haluk, M., Raschzok, N., Gong, X.B., Cheng, X.D., Kehr, D. and Sauer, I.M. Isolation of primary human hepatocytes after partial hepatectomy: criteria for identification of the most promising liver specimen. Artif. Organs 32 (2008) 205–213.

    Article  PubMed  Google Scholar 

  4. Estes, M.D., Do J. and Ahn, C.H. On chip cell separator using magnetic bead-based enrichment and depletion of various surface markers. Biomed. Microdevices 11 (2009) 509–515.

    Article  PubMed  CAS  Google Scholar 

  5. Xu, C.S., Chen, X.G., Chang, C.F., Wang, G.P., Wang, W.B. and Zhang, L.X. Transcriptome analysis of hepatocytes after partial hepatectomy in rats. Dev. Genes. Evol. 220 (2010) 263–274.

    Article  PubMed  CAS  Google Scholar 

  6. Hehlgans, S., Haase, M., and Cordes, N. Signalling via integrins: implications for cell survival and anticancer strategies. Biochim. Biophys. Acta. 1775 (2007) 163–180.

    PubMed  CAS  Google Scholar 

  7. Donthamsetty, S., Bowen, W., Mars, W., Bhave, V., Luo, J.H., Wu, C., Hurd, J., Orr, A., Bell, A. and Michalopoulos, G.K. Liver-specific ablation of integrin-linked kinase in mice results in enhanced and prolonged cell proliferation and hepatomegaly after phenobarbital administration. Toxicol. Sci. 113 (2010) 358–366.

    Article  PubMed  CAS  Google Scholar 

  8. Mayoral, R., Fernández-Martínez, A., Roy, R., Boscá, L. and Martín-Sanz, P. Dispensability and dynamics of caveolin-1 during liver regeneration and in isolated hepatic cells. Hepatology 46 (2007) 813–822.

    Article  PubMed  CAS  Google Scholar 

  9. Zouq, N.K., Keeble, J.A., Lindsay, J., Valentijn, A.J., Zhang, L., Mills, D., Turner, C.E., Streuli, C.H. and Gilmore, A.P. FAK engages multiple pathways to maintain survival of fibroblasts and epithelia: differential roles for paxillin and p130Cas. J. Cell Sci. 122 (2009) 357–367.

    Article  PubMed  CAS  Google Scholar 

  10. Tabe, Y., Jin, L., Tsutsumi-Ishii, Y., Xu, Y., McQueen, T., Priebe, W., Mills, G.B., Ohsaka, A., Nagaoka, I., Andreeff, M. and Konopleva, M. Activation of integrin-linked kinase is a critical prosurvival pathway induced in leukemiccells by bone marrow-derived stromal cells. Cancer Res. 67 (2007) 684–694.

    Article  PubMed  CAS  Google Scholar 

  11. Lemons, M.L. and Condic, M.L. Integrin signaling is integral to regeneration. Exp. Neurol. 209 (2008) 343–352.

    Article  PubMed  CAS  Google Scholar 

  12. Zhang, X., Li, C., Gao, H., Nabeka, H., Shimokawa, T., Wakisaka, H., Matsuda, S. and Kobayashi, N. Rho kinase inhibitors stimulate the migration of human cultured osteoblastic cells by regulating actmyosin activity. Cell. Mol. Biol. Lett. 16 (2011) 279–295.

    Article  PubMed  CAS  Google Scholar 

  13. Auriemma, C., Viscardi, M., Tafuri, S., Pavone, L.M., Capuano, F., Rinaldi, L., Della Morte, R., Iovane, G. and Staiano, N. Integrin receptors play a role in the integrin β-dependent entry of Listeria monocytogenes into host cells. Cell. Mol. Biol. Lett. 15 (2010) 496–506.

    Article  PubMed  CAS  Google Scholar 

  14. Brown, E.J. and Frazier, W.A. Integrin-associated protein (CD47) and its ligands. Trends Cell Biol. 11 (2001) 130–135.

    Article  PubMed  CAS  Google Scholar 

  15. Higgins, G.M. and Anderson, R.M. Experimental pathology of the liver: Restoration of the liver of the white rat following partial surgical removal. Arch. Pathol. 12 (1931) 186–202.

    Google Scholar 

  16. Grisham, J.W. Cell types in rat liver cultures: their identification and isolation. Mol. Cell. Biochem. 54 (2008) 23–33.

    Google Scholar 

  17. Qin, Y. and Tian, Y.P. A microarray gene analysis of peripheral whole blood in normal adult male ratsafter long-term GH gene therapy. Cell. Mol. Biol. Lett. 15 (2010) 177–195.

    Article  PubMed  CAS  Google Scholar 

  18. Twigger, S.N., Smith J., Zuniga-Meyer, A. and Bromberg, S.K. Exploring phenotypic data at the rat genome database. Curr. Protoc. Bioinformatics (2006) Chapter 1, Unit 1.14.

  19. Wang, J.Z., Du, Z., Payattakool, R., Yu, P.S. and Chen, C.F. A new method to measure the semantic similarity of GO terms. Bioinformatics 23 (2007) 1274–1281.

    Article  PubMed  CAS  Google Scholar 

  20. Guo, W., Cai, C., Wang, C., Zhao, L., Wang, L. and Zhang, T. A preliminary analysis of genome structure and composition in Gossypium hirsutum. BMC Genomics 9 (2008) 314.

    Article  PubMed  Google Scholar 

  21. Wang, G.P. and Xu, C.S. Reference gene selection for real-time RT-PCR in eight kinds of rat regenerating hepatic cells. Mol. Biotechnol. 46 (2010) 49–57.

    Article  PubMed  Google Scholar 

  22. Hynes, R.O. A reevaluation of integrins as regulators of angiogenesis. Nat. Med. 8 (2002) 918–921.

    Article  PubMed  CAS  Google Scholar 

  23. Katz, B.Z., Romer, L., Miyamoto, S., Volberg, T., Matsumoto, K., Cukierman, E., Geiger, B. and Yamada, K.M. Targeting membrane-localized focal adhesion kinase to focal adhesion: roles of tyrosinephosphorylation and SRC family kinases. J. Biol. Chem. 278 (2003) 29115–29120.

    Article  PubMed  CAS  Google Scholar 

  24. Lee, J.W. and Juliano, R. Mitogenic signal transduction by integrin- and growth factor receptor-mediated pathways. Mol. Cells 17 (2004) 188–202.

    PubMed  CAS  Google Scholar 

  25. Wang, W.B., Fan, J.M., Zhang, X.L., Xu, J. and Yao, W. Serial expression analysis of liver regeneration-related genes in rat regenerating liver. Mol. Biotechnol. 43 (2009) 221–231.

    Article  PubMed  CAS  Google Scholar 

  26. Tong, H. On a threshold model, pattern recognition and signal processing, In: NATO ASI series E: Applied Sc No. 29.(Chen, C.H. Ed.) Alphen aan den Rijn, The Netherland: Sijthoff & Noordhoff, 1978.

    Google Scholar 

  27. Eisen, M.B., Spellman, P.T., Brown, P.O. and Botstein, D. Cluster analysis and display of genome-wide expression patterns. Proc. Nat. Acad. Sci. USA 95 (1998) 14863–14868.

    Article  PubMed  CAS  Google Scholar 

  28. Li, H., Chen, X.G, Zhang, F.C., Ma, J. and Xu, C.S. Expression patterns of the cell junction-associated genes during rat liver regeneration. J. Genet. Genomics 34 (2007) 892–908.

    Article  PubMed  CAS  Google Scholar 

  29. Nguyen, L.N., Furuya, M.H., Wolfraim, L.A., Nguyen, A.P., Holdren, M.S., Campbell, J.S., Knight, B., Yeoh, G.C., Fausto, N. and Parks, W.T. Transforming growth factor-beta differentially regulates oval cell and hepatocyte proliferation. Hepatology 45 (2007) 31–41.

    Article  PubMed  CAS  Google Scholar 

  30. Fausto, N., Campbell, J.S. and Riehle, K.J. Liver regeneration. Hepatology 43 (2006) S45–53.

    Article  PubMed  CAS  Google Scholar 

  31. Frank, P.G. and Lisanti, M.P. Caveolin-1 and liver regeneration: role in proliferation and lipogenesis. Cell Cycle 6 (2007) 115–116.

    Article  PubMed  CAS  Google Scholar 

  32. Williams, T.M. and Listanti, M.P. Caveolin-1 in oncogeic transformation, cancer, and metastasis. Am. J. Physiol. Cell Physiol. 288 (2005) C494–506.

    Article  PubMed  CAS  Google Scholar 

  33. Martin, K.H., Slack, J.K., Boemer, S.A., Martin, C.C. and Parsons, J.T. Integrin connections map: to infinity and beyond. Science 296 (2002) l652–l653.

    Article  Google Scholar 

  34. Gilmore, A.P. and Romer, L.H. Inhibition of focal adhesion kinase (FAK) signaling in focal adhesions decreases cell motility and proliferation. Mol. Cell. Biol. 7 (1997) 1209–1224.

    Google Scholar 

  35. Gohbovskaya, V., Kaur, A. and Cance, W. Cloning and characterization of the promoter region of human focal adhesion kinase gene: nuclear factor kappa B and p53 binding sites. Biochim. Biophys. Acta 1678 (2004) 11–25.

    Google Scholar 

  36. Post, G.R. and Brown, J.H. G protein-coupled receptors and signaling pathways regulating growth responses. FASEB J. 10 (1996) 741–749.

    PubMed  CAS  Google Scholar 

  37. Fukuhara, Y., Hirasawa, A., Li, X.K., Kawasaki, M., Fujino, M. and Funeshima, N. Gene expression profile in the regenerating rat liver after partial hepatectomy. J. Hepatol. 38 (2003) 784–792.

    Article  PubMed  CAS  Google Scholar 

  38. Reissig, D., Clement, J., Sänger, J., Berndt, A., Kosmehl, H. and Böhmer, F.D. Elevated activity and expression of Src-family kinases in human breast carcinoma tissue versus matched no tumor tissue. J. Cancer Res. Clin. Oncol. 127 (2001) 226–230.

    Article  PubMed  CAS  Google Scholar 

  39. Biscardi, J.S., Ishizawar, R.C., Silva, C.M. and Parsons, S.J. Tyrosine kinase signaling in breast cancer: epidermal growth f actor receptor and c- Src interactions in breast cancer. Breast Cancer Res. 2 (2002) 203–210.

    Article  Google Scholar 

  40. Xu, C.S., Chang, C.F., Yuan, J.Y., Li, W.Q., Han, H.P. and Yang, K.J. Expressed genes in regenerating rat liver after partial hepatectomy. World J. Gastroenterol. 11 (2005) 2932–2940.

    PubMed  CAS  Google Scholar 

  41. Michalopoulos, G.K. and DeFrances, M. Liver regeneration. Adv. Biochem. Eng. Biotechnol. 93 (2005) 101–134.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. College of Life Science, Henan Normal University, Xinxiang, 453007, P.R. China

    Cunshuan Xu & Yanjie Yang

  2. Key Laboratory for Cell Differentiation Regulation, Xinxiang, 453007, P.R. China

    Cunshuan Xu, Yanjie Yang, Junying Yang, Xiaoguang Chen & Gaiping Wang

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  1. Cunshuan Xu
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  2. Yanjie Yang
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  3. Junying Yang
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Correspondence to Cunshuan Xu.

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Xu, C., Yang, Y., Yang, J. et al. Analysis of the role of the integrin signaling pathway in hepatocytes during rat liver regeneration. Cell Mol Biol Lett 17, 274–288 (2012). https://doi.org/10.2478/s11658-012-0011-x

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  • DOI: https://doi.org/10.2478/s11658-012-0011-x

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Cellular & Molecular Biology Letters

ISSN: 1689-1392

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