Skip to main content

Decreased expression of the human carbonyl reductase 2 gene HCR2 in hepatocellular carcinoma

Abstract

Altered gene expression was associated with the induction and maintenance of hepatocellular carcinoma (HCC). To determine the significance of HCR2 in HCC, here we compare the expression levels of HCR2 in carcinoma and in paired non-carcinoma tissues using semiquantitative reverse-transcription polymerase chain reaction (RT-PCR), Western blot analysis, and immunohistochemical staining. The expression ratio (ER) of HCR2 between the tumor and paired tumor-free tissues was calculated for each case and the data was clinicopathologically analyzed. The expression of HCR2 mRNA was found to be significantly decreased in HCC tissues compared with paired normal tissues (P < 0.001). HCR2 was downregulated in 58% (n = 22) of 38 HCC patients. The ER of HCR2 was higher in Edmondson’s grade I/II carcinomas than that in Edmondson’s grade III/IV carcinomas (P < 0.05). Western blot analysis showed HCR2 to be notably depressed in carcinoma tissues in 3 out of 4 HCC patients. Immunohistochemical staining indicated most HCR2 protein accumulated in non-carcinoma cells. These results suggested that altered HCR2 expression might play roles in the carcinogenesis and progression of HCC, and it could be a clinical marker for prognosis, and a molecular target for screening potential anti-HCC drugs.

Abbreviations

AFP:

alpha fetoprotein

β2-MG gene:

β2-microglobulin gene

CAT:

catalase

CBR1:

carbonyl reductase 1

ER:

expression ratio

GPx:

glutathione peroxidase

HCC:

hepatocellular carcinoma

HCR2:

carbonyl reductase 2

IgG:

immunoglobulin

ROS:

reactive oxygen species

RT-PCR:

reverse-transcription polymerase chain reaction

SDR:

short chain dehydrogenases/reductases

SOD:

superoxide dismutase

References

  1. 1.

    Tang, Z.Y. Hepatocellular carcinoma — cause, treatment and metastasis. World J. Gastroenterol. 7 (2001) 445–454.

    PubMed  CAS  Google Scholar 

  2. 2.

    Mori, T., Nomoto, S., Koshikawa, K., Fujii, T., Sakai, M., Nishikawa, Y., Inoue, S., Takeda, S., Kaneko, T. and Nakao, A. Decreased expression and frequent allelic inactivation of the RUNX3 gene at 1p36 in human hepatocellular carcinoma. Liver Int. 25 (2005) 380–388.

    PubMed  CAS  Article  Google Scholar 

  3. 3.

    Zhang, Y.J., Chen, Y., Ahsan, H., Lunn, R.M., Chen, S.Y., Lee, P.H., Chen, C.J. and Santella, R.M. Silencing of glutathione S-transferaseP1 by promoter hypermethylation and its relationship to environmental chemical carcinogens in hepatocellular carcinoma. Cancer Lett. 221 (2005) 135–143.

    PubMed  CAS  Article  Google Scholar 

  4. 4.

    Moriyama, M., Mikuni, M., Longren, W., Zhao, Z.Y., Wang, X.Q., Oshiro, S., Matsumura, H., Aoki, H., Ichijima, S., Iwasaki, H., Tanaka, N., Abe, K. and Arakawa, Y. Epidemiology of SEN virus infection among patients with hepatitis B and C in China. Hepatol. Res. 27 (2003) 174–180.

    PubMed  Article  Google Scholar 

  5. 5.

    Nakagawa, J., Ishikura, S., Asami, J., Isaji, T., Usami, N., Hara, A., Sakurai, T., Tsuritani, K., Oda, K., Takahashi, M., Yoshimoto, M., Otsuka, N. and Kitamura, K. Molecular characterization of mammalian Dicarbonyl/L-Xylulose reductase and its localization in kidney. J. Bio. Chem. 277 (2002) 17883–17891.

    CAS  Article  Google Scholar 

  6. 6.

    Roberts, M.J., Wondrak, G.T., Laurean, D.C., Jacobson, M.K. and Jacobson, E.L. DNA damage by carbonyl stress in human skin cells. Mutat. Res. 522 (2003) 45–56.

    PubMed  CAS  Google Scholar 

  7. 7.

    Weiss, M.F., Erhard, P., Kader-Attia, F.A., Wu, Y.C., DeOreo, P.B., Araki, A., Glomb, M.A. and Monnier, V.M. Mechanisms for the formation of glycoxidation products in end-stage renal disease. Kidney Int. 57 (2000) 2571–2585.

    PubMed  CAS  Article  Google Scholar 

  8. 8.

    Wiseman, H. and Halliwell, B. Damage to DNA by reactive oxygen and mitogen species: role in inflammatory disease and progression to cancer. Biochem. J. 313 (1996) 17–29.

    PubMed  CAS  Google Scholar 

  9. 9.

    Cerutti, P.A. Oxy-radicals and cancer. Lancet 344 (1994) 862–863.

    PubMed  CAS  Article  Google Scholar 

  10. 10.

    Edmondson, H.A. and Steiner, P.E. Primary carcinoma of the liver. A study of 100 cases among 48,900 necropsies. Cancer 7 (1954) 462–503.

    PubMed  CAS  Google Scholar 

  11. 11.

    Gussow, D., Rein, R., Ginjaar, I., Hochstenbach, F., Seemann, G., Kottman, A. and Ploegh, H.L. The human beta-2-microglobulin gene: primary structure and definition of the transcriptional unit. J. Immunol. 139 (1987) 3132–3138.

    PubMed  CAS  Google Scholar 

  12. 12.

    Ozaki, I., Mizuta, T., Zhao, G., Yotsumoto, H., Hara, T., Kajihara, S., Hisatomi, A., Sakai, T. and Yamamoto K. Involvement of the Ets-1 gene in overexpression of matrilysin in human hepatocellular carcinoma. Cancer Res. 60 (2000) 6519–6525.

    PubMed  CAS  Google Scholar 

  13. 13.

    Iizuka, N., Oka, M., Yamada-Okabe, H., Mori, N., Tamesa, T., Okada, T., Takemoto, N., Tangoku, A., Hamada, K., Nakayama, H., Miyamoto, T., Uchimura, S. and Hamamoto, Y. Comparison of gene expression profiles between hepatitis B virus-and hepatitis C virus-infected hepatocellular carcinoma by oligonucleotide microarray data on the basis of a supervised learning method. Cancer Res. 62 (2002) 3939–3944.

    PubMed  CAS  Google Scholar 

  14. 14.

    Craemer, D.D., Pauwels, M., Hautekeete, M. and Roels, F. Alteration of hepatocellular peroxisomes in patients with cancer. Cancer 71 (1993) 3851–3858.

    PubMed  Google Scholar 

  15. 15.

    Kawaguchi, T., Suzuki, K. and Matsuda, Y. Serum-manganese-superoxide dismutase: normal values and increased levels in patients with acute myocardial infarction and several malignant dieseases determined by an enzyme-linked immunosorbent assay using a monoclonal antibody. J. Immunol. Methods 127 (1990) 249–254.

    PubMed  CAS  Article  Google Scholar 

  16. 16.

    Suto, K., Kajihara-Kano, H., Yokoyama, Y., Hayakari, M., Kimura, J., Kumano, T., Takahata, T., Kudo, H. and Tsuchida, S. Decreased expression of the peroxisomal bifunctional enzyme and carbonyl reductase in human hepatocellular carcinomas. J. Cancer. Res. Clin. Oncol. 125 (1999) 83–88.

    PubMed  CAS  Article  Google Scholar 

  17. 17.

    Tada, M., Yokosuka, O., Fukai, K., Chiba, T., Imazeki, F., Tokuhisa, T. and Saisho, H. Hypermethylation of NAD(P)H: quinone oxidoreductase 1 (NQO1) gene in human hepatocellular carcinoma. J. Hepatol. 42 (2005) 511–519.

    PubMed  CAS  Article  Google Scholar 

  18. 18.

    Zhong, S., Tang, M.W., Yeo, W., Liu, C., Lo, Y.M. and Johnson, P.J. Silencing of GSTP1 gene by CpG island DNA hypermethylation in HBV-associated hepatocellular carcinomas. Clin. Cancer Res. 8 (2002) 1087–1092.

    PubMed  CAS  Google Scholar 

  19. 19.

    Forrest, G.L. and Gonzalez, B. Carbonyl reductase. Chem. Biol. Interact. 129 (2000) 21–40.

    PubMed  CAS  Article  Google Scholar 

  20. 20.

    Pulling, L.C., Klinge, D.M. and Belinsky, S.A. p16INK4a and beta-catenin alterations in rat liver tumors induced by NNK. Carcinogenesis 22 (2001) 461–466.

    PubMed  CAS  Article  Google Scholar 

  21. 21.

    Ismail, E., Al-Mulla, F., Tsuchida, S., Suto, K., Motley, P., Harrison, P.R. and Birnie, G.D. Carbonyl reductase: a novel metastasis modulating function. Cancer Res. 60 (2000) 1173–1176.

    PubMed  CAS  Google Scholar 

  22. 22.

    Umemotol, M., Yokoyamal, Y., Satol, S., Tsuchida, S., Al-Mulla, F. and Saitol, Y. Carbonyl reductase as a significant predictor of survival and lymph node metastasis in epithelial ovarian cancer. Br. J. Cancer 85 (2001) 1032–1036.

    Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Long Yu.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Liu, S., Ma, L., Huang, W. et al. Decreased expression of the human carbonyl reductase 2 gene HCR2 in hepatocellular carcinoma. Cell. Mol. Biol. Lett. 11, 230–241 (2006). https://doi.org/10.2478/s11658-006-0022-6

Download citation

Key words

  • HCR2
  • Hepatocellular carcinoma
  • Gene expression