Skip to main content
Log in

Gender disparity in hepatocellular carcinoma (HCC): multiple underlying mechanisms

  • Review
  • Published:
Science China Life Sciences Aims and scope Submit manuscript

Abstract

On the global scale, hepatitis B virus (HBV) infection is the main cause of hepatocellular carcinoma (HCC) especially in regions of Asia where HBV infection is endemic. Epidemiological studies show that the incidence of inflammation-driven HCC in males is three times as high as in females. Recent studies suggest that sex hormones have a crucial role in the pathogenesis and development of HBV-induced HCC. We found that the estrogen/androgen signaling pathway is associated with decreased/increased transcription and replication of HBV genes and can promote the development of HBV infections by up/downregulating HBV RNA transcription and inflammatory cytokines levels, which in turn slow down the progression of HBV-induced HCC. Additionally, sex hormones can also affect HBV-related HCC by inducing epigenetic changes. The evidence that both morphology and function of the human liver are affected by sex hormones was found over 60 years ago. However, the underlying molecular mechanism largely remains to be elucidated. This review focuses mainly on the molecular mechanisms behind the sex difference in HCC associated with HBV and other factors. In addition, several potential treatment and therapeutic strategies for inflammation-driven HCC will be introduced in this review.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Ahmed, H.H., Shousha, W.G., Shalby, A.B., El-Mezayen, H.A., Ismaiel, N.N., and Mahmoud, N.S. (2015). Implications of sex hormone receptor gene expression in the predominance of hepatocellular carcinoma in males: role of natural products. Asian Pac J Cancer Prev 16, 4949–4954.

    Article  PubMed  Google Scholar 

  • Anbalagan, M., and Rowan, B.G. (2015). Estrogen receptor alpha phosphorylation and its functional impact in human breast cancer. Mol Cell Endocrinol 418 Pt 3, 264–272.

    Article  CAS  PubMed  Google Scholar 

  • Ao, J., Meng, J., Zhu, L., Nie, H., Yang, C., Li, J., Gu, J., Lin, Q., Long, W., Dong, X., and Li, C. (2012). Activation of androgen receptor induces ID1 and promotes hepatocellular carcinoma cell migration and invasion. Mol Oncol 6, 507–515.

    Article  CAS  PubMed  Google Scholar 

  • Baig, S. (2009). Gender disparity in infections of Hepatitis B virus. J Coll Physicians Surg Pak 19, 598–600.

    PubMed  Google Scholar 

  • Bosch, F.X., Ribes, J., Diaz, M., and Cleries, R. (2004). Primary liver cancer: worldwide incidence and trends. Gastroenterology 127, S5–S16.

    Article  PubMed  Google Scholar 

  • Bouchard, M.J., Wang, L., and Schneider, R.J. (2006). Activation of focal adhesion kinase by hepatitis B virus HBx protein: multiple functions in viral replication. J Virol 80, 4406–4414.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carruba, G. (2009). Aromatase in nontumoral and malignant human liver tissues and cells. Ann N Y Acad Sci 1155, 187–193.

    Article  CAS  PubMed  Google Scholar 

  • Cha, M.Y., Kim, C.M., Park, Y.M., and Ryu, W.S. (2004). Hepatitis B virus X protein is essential for the activation of Wnt/beta-catenin signaling in hepatoma cells. Hepatology 39, 1683–1693.

    Article  CAS  PubMed  Google Scholar 

  • Chen, C.J., Yang, H.I., and Iloeje, U.H. (2009). Hepatitis B virus DNA levels and outcomes in chronic hepatitis B. Hepatology 49, S72–84.

    Article  CAS  PubMed  Google Scholar 

  • Chen, G.G., Lee, J.F., Wang, S.H., Chan, U.P., Ip, P.C., and Lau, W.Y. (2002). Apoptosis induced by activation of peroxisome-proliferator activated receptor-gamma is associated with Bcl-2 and NF-kappaB in human colon cancer. Life Sci 70, 2631–2646.

    Article  CAS  PubMed  Google Scholar 

  • Chen, J.J., Tang, Y.S., Huang, S.F., Ai, J.G., Wang, H.X., and Zhang, L.P. (2015). HBx protein-induced upregulation of microRNA-221 promotes aberrant proliferation in HBVrelated hepatocellular carcinoma by targeting estrogen receptor-alpha. Oncol Rep 33, 792–798.

    CAS  PubMed  Google Scholar 

  • Chen, P.J., Yeh, S.H., Liu, W.H., Lin, C.C., Huang, H.C., Chen, C.L., and Chen, D.S. (2012). Androgen pathway stimulates microRNA-216a transcription to suppress the tumor suppressor in lung cancer-1 gene in early hepatocarcinogenesis. Hepatology 56, 632–643.

    Article  CAS  PubMed  Google Scholar 

  • Chiu, C.M., Yeh, S.H., Chen, P.J., Kuo, T.J., Chang, C.J., Yang, W.J., and Chen, D.S. (2007). Hepatitis B virus X protein enhances androgen receptor-responsive gene expression depending on androgen level. Proc Natl Acad Sci USA 104, 2571–2578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chu, J.S., Ge, F.J., Zhang, B., Wang, Y., Silvestris, N., Liu, L.J., Zhao, C.H., Lin, L., Brunetti, A.E., Fu, Y.L., Wang, J., Paradiso, A., and Xu, J.M. (2013). Expression and prognostic value of VEGFR-2, PDGFR-beta, and c-Met in advanced hepatocellular carcinoma. J Exp Clin Cancer Res 32, 16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ciarrocchi, A., Piana, S., Valcavi, R., Gardini, G., and Casali, B. (2011). Inhibitor of DNA binding-1 induces mesenchymal features and promotes invasiveness in thyroid tumour cells. Eur J Cancer 47, 934–945.

    Article  CAS  PubMed  Google Scholar 

  • Cocciadiferro, L., Miceli, V., Granata, O.M., and Carruba, G. (2016). Merlin, the product of NF2 gene, is associated with aromatase expression and estrogen formation in human liver tissues and liver cancer cells. J Steroid Biochem Mol Biol doi: 10.1016/j.jsbmb.2016.05.023.

    Google Scholar 

  • Deng, L., Yang, H., Tang, J., Lin, Z., Yin, A., Gao, Y., Wang, X., Jiang, R., and Sun, B. (2015). Inhibition of MTA1 by ERalpha contributes to protection hepatocellular carcinoma from tumor proliferation and metastasis. J Exp Clin Cancer Res 34, 128.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ding, Q., Xia, W., Liu, J.C., Yang, J.Y., Lee, D.F., Xia, J., Bartholomeusz, G., Li, Y., Pan, Y., Li, Z., Bargou, R.C., Qin, J., Lai, C.C., Tsai, F.J., Tsai, C.H., and Hung, M.C. (2005). Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin. Mol Cell 19, 159–170.

    Article  CAS  PubMed  Google Scholar 

  • Du, B., Wang, S.Y., Shi, X.F., Zhang, C.F., and Zhang, Z.Z. (2011). The effect of 2-methoxyestradiol liposome on growth inhibition, angiogenesis and expression of VEGF and Ki67 in mice bearing H22 hepatocellular carcinoma. Tumori 97, 660–665.

    CAS  PubMed  Google Scholar 

  • El-Serag, H.B., and Rudolph, K.L. (2007). Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132, 2557–2576.

    Article  CAS  PubMed  Google Scholar 

  • El Naga, R.N., El-Demerdash, E., Youssef, S.S., Abdel-Naim, A.B., and El-Merzabani, M. (2009). Cytotoxic effects of 2-methoxyestradiol in the hepatocellular carcinoma cell line HepG2. Pharmacology 84, 9–16.

    Article  PubMed  CAS  Google Scholar 

  • Farinati, F., De Maria, N., Marafin, C., Fagiuoli, S., Della Libera, G., and Naccarato, R. (1995). Hepatocellular carcinoma in alcoholic cirrhosis: is sex hormone imbalance a pathogenetic factor? Eur J Gastroenterol Hepatol 7, 145–150.

    CAS  PubMed  Google Scholar 

  • Feng, H., Cheng, A.S., Tsang, D.P., Li, M.S., Go, M.Y., Cheung, Y.S., Zhao, G.J., Ng, S.S., Lin, M.C., Yu, J., Lai, P.B., To, K.F., and Sung, J.J. (2011). Cell cycle-related kinase is a direct androgen receptor-regulated gene that drives beta-catenin/T cell factor-dependent hepatocarcinogenesis. J Clin Invest 121, 3159–3175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Freise, C., Ruehl, M., Seehofer, D., Hoyer, J., and Somasundaram, R. (2013). The inhibitor of Ca2+-dependent K+ channels TRAM-34 blocks growth of hepatocellular carcinoma cells via downregulation of estrogen receptor alpha mRNA and nuclear factor-kappaB. Invest New Drugs 31, 452–457.

    Article  CAS  PubMed  Google Scholar 

  • Gailhouste, L., and Ochiya, T. (2013). Cancer-related microRNAs and their role as tumor suppressors and oncogenes in hepatocellular carcinoma. Histol Histopathol 28, 437–451.

    CAS  PubMed  Google Scholar 

  • Galbiati, E., Caruso, P.L., Amari, G., Armani, E., Ghirardi, S., Delcanale, M., and Civelli, M. (2002). Pharmacological actions of a novel, potent, tissue-selective benzopyran estrogen. J Pharmacol Exp Ther 303, 196–203.

    Article  CAS  PubMed  Google Scholar 

  • Gao, J., Ding, F., Liu, Q., and Yao, Y. (2013). Knockdown of MACC1 expression suppressed hepatocellular carcinoma cell migration and invasion and inhibited expression of MMP2 and MMP9. Mol Cell Biochem 376, 21–32.

    Article  CAS  PubMed  Google Scholar 

  • Giannitrapani, L., Soresi, M., La Spada, E., Cervello, M., D’Alessandro, N., and Montalto, G. (2006). Sex hormones and risk of liver tumor. Ann N Y Acad Sci 1089, 228–236.

    Article  CAS  PubMed  Google Scholar 

  • Gramantieri, L., Fornari, F., Callegari, E., Sabbioni, S., Lanza, G., Croce, C.M., Bolondi, L., and Negrini, M. (2008). MicroRNA involvement in hepatocellular carcinoma. J Cell Mol Med 12, 2189–2204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hamatsu, T., Rikimaru, T., Yamashita, Y., Aishima, S., Tanaka, S., Shirabe, K., Shimada, M., Toh, Y., and Sugimachi, K. (2003). The role of MTA1 gene expression in human hepatocellular carcinoma. Oncol Rep 10, 599–604.

    CAS  PubMed  Google Scholar 

  • Hartwell, H.J., Petrosky, K.Y., Fox, J.G., Horseman, N.D., and Rogers, A.B. (2014). Prolactin prevents hepatocellular carcinoma by restricting innate immune activation of c-Myc in mice. Proc Natl Acad Sci USA 111, 11455–11460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hirankarn, N., Kimkong, I., Kummee, P., Tangkijvanich, P., and Poovorawan, Y. (2006). Interleukin-1beta gene polymorphism associated with hepatocellular carcinoma in hepatitis B virus infection. World J Gastroenterol 12, 776–779.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hou, J., Xu, J., Jiang, R., Wang, Y., Chen, C., Deng, L., Huang, X., Wang, X., and Sun, B. (2013). Estrogen-sensitive PTPRO expression represses hepatocellular carcinoma progression by control of STAT3. Hepatology 57, 678–688.

    Article  CAS  PubMed  Google Scholar 

  • Hou, J., Zhou, Y., Zheng, Y., Fan, J., Zhou, W., Ng, I.O., Sun, H., Qin, L., Qiu, S., Lee, J.M., Lo, C.M., Man, K., Yang, Y., Zhang, Q., Zhu, X., Li, N., Wang, Z., Ding, G., Zhuang, S.M., Zheng, L., Luo, X., Xie, Y., Liang, A., Zhang, M., Xia, Q., Liang, T., Yu, Y., and Cao, X. (2014). Hepatic RIG-I predicts survival and interferon-alpha therapeutic response in hepatocellular carcinoma. Cancer Cell 25, 49–63.

    Article  CAS  PubMed  Google Scholar 

  • Huang, F.Y., Wong, D.K., Seto, W.K., Lai, C.L., and Yuen, M.F. (2015). Estradiol induces apoptosis via activation of miRNA-23a and p53: implication for gender difference in liver cancer development. Oncotarget 6, 34941–34952.

    PubMed  PubMed Central  Google Scholar 

  • Iyoda, K., Sasaki, Y., Horimoto, M., Toyama, T., Yakushijin, T., Sakakibara, M., Takehara, T., Fujimoto, J., Hori, M., Wands, J.R., and Hayashi, N. (2003). Involvement of the p38 mitogen-activated protein kinase cascade in hepatocellular carcinoma. Cancer 97, 3017–3026.

    Article  CAS  PubMed  Google Scholar 

  • Jemal, A., Bray, F., Center, M.M., Ferlay, J., Ward, E., and Forman, D. (2011). Global cancer statistics. CA Cancer J Clin 61, 69–90.

    Article  PubMed  Google Scholar 

  • Jiang, L., Shan, J., Shen, J., Wang, Y., Yan, P., Liu, L., Zhao, W., Xu, Y., Zhu, W., Su, L., Chen, J., Cheng, F., Yao, H., Xu, H., Qian, C., and Liang, Z. (2016). Androgen/androgen receptor axis maintains and promotes cancer cell stemness through direct activation of nanog transcription in hepatocellular carcinoma. Oncotarget 7, 36814–36828

    PubMed  PubMed Central  Google Scholar 

  • Jiang, P., Cao, J., and Bai, W.H. (2015). Lentivirus-mediated siRNA targeting ER-alpha inhibits tumorigenesis and induces apoptosis in hepatocarcinoma cells. Biomed Res Int 2015, 490681.

    PubMed  PubMed Central  Google Scholar 

  • Jiang, R., Deng, L., Zhao, L., Li, X., Zhang, F., Xia, Y., Gao, Y., Wang, X., and Sun, B. (2011). miR-22 promotes HBV-related hepatocellular carcinoma development in males. Clin Cancer Res 17, 5593–5603.

    Article  CAS  PubMed  Google Scholar 

  • Jiang, X., Kanda, T., Nakamoto, S., Miyamura, T., Wu, S., and Yokosuka, O. (2014). Involvement of androgen receptor and glucose-regulated protein 78 kDa in human hepatocarcinogenesis. Exp Cell Res 323, 326–336.

    Article  CAS  PubMed  Google Scholar 

  • Kalra, M., Mayes, J., Assefa, S., Kaul, A.K., and Kaul, R. (2008). Role of sex steroid receptors in pathobiology of hepatocellular carcinoma. World J Gastroenterol 14, 5945–5961.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kar, S., Wang, M., and Carr, B.I. (2008). 2-Methoxyestradiol inhibits hepatocellular carcinoma cell growth by inhibiting Cdc25 and inducing cell cycle arrest and apoptosis. Cancer Chemother Pharmacol 62, 831–840.

    Article  CAS  PubMed  Google Scholar 

  • Kaufman, R.J. (1999). Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev 13, 1211–1233.

    Article  CAS  PubMed  Google Scholar 

  • Komyod, W., Bohm, M., Metze, D., Heinrich, P.C., and Behrmann, I. (2007). Constitutive suppressor of cytokine signaling 3 expression confers a growth advantage to a human melanoma cell line. Mol Cancer Res 5, 271–281.

    Article  CAS  PubMed  Google Scholar 

  • Koul, H.K., Pal, M., and Koul, S. (2013). Role of p38 MAP kinase signal transduction in solid tumors. Genes Cancer 4, 342–359.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lai, H.C., Yeh, C.C., Jeng, L.B., Huang, S.F., Liao, P.Y., Lei, F.J., Cheng, W.C., Hsu, C.L., Cai, X., Chang, C., and Ma, W.L. (2016). Androgen receptor mitigates postoperative disease progression of hepatocellular carcinoma by suppressing CD90+ populations and cell migration and by promoting anoikis in circulating tumor cells. Oncotarget 7, 46448–46465.

    PubMed  PubMed Central  Google Scholar 

  • Lee, A.S. (2001). The glucose-regulated proteins: stress induction and clinical applications. Trends Biochem Sci 26, 504–510.

    Article  CAS  PubMed  Google Scholar 

  • Lee, S.A., Kim, H., Won, Y.S., Seok, S.H., Na, Y., Shin, H.B., Inn, K.S., and Kim, B.J. (2015). Male-specific hepatitis B virus large surface protein variant W4P potentiates tumorigenicity and induces gender disparity. Mol Cancer 14, 23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee, T.K., Poon, R.T., Yuen, A.P., Ling, M.T., Wang, X.H., Wong, Y.C., Guan, X.Y., Man, K., Tang, Z.Y., and Fan, S.T. (2006). Regulation of angiogenesis by Id-1 through hypoxia-inducible factor-1alpha-mediated vascular endothelial growth factor up-regulation in hepatocellular carcinoma. Clin Cancer Res 12, 6910–6919.

    Article  CAS  PubMed  Google Scholar 

  • Li, M.Y., Deng, H., Zhao, J.M., Dai, D., and Tan, X.Y. (2003). Peroxisome proliferator-activated receptor gamma ligands inhibit cell growth and induce apoptosis in human liver cancer BEL-7402 cells. World J Gastroenterol 9, 1683–1688.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li, M.Y., Hsin, M.K., Yip, J., Mok, T.S., Underwood, M.J., and Chen, G.G. (2010). PPARgamma activation extinguishes smoking carcinogen by inhibiting NNK-mediated proliferation. Am J Respir Cell Mol Biol 42, 113–122.

    Article  CAS  PubMed  Google Scholar 

  • Li, T., Qin, L.X., Gong, X., Zhou, J., Sun, H.C., Wang, L., Qiu, S.J., Ye, Q.H., and Fan, J. (2014). Clinical characteristics, outcome, and risk factors for early and late intrahepatic recurrence of female patients after curative resection of hepatocellular carcinoma. Surgery 156, 651–660.

    Article  PubMed  Google Scholar 

  • Li, Y., Chao, Y., Fang, Y., Wang, J., Wang, M., Zhang, H., Ying, M., Zhu, X., and Wang, H. (2013). MTA1 promotes the invasion and migration of non-small cell lung cancer cells by downregulating miR-125b. J Exp Clin Cancer Res 32, 33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin, Y.M., Velmurugan, B.K., Yeh, Y.L., Tu, C.C., Ho, T.J., Lai, T.Y., Tsai, C.H., Tsai, F.J., and Huang, C.Y. (2013). Activation of estrogen receptors with E2 downregulates peroxisome proliferator-activated receptor gamma in hepatocellular carcinoma. Oncol Rep 30, 3027–3031.

    CAS  PubMed  Google Scholar 

  • Liu, F., Yuan, J.H., Huang, J.F., Yang, F., Wang, T.T., Ma, J.Z., Zhang, L., Zhou, C.C., Wang, F., Yu, J., Zhou, W.P., and Sun, S.H. (2016). Long noncoding RNA FTX inhibits hepatocellular carcinoma proliferation and metastasis by binding MCM2 and miR-374a. Oncogene 35, 5422–5434.

    Article  CAS  PubMed  Google Scholar 

  • Liu, W.C., and Liu, Q.Y. (2014). Molecular mechanisms of gender disparity in hepatitis B virus-associated hepatocellular carcinoma. World J Gastroenterol 20, 6252–6261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lovat, P.E., Oliverio, S., Ranalli, M., Corazzari, M., Rodolfo, C., Bernassola, F., Aughton, K., Maccarrone, M., Hewson, Q.D., Pearson, A.D., Melino, G., Piacentini, M., and Redfern, C.P. (2002). GADD153 and 12-lipoxygenase mediate fenretinide-induced apoptosis of neuroblastoma. Cancer Res 62, 5158–5167.

    CAS  PubMed  Google Scholar 

  • Ma, W.L., Hsu, C.L., Yeh, C.C., Wu, M.H., Huang, C.K., Jeng, L.B., Hung, Y.C., Lin, T.Y., Yeh, S., and Chang, C. (2012). Hepatic androgen receptor suppresses hepatocellular carcinoma metastasis through modulation of cell migration and anoikis. Hepatology 56, 176–185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma, W.L., Jeng, L.B., Lai, H.C., Liao, P.Y., and Chang, C. (2014). Androgen receptor enhances cell adhesion and decreases cell migration via modulating beta1-integrin-AKT signaling in hepatocellular carcinoma cells. Cancer Lett 351, 64–71.

    Article  CAS  PubMed  Google Scholar 

  • Maeda, S., Kamata, H., Luo, J.L., Leffert, H., and Karin, M. (2005). IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121, 977–990.

    Article  CAS  PubMed  Google Scholar 

  • Matsuda, Y., and Ichida, T. (2006). p16 and p27 are functionally correlated during the progress of hepatocarcinogenesis. Med Mol Morphol 39, 169–175.

    Article  PubMed  Google Scholar 

  • Matsuda, Y., Ichida, T., Genda, T., Yamagiwa, S., Aoyagi, Y., and Asakura, H. (2003). Loss of p16 contributes to p27 sequestration by cyclin D(1)-cyclin-dependent kinase 4 complexes and poor prognosis in hepatocellular carcinoma. Clin Cancer Res 9, 3389–3396.

    CAS  PubMed  Google Scholar 

  • Minn, A.J., Gupta, G.P., Siegel, P.M., Bos, P.D., Shu, W., Giri, D.D., Viale, A., Olshen, A.B., Gerald, W.L., and Massague, J. (2005). Genes that mediate breast cancer metastasis to lung. Nature 436, 518–524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Montalto, G., Cervello, M., Giannitrapani, L., Dantona, F., Terranova, A., and Castagnetta, L.A. (2002). Epidemiology, risk factors, and natural history of hepatocellular carcinoma. Ann N Y Acad Sci 963, 13–20.

    Article  PubMed  Google Scholar 

  • Montella, M., Crispo, A., and Giudice, A. (2011). HCC, diet and metabolic factors: diet and HCC. Hepat Mon 11, 159–162.

    PubMed  PubMed Central  Google Scholar 

  • Moser, C., Lang, S.A., Mori, A., Hellerbrand, C., Schlitt, H.J., Geissler, E.K., Fogler, W.E., and Stoeltzing, O. (2008). ENMD-1198, a novel tubulin-binding agent reduces HIF-1alpha and STAT3 activity in human hepatocellular carcinoma(HCC) cells, and inhibits growth and vascularization in vivo. BMC Cancer 8, 206.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Murakami, S. (2001). Hepatitis B virus X protein: a multifunctional viral regulator. J Gastroenterol 36, 651–660.

    Article  CAS  PubMed  Google Scholar 

  • Nakatani, T., Roy, G., Fujimoto, N., Asahara, T., and Ito, A. (2001). Sex hormone dependency of diethylnitrosamine-induced liver tumors in mice and chemoprevention by leuprorelin. Jpn J Cancer Res 92, 249–256.

    Article  CAS  PubMed  Google Scholar 

  • Naugler, W.E., Sakurai, T., Kim, S., Maeda, S., Kim, K., Elsharkawy, A.M., and Karin, M. (2007). Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317, 121–124.

    Article  CAS  PubMed  Google Scholar 

  • Parkin, D.M., Bray, F., Ferlay, J., and Pisani, P. (2001). Estimating the world cancer burden: Globocan 2000. Int J Cancer 94, 153–156.

    Article  CAS  PubMed  Google Scholar 

  • Persson, I. (2000). Estrogens in the causation of breast, endometrial and ovarian cancers — evidence and hypotheses from epidemiological findings. J Steroid Biochem Mol Biol 74, 357–364.

    Article  CAS  PubMed  Google Scholar 

  • Pok, S., Barn, V.A., Wong, H.J., Blackburn, A.C., Board, P., Farrell, G.C., and Teoh, N.C. (2016). Testosterone regulation of cyclin E kinase: a key factor in determining gender differences in hepatocarcinogenesis. J Gastroenterol Hepatol 31, 1210–1219.

    Article  CAS  PubMed  Google Scholar 

  • Poynard, T., Ratziu, V., Charlotte, F., Goodman, Z., McHutchison, J., and Albrecht, J. (2001). Rates and risk factors of liver fibrosis progression in patients with chronic hepatitis c. J Hepatol 34, 730–739.

    Article  CAS  PubMed  Google Scholar 

  • Ren, J., Chen, G.G., Liu, Y., Su, X., Hu, B., Leung, B.C., Wang, Y., Ho, R.L., Yang, S., Lu, G., Lee, C.G., and Lai, P.B. (2016). Cytochrome P450 1A2 metabolizes 17beta-Estradiol to suppress hepatocellular carcinoma. PLoS One 11, e0153863.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ruggieri, A., Barbati, C., and Malorni, W. (2010). Cellular and molecular mechanisms involved in hepatocellular carcinoma gender disparity. Int J Cancer 127, 499–504.

    Article  CAS  PubMed  Google Scholar 

  • Ryu, S.H., Jang, M.K., Kim, W.J., Lee, D., and Chung, Y.H. (2014). Metastatic tumor antigen in hepatocellular carcinoma: golden roads toward personalized medicine. Cancer Metastasis Rev 33, 965–980.

    Article  CAS  PubMed  Google Scholar 

  • Shen, M., and Shi, H. (2016). Estradiol and estrogen receptor agonists oppose oncogenic actions of leptin in HepG2 cells. PLoS One 11, e0151455.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Shen, N., Gong, J., Wang, Y., Tian, J., Qian, J., Zou, L., Chen, W., Zhu, B., Lu, X., Zhong, R., Guo, A., Wang, L., and Miao, X. (2014). Integrative genomic analysis identifies that SERPINA6-rs1998056 regulated by FOXA/ERalpha is associated with female hepatocellular carcinoma. PLoS One 9, e107246.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Shi, L., Lin, H., Li, G., Jin, R.A., Xu, J., Sun, Y., Ma, W.L., Yeh, S., Cai, X., and Chang, C. (2016a). Targeting androgen receptor (AR)→IL12A signal enhances efficacy of Sorafenib plus NKcells immunotherapy to better suppress HCC progression. Mol Cancer Ther 15, 731–742.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shi, L., Lin, H., Li, G., Sun, Y., Shen, J., Xu, J., Lin, C., Yeh, S., Cai, X., and Chang, C. (2016b). Cisplatin enhances NKcells immunotherapy efficacy to suppress HCC progression via altering the androgen receptor (AR)-ULBP2 signals. Cancer Lett 373, 45–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shuda, M., Kondoh, N., Imazeki, N., Tanaka, K., Okada, T., Mori, K., Hada, A., Arai, M., Wakatsuki, T., Matsubara, O., Yamamoto, N., and Yamamoto, M. (2003). Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ERstress pathway in hepatocarcinogenesis. J Hepatol 38, 605–614.

    Article  CAS  PubMed  Google Scholar 

  • Song, Q., Zhang, H., Wang, M., Song, W., Ying, M., Fang, Y., Li, Y., Chao, Y., and Zhu, X. (2013). MTA1 promotes nasopharyngeal carcinoma growth in vitro and in vivo. J Exp Clin Cancer Res 32, 54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Su, F.H., Chen, J.D., Cheng, S.H., Lin, C.H., Liu, Y.H., and Chu, F.Y. (2007). Seroprevalence of Hepatitis-B infection amongst Taiwanese university students 18 years following the commencement of a national Hepatitis-B vaccination program. J Med Virol 79, 138–143.

    Article  CAS  PubMed  Google Scholar 

  • Su, Y., Gao, L., Teng, L., Wang, Y., Cui, J., Peng, S., and Fu, S. (2013). Id1 enhances human ovarian cancer endothelial progenitor cell angiogenesis via PI3K/Akt and NF-kappaB/MMP-2 signaling pathways. J Transl Med 11, 132.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takahashi, K., Yan, I., Wen, H.J., and Patel, T. (2013). microRNAs in liver disease: from diagnostics to therapeutics. Clin Biochem 46, 946–952.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tian, Y.E., Xie, X.U., Lin, Y., Tan, G., and Zhong, W.U. (2015). Androgen receptor in hepatocarcinogenesis: recent developments and perspectives. Oncol Lett 9, 1983–1988.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tsuei, D.J., Hsu, H.C., Lee, P.H., Jeng, Y.M., Pu, Y.S., Chen, C.N., Lee, Y.C., Chou, W.C., Chang, C.J., Ni, Y.H., and Chang, M.H. (2004). RBMY, a male germ cell-specific RNA-binding protein, activated in human liver cancers and transforms rodent fibroblasts. Oncogene 23, 5815–5822.

    Article  CAS  PubMed  Google Scholar 

  • Tsuei, D.J., Lee, P.H., Peng, H.Y., Lu, H.L., Su, D.S., Jeng, Y.M., Hsu, H.C., Hsu, S.H., Wu, J.F., Ni, Y.H., and Chang, M.H. (2011). Male germ cell-specific RNA binding protein RBMY: a new oncogene explaining male predominance in liver cancer. PLoS One 6, e26948.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tu, C.C., Kumar, V.B., Day, C.H., Kuo, W.W., Yeh, S.P., Chen, R.J., Liao, C.R., Chen, H.Y., Tsai, F.J., Wu, W.J., and Huang, C.Y. (2013). Estrogen receptor alpha (ESR1) over-expression mediated apoptosis in Hep3B cells by binding with SP1 proteins. J Mol Endocrinol 51, 203–212.

    Article  CAS  PubMed  Google Scholar 

  • Villa, E., Camellini, L., Dugani, A., Zucchi, F., Grottola, A., Merighi, A., Buttafoco, P., Losi, L., and Manenti, F. (1995). Variant estrogen receptor messenger RNA species detected in human primary hepatocellular carcinoma. Cancer Res 55, 498–500.

    CAS  PubMed  Google Scholar 

  • Villa, E., Colantoni, A., Camma, C., Grottola, A., Buttafoco, P., Gelmini, R., Ferretti, I., and Manenti, F. (2003). Estrogen receptor classification for hepatocellular carcinoma: comparison with clinical staging systems. J Clin Oncol 21, 441–446.

    Article  CAS  PubMed  Google Scholar 

  • Villa, E., Colantoni, A., Grottola, A., Ferretti, I., Buttafoco, P., Bertani, H., De Maria, N., and Manenti, F. (2002). Variant estrogen receptors and their role in liver disease. Mol Cell Endocrinol 193, 65–69.

    Article  CAS  PubMed  Google Scholar 

  • Villa, E., Dugani, A., Moles, A., Camellini, L., Grottola, A., Buttafoco, P., Merighi, A., Ferretti, I., Esposito, P., Miglioli, L., Bagni, A., Troisi, R., De Hemptinne, B., Praet, M., Callea, F., and Manenti, F. (1998). Variant liver estrogen receptor transcripts already occur at an early stage of chronic liver disease. Hepatology 27, 983–988.

    Article  CAS  PubMed  Google Scholar 

  • Wang, S.H., Yeh, S.H., Lin, W.H., Wang, H.Y., Chen, D.S., and Chen, P.J. (2009). Identification of androgen response elements in the enhancer I of hepatitis B virus: a mechanism for sex disparity in chronic hepatitis B. Hepatology 50, 1392–1402.

    Article  CAS  PubMed  Google Scholar 

  • Wang, Y., Cheng, J., Xu, C., Liu, S., Jiang, S., Xu, Q., Chen, X., Zhuang, H., and Lu, F. (2012a). Quantitative methylation analysis reveals gender and age differences in p16INK4a hypermethylation in hepatitis B virus-related hepatocellular carcinoma. Liver Int 32, 420–428.

    PubMed  Google Scholar 

  • Wang, Y.C., Xu, G.L., Jia, W.D., Han, S.J., Ren, W.H., Wang, W., Liu, W.B., Zhang, C.H., and Chen, H. (2012b). Estrogen suppresses metastasis in rat hepatocellular carcinoma through decreasing interleukin-6 and hepatocyte growth factor expression. Inflammation 35, 143–149.

    Article  PubMed  CAS  Google Scholar 

  • Wang, Z., Zhang, X., Shen, P., Loggie, B.W., Chang, Y., and Deuel, T.F. (2006). A variant of estrogen receptor-{alpha}, hER-{alpha}36: transduction of estrogen- and antiestrogen-dependent membrane-initiated mitogenic signaling. Proc Natl Acad Sci USA 103, 9063–9068.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wei, Q., Guo, P., Mu, K., Zhang, Y., Zhao, W., Huai, W., Qiu, Y., Li, T., Ma, X., Liu, Y., Chen, X., and Han, L. (2015). Estrogen suppresses hepatocellular carcinoma cells through ERbeta-mediated upregulation of the NLRP3 inflammasome. Lab Invest 95, 804–816.

    Article  CAS  PubMed  Google Scholar 

  • Wong, V.W., Yu, J., Cheng, A.S., Wong, G.L., Chan, H.Y., Chu, E.S., Ng, E.K., Chan, F.K., Sung, J.J., and Chan, H.L. (2009). High serum interleukin-6 level predicts future hepatocellular carcinoma development in patients with chronic hepatitis B. Int J Cancer 124, 2766–2770.

    Article  CAS  PubMed  Google Scholar 

  • Yang, M.D., Hsu, C.M., Chang, W.S., Yueh, T.C., Lai, Y.L., Chuang, C.L., Wang, S.C., Jeng, L.B., Ji, H.X., Hsiao, C.L., Wu, C.N., Tsai, C.W., Chung, J.G., and Bau, D.T. (2015). Tumor necrosis factor-alpha genotypes are associated with hepatocellular carcinoma risk in Taiwanese males, smokers and alcohol drinkers. Anticancer Res 35, 5417–5423.

    CAS  PubMed  Google Scholar 

  • Yang, W., Lu, Y., Xu, Y., Xu, L., Zheng, W., Wu, Y., Li, L., and Shen, P. (2012). Estrogen represses hepatocellular carcinoma (HCC) growth via inhibiting alternative activation of tumor-associated macrophages (TAMs). J Biol Chem 287, 40140–40149.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang, W.J., Chang, C.J., Yeh, S.H., Lin, W.H., Wang, S.H., Tsai, T.F., Chen, D.S., and Chen, P.J. (2009). Hepatitis B virus X protein enhances the transcriptional activity of the androgen receptor through c-Src and glycogen synthase kinase-3beta kinase pathways. Hepatology 49, 1515–1524.

    Article  CAS  PubMed  Google Scholar 

  • Yeh, S.H., and Chen, P.J. (2010). Gender disparity of hepatocellular carcinoma: the roles of sex hormones. Oncology 78 Suppl 1, 172–179.

    Article  CAS  PubMed  Google Scholar 

  • Yu, M.W., Yang, Y.C., Yang, S.Y., Cheng, S.W., Liaw, Y.F., Lin, S.M., and Chen, C.J. (2001). Hormonal markers and hepatitis B virus-related hepatocellular carcinoma risk: a nested case-control study among men. J Natl Cancer Inst 93, 1644–1651.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, M., Dai, C., Zhu, H., Chen, S., Wu, Y., Li, Q., Zeng, X., Wang, W., Zuo, J., Zhou, M., Xia, Z., Ji, G., Saiyin, H., Qin, L., and Yu, L. (2011). Cyclophilin A promotes human hepatocellular carcinoma cell metastasis via regulation of MMP3 and MMP9. Mol Cell Biochem 357, 387–395.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, Y., Li, J., Cao, L., Xu, W., and Yin, Z. (2012). Circulating tumor cells in hepatocellular carcinoma: detection techniques, clinical implications, and future perspectives. Semin Oncol 39, 449–460.

    Article  CAS  PubMed  Google Scholar 

  • Zhao, Q., Li, T., Qi, J., Liu, J., and Qin, C. (2014). The miR-545/374a cluster encoded in the Ftx lncRNA is overexpressed in HBV-related hepatocellular carcinoma and promotes tumorigenesis and tumor progression. PLoS One 9, e109782.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhao, Y., and Li, Z. (2015). Interplay of estrogen receptors and FOXA factors in the liver cancer. Mol Cell Endocrinol 418 Pt 3, 334–339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu, Z.Z., Wang, D., Cong, W.M., Jiang, H., Yu, Y., Wen, B.J., Dong, H., Zhang, X., Liu, S.F., Wang, A.Z., Zhu, G., and Hou, L. (2012). Sex-related differences in DNA copy number alterations in hepatitis B virus-associated hepatocellular carcinoma. Asian Pac J Cancer Prev 13, 225–229.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the State Key Project for Liver Cancer (2012ZX10002009), National Natural Science Foundation of China (81301811, 81521091, 81422032, 81272212, 81672860, 81372674, and 91529303), Science Foundation of Shanghai (134119a3700), and Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12010201).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Hong-Yang Wang or Lei Chen.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zheng, B., Zhu, YJ., Wang, HY. et al. Gender disparity in hepatocellular carcinoma (HCC): multiple underlying mechanisms. Sci. China Life Sci. 60, 575–584 (2017). https://doi.org/10.1007/s11427-016-9043-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11427-016-9043-9

Keywords

Navigation