Activation of SRY accounts for male-specific hepatocarcinogenesis: Implication in gender disparity of hepatocellular carcinoma

Cancer Lett. 2017 Dec 1;410:20-31. doi: 10.1016/j.canlet.2017.09.013. Epub 2017 Sep 21.


Sex affects the risk, treatment responses and outcome of many types of cancers. The mechanism of gender disparity in development of hepatocellular carcinoma (HCC) remains obscure. Sex-determining region on Y chromosome (SRY) was overexpressed in approximate 84% male patient HCC. Moreover, we are the first to generate a liver-specific transgenic (TG) murine model with overexpression of the male specific gene SRY. Subject to a single intraperitoneal injection N-nitrosodiethylamine (DEN) at day 14, TG and wildtype (WT) mice of both genders were sacrificed at different time points (6-13.5 months). Overexpression of SRY in male TG and ectopic expression of SRY in female TG livers promoted DEN-induced hepatocarcinogenesis compared to age- and sex-matched WT. This accelerated tumorigenesis in TG of both genders was a consequence of increased injury and inflammation, fibrosis, and compensatory enhancement in hepatocytes proliferation secondary to activation of downstream targets Sox9 and platelet-derived growth factor receptor α (PDGFRα)/phosphoinositide 3-kinase (PI3K)/Akt and c-myc/CyclinD1. In conclusion, activation of SRY and its downstream Sox9 and PDGFRα pathways are commonly involved in male hepatocarcinogenesis, which provides novel insights into gender disparity and sex-specific therapeutic strategies of HCC.

Keywords: Liver; Sex; Sex-determining region on Y chromosome; Sox9; Transgenic.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / chemically induced
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Cyclin D1 / metabolism
  • Diethylnitrosamine
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease
  • Health Status Disparities*
  • Humans
  • Liver Neoplasms / chemically induced
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Phenotype
  • Phosphatidylinositol 3-Kinase / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-myc / metabolism
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • SOX9 Transcription Factor / metabolism
  • Sex Factors
  • Sex-Determining Region Y Protein / genetics
  • Sex-Determining Region Y Protein / metabolism*
  • Signal Transduction
  • Time Factors
  • Tumor Microenvironment
  • Up-Regulation


  • Ccnd1 protein, mouse
  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • SOX9 Transcription Factor
  • SRY protein, human
  • Sex-Determining Region Y Protein
  • Sox9 protein, mouse
  • Sry protein, mouse
  • Cyclin D1
  • Diethylnitrosamine
  • Phosphatidylinositol 3-Kinase
  • Receptor, Platelet-Derived Growth Factor alpha
  • Proto-Oncogene Proteins c-akt