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

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

Author information

1
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China; Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China; Shaanxi Provincial Regenerative Medicine and Surgical Engineering Research Center, Xi'an, Shaanxi Province, 710061, China.
2
Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China; Shaanxi Provincial Regenerative Medicine and Surgical Engineering Research Center, Xi'an, Shaanxi Province, 710061, China.
3
Department of Pathology and Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
4
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China; Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China; Shaanxi Provincial Regenerative Medicine and Surgical Engineering Research Center, Xi'an, Shaanxi Province, 710061, China. Electronic address: luyi169@126.com.
5
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China; Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China; Shaanxi Provincial Regenerative Medicine and Surgical Engineering Research Center, Xi'an, Shaanxi Province, 710061, China. Electronic address: xfzhang125@126.com.

Abstract

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

PMID:
28942012
DOI:
10.1016/j.canlet.2017.09.013
[Indexed for MEDLINE]

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