Liu Chang, Ren Yi-Fan, Dong Jian, Ke Meng-Yun, Ma Feng, Monga Satdarshan P S, Wu Rongqian, Lv Yi, Zhang Xu-Feng
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.
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.
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.
性别影响多种癌症的风险、治疗反应及预后。肝细胞癌（HCC）发生过程中性别差异的机制仍不清楚。Y染色体性别决定区（SRY）在约84%的男性HCC患者中过表达。此外，我们首次构建了雄性特异性基因SRY过表达的肝脏特异性转基因（TG）小鼠模型。在第14天对TG和野生型（WT）雌雄小鼠进行单次腹腔注射N-亚硝基二乙胺（DEN），并在不同时间点（6 - 13.5个月）处死。与年龄和性别匹配的WT相比，雄性TG中SRY的过表达以及雌性TG肝脏中SRY的异位表达促进了DEN诱导的肝癌发生。两性TG中这种加速的肿瘤发生是损伤和炎症增加、纤维化以及肝细胞增殖的代偿性增强的结果，这继发于下游靶点Sox9和血小板衍生生长因子受体α（PDGFRα）/磷脂酰肌醇3激酶（PI3K）/Akt以及c-myc/细胞周期蛋白D1的激活。总之，SRY及其下游Sox9和PDGFRα途径的激活共同参与男性肝癌发生，这为HCC的性别差异和性别特异性治疗策略提供了新的见解。
