Activation of SRY accounts for male-specific hepatocarcinogenesis: Implication in gender disparity of hepatocellular carcinoma
Activation of SRY accounts for male-specific hepatocarcinogenesis: Implication in gender disparity of hepatocellular carcinoma
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SRY 的激活导致男性特异性肝癌发生：对肝细胞癌性别差异的影响。
DOI：
10.1016/j.canlet.2017.09.013
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发表时间：
2017-12-01
期刊：
影响因子：
9.7
通讯作者：
Zhang, Xu-Feng
中科院分区：
文献类型：
--
作者：
Liu, Chang;Ren, Yi-Fan;Zhang, Xu-Feng
性别影响许多类型癌症的风险、治疗反应和结果。肝细胞癌发生发展过程中的性别差异机制尚不清楚。Y染色体性别决定区(SRY)在大约84%的男性肝细胞癌中过度表达。此外，我们还首次建立了男性特异性基因SRY过表达的肝脏特异性转基因(TG)小鼠模型。于第14天一次性腹腔注射N-亚硝酸二乙胺(DEN)，于不同时间点(6~13.5月龄)处死TG小鼠和野生型(WT)小鼠。与年龄和性别匹配的WT相比，男性TG中SRY的过度表达和女性TG肝脏中SRY的异位表达促进了DEN诱导的肝癌的发生。无论男女，TG中肿瘤形成的加速是由于损伤和炎症、纤维化的增加，以及下游靶基因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和c-myc/Cycld1的激活继而导致肝细胞增殖的代偿性增强。总之，SRY及其下游的SOX9和PDGFRα通路的激活通常与男性肝癌的发生有关，这为研究肝癌的性别差异和性别特异性治疗策略提供了新的见解。(C)2017爱思唯尔B.V.保留所有权利。
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 alpha (PDGFR alpha)/phosphoinositide 3-kinase (PI3K)/Akt and c-myc/CyclinD1. In conclusion, activation of SRY and its downstream Sox9 and PDGFR alpha pathways are commonly involved in male hepatocarcinogenesis, which provides novel insights into gender disparity and sex-specific therapeutic strategies of HCC. (C) 2017 Elsevier B.V. All rights reserved.