Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cell. 2012 Jan 20;148(1-2):72-83. doi: 10.1016/j.cell.2011.11.026.
Hepatocellular carcinoma (HCC) is sexually dimorphic in both rodents and humans, with significantly higher incidence in males, an effect that is dependent on sex hormones. The molecular mechanisms by which estrogens prevent and androgens promote liver cancer remain unclear. Here, we discover that sexually dimorphic HCC is completely reversed in Foxa1- and Foxa2-deficient mice after diethylnitrosamine-induced hepatocarcinogenesis. Coregulation of target genes by Foxa1/a2 and either the estrogen receptor (ERα) or the androgen receptor (AR) was increased during hepatocarcinogenesis in normal female or male mice, respectively, but was lost in Foxa1/2-deficient mice. Thus, both estrogen-dependent resistance to and androgen-mediated facilitation of HCC depend on Foxa1/2. Strikingly, single nucleotide polymorphisms at FOXA2 binding sites reduce binding of both FOXA2 and ERα to their targets in human liver and correlate with HCC development in women. Thus, Foxa factors and their targets are central for the sexual dimorphism of HCC.
肝细胞癌（HCC）在啮齿动物和人类中存在性别二态性，男性发病率明显更高，这种效应依赖于性激素。雌激素预防和雄激素促进肝癌的分子机制尚不清楚。在这里，我们发现，在二乙基亚硝胺诱导的肝癌发生后，Foxa1 和 Foxa2 缺陷小鼠中的性别二态性 HCC 完全逆转。在正常雌性或雄性小鼠的肝癌发生过程中，Foxa1/a2 与雌激素受体（ERα）或雄激素受体（AR）共同调控靶基因的表达分别增加，但在 Foxa1/2 缺陷小鼠中丢失。因此，雌激素依赖性抵抗和雄激素介导的 HCC 促进均依赖于 Foxa1/2。引人注目的是，FOXA2 结合位点的单核苷酸多态性降低了 FOXA2 和 ERα 与其在人类肝脏中靶标的结合，并与女性 HCC 的发生相关。因此，Foxa 因子及其靶标是 HCC 性别二态性的核心。
