Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer.
Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer.
复制标题
DOI：
10.1016/j.cell.2011.11.026
复制
发表时间：
2012-01-20
期刊：
影响因子：
64.5
通讯作者：
Kaestner KH
中科院分区：
文献类型：
--
作者：
Li Z;Tuteja G;Schug J;Kaestner KH
肝细胞癌（HCC）在啮齿类动物和人类中具有性别二型性，男性的发病率显著较高，这一效应依赖于性激素。雌激素预防肝癌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Foxa 1-和Foxa 2-缺陷小鼠中，二乙基亚硝胺诱导的肝癌发生后，性二态性HCC完全逆转。在正常雌性或雄性小鼠的肝癌发生过程中，Foxa 1/a2与雌激素受体（ERα）或雄激素受体（AR）的靶基因的共调节分别增加，但在Foxa 1/2缺陷小鼠中丧失。因此，雌激素依赖性肝癌抵抗和雄激素介导的促进作用都依赖于Foxa 1/2。引人注目的是，FOXA 2结合位点的单核苷酸多态性减少了FOXA 2和ERα与人类肝脏靶点的结合，并与女性HCC的发生相关。因此，Foxa因子及其靶点是HCC性别二型性的核心。
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. Co-regulation 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.
登录
查看更多内容
影响因子：
4
作者：
Kaestner, Klaus H.
通讯作者：
Kaestner, Klaus H.
DOI：
10.1016/j.bbrc.2007.11.069
发表时间：
2008-01-25
影响因子：
3.1
作者：
Liu, Zhilin;Ukomadu, Chinweike
通讯作者：
Ukomadu, Chinweike
影响因子：
3.3
作者：
Chen, X;Cheung, ST;Brown, PO
通讯作者：
Brown, PO
影响因子：
5.2
作者：
May, Randal;Sureban, Sripathi M.;Hoang, Nguyet;Riehl, Terrence E.;Lightfoot, Stan A.;Ramanujam, Rama;Wyche, James H.;Anant, Shrikant;Houchen, Courtney W.
通讯作者：
Houchen, Courtney W.
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK