雄激素是男性肝癌高发的罪魁祸首

http://www.nature.com/onc/journal/v26/n39/abs/1210362a.html

Androgen activates PEG10 to promote carcinogenesis in hepatic cancer cells

The molecular mechanism of striking higher prevalence of hepatocellular carcinoma (HCC) in male subjects has not yet been fully elucidated. Here, we report that androgen receptor (AR) is differentially expressed in different HCC cell lines. AR agonist dihydrotestosterone (DHT) enhances HCC cell growth and apoptotic resistance. Antagonist flutamide (FLU) blocks the effects of DHT on the HCC cell lines. Paternally expressed gene 10 (PEG10) is expressed in HCC cell lines at substantial high level. Using small interfering RNAs against AR and PEG10 in AR- and PEG10-expressing BEL-7404 hepatoma cells and HuH7 hepatoma cells (HuH7) cells, and AR-transfection technique in AR-lacking and PEG10-expressing HepG2 cells, we have confirmed that through upregulation and activation of PEG10, DHT enhances HCC cell growth and apoptotic resistance. We have further demonstrated that DHT upregulates expression of human telomerase reverse transcriptase (hTERT) in HCC cell lines in a PEG10-dependent manner. Moreover, AR directly interacts in vivo with androgen-responsive elements in the regions of promoter and exon 2 of PEG10 gene in HCC cell lines. DHT promotes the hepatoma formation in vivo nude mice through PEG10 activation. AR antagonists (FLU and valproate) inhibit the hepatoma formation. These findings suggest that PEG10 plays an essential role in hepatocarcinogenesis. The PEG10 inhibition can be a novel approach for therapy of HCC.
男性高发肝细胞癌分子机制尚未阐明。我们研究发现，雄激素受体（AR）在不同的肝细胞系中存在表达差异。雄激素受体激动剂双氢睾酮（DHT）促进肝细胞癌细胞株生长并增强其抗凋亡能力；而拮抗剂氟他胺可阻断双氢睾酮的作用。肝细胞癌细胞株管家基因10（PEG10）表达水平较高。在表达AR和PEG10的肝癌细胞株BEL-7404和HuH7通过针对AR和PEG10的小干扰RNA，在不表达AR但有PEG10基因表达的HepG2细胞株通过AR基因转染，我们验证了双氢睾酮通过上调、激活PEG10基因表达来促进肝癌细胞生长并提高抗凋亡能力。我们进一步的研究证明，在肝癌细胞株中DHT依赖PEG10上调人端粒酶逆转录酶（hTERT）表达。此外，在肝癌细胞株中雄激素受体直接作用于PEG10基因的雄激素应答元件——启动子和外显子2区域。在裸鼠体内双氢睾酮通过PEG10激活促进肝肿瘤形成；雄激素受体拮抗剂（氟他胺和丙戊酸盐）抑制肝脏肿瘤形成。这些研究结果表明，PEG10在肝细胞癌发生中起关键作用。PEG10基因抑制有望成为肝细胞癌治疗的新靶点。