Androgen activates PEG10 to promote carcinogenesis in hepatic cancer cells (Retracted article. See vol. 30, pg. 2798, 2011)
Androgen activates PEG10 to promote carcinogenesis in hepatic cancer cells (Retracted article. See vol. 30, pg. 2798, 2011)
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雄激素激活PEG10促进肝癌细胞癌变
DOI：
10.1038/sj.onc.1210362
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发表时间：
2007-08-01
期刊：
影响因子：
8
通讯作者：
Jinquan, T.
中科院分区：
文献类型：
--
作者：
Jie, X.;Lang, C.;Jinquan, T.
肝细胞癌（HCC）男性发病率高的分子机制尚未完全阐明。在这里，我们报告，雄激素受体（AR）的差异表达在不同的肝癌细胞系。AR激动剂二氢睾酮（DHT）增强HCC细胞生长和抗凋亡。拮抗剂氟替卡松（FLU）阻断DHT对HCC细胞系的作用。父系表达基因10（PEG 10）在肝癌细胞系中以相当高的水平表达。在表达AR和PEG 10的BEL-7404肝癌细胞和HuH 7肝癌细胞（HuH 7）中使用针对AR和PEG 10的小干扰RNA，以及在缺乏AR和表达PEG 10的HepG 2细胞中使用AR转染技术，我们已经证实，通过上调和激活PEG 10，DHT增强HCC细胞的生长和抗凋亡。我们进一步证明了DHT以PEG 10依赖的方式上调HCC细胞系中人端粒酶逆转录酶（hTERT）的表达。此外，在肝癌细胞系中，AR直接与PEG 10基因启动子和外显子2区域的雄激素反应元件相互作用。DHT通过激活PEG 10促进裸鼠体内肝癌形成。AR拮抗剂（FLU和丙戊酸盐）抑制肝癌形成。这些结果表明，PEG 10在肝癌发生中起着重要作用。PEG 10抑制剂可能成为治疗HCC的新途径。
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.