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Androgen activates PEG10 to promote carcinogenesis in hepatic cancer cells

机译：雄激素激活PEG10促进肝癌细胞的癌变

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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.
机译：尚未完全阐明男性受试者中肝细胞癌（HCC）患病率较高的分子机制。在这里，我们报告雄激素受体（AR）在不同的HCC细胞系中差异表达。 AR激动剂二氢睾丸激素（DHT）可增强HCC细胞生长和凋亡抗性。拮抗剂氟他胺（FLU）阻断DHT对HCC细胞系的作用。父本表达的基因10（PEG10）在HCC细胞系中以高水平表达。通过在表达AR和PEG10的BEL-7404肝癌细胞和HuH7肝癌细胞（HuH7）细胞中使用针对AR和PEG10的小干扰RNA，并在缺少AR和表达PEG10的HepG2细胞中使用AR转染技术，我们已经证实上调和激活PEG10，DHT可增强HCC细胞生长和凋亡抗性。我们进一步证明，DHT以PEG10依赖性方式上调HCC细胞系中人端粒酶逆转录酶（hTERT）的表达。此外，AR在体内直接与HCC细胞系中PEG10基因的启动子和外显子2区域中的雄激素响应元件相互作用。 DHT通过PEG10激活促进体内裸鼠肝癌的形成。 AR拮抗剂（FLU和丙戊酸盐）抑制肝癌的形成。这些发现表明PEG10在肝癌发生中起重要作用。 PEG10抑制可能是治疗HCC的新方法。

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