Due to its intricate heterogeneity and limited treatment, hepatocellular carcinoma (HCC) has been considered a major cause of cancer-related mortality worldwide. Increasing evidence indicates that G-protein-coupled estrogen receptor 1 (GPER1) can promote estrogen-dependent hepatocellular proliferation by activating AKT signaling. The mTOR complex 2 (mTORC2), whose integrity and activity are modulated by its subunit Sin1, controls the activation of AKT by phosphorylation at position S473. In this study, we investigate the modulation of Sin1 and how estrogen signaling may influence the mTORC2–AKT cascade in HCC cells and a DEN-induced mouse model. We have found that estradiol-dependent Sin1 expression is transcriptionally modulated by GPER1 as well as ERα. GPER1 is able to regulate Sin1 stability via nuclear translocation, therefore increasing Sin1–mTORC2–AKT activation. Moreover, Sin1 interacts with ERα and further enhances its transcriptional activity. Sin1 is highly expressed in acute liver injury and in cases of HCC harboring high expression of GPER1 and constitutive activation of mTORC2–AKT signaling. GPER1 inhibition using the antagonist G-15 reverses DEN-induced acute liver injury by suppressing Sin1 expression and mTORC2–AKT activation. Notably, SIN1 expression varies between male and female mice in the context of both liver injury and liver cancer. In addition, high SIN1 expression is predictive of good prognosis in both male and female patients with HCC who are free from hepatitis virus infection and who report low alcohol consumption. Hence, here we demonstrate that Sin1 can be regulated by GPER1 both through nongenomic and indirect genomic signaling. Implications: This study suggests that Sin1 may be a novel HCC biomarker which is gender-dependent and sensitive to particular risk factor.

中文翻译：

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G-偶联雌激素受体 1 通过调节 SIN1 和 mTOR 复合物 2 活性促进肝细胞癌的性别差异

由于其复杂的异质性和有限的治疗，肝细胞癌 (HCC) 已被认为是全球癌症相关死亡的主要原因。越来越多的证据表明 G 蛋白偶联雌激素受体 1 (GPER1) 可以通过激活 AKT 信号促进雌激素依赖性肝细胞增殖。mTOR 复合物 2 (mTORC2) 的完整性和活性受其亚基 Sin1 调节，通过 S473 位点的磷酸化控制 AKT 的激活。在这项研究中，我们研究了 Sin1 的调节以及雌激素信号如何影响 HCC 细胞和 DEN 诱导的小鼠模型中的 mTORC2-AKT 级联反应。我们发现雌二醇依赖性 Sin1 表达受 GPER1 和 ERα 的转录调节。GPER1 能够通过核易位调节 Sin1 的稳定性，因此增加了 Sin1-mTORC2-AKT 的激活。此外，Sin1 与 ERα 相互作用并进一步增强其转录活性。Sin1 在急性肝损伤和 GPER1 高表达和 mTORC2-AKT 信号的组成型激活的 HCC 病例中高表达。使用拮抗剂 G-15 抑制 GPER1 通过抑制 Sin1 表达和 mTORC2-AKT 激活逆转 DEN 诱导的急性肝损伤。值得注意的是，在肝损伤和肝癌的背景下，雄性和雌性小鼠的 SIN1 表达不同。此外，高 SIN1 表达预示着男性和女性 HCC 患者的良好预后，这些患者没有肝炎病毒感染并且报告低饮酒量。因此，在这里我们证明 Sin1 可以通过非基因组和间接基因组信号被 GPER1 调节。