Phosphorylation of androgen receptor by mTORC1 promotes liver steatosis and tumorigenesis.
Phosphorylation of androgen receptor by mTORC1 promotes liver steatosis and tumorigenesis.
复制标题
mTORC1 磷酸化雄激素受体可促进肝脏脂肪变性和肿瘤发生。
DOI：
10.1002/hep.32120
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发表时间：
2022-05
期刊：
影响因子：
13.5
通讯作者：
Wang, Hui-Yun
中科院分区：
文献类型：
--
作者：
Ren, Qian-Nan;Zhang, Hong;Sun, Chao-Yue;Zhou, Yu-Feng;Yang, Xue-Feng;Long, Jian-Wu;Li, Xiao-Xing;Mai, Shi-Juan;Zhang, Mei-Yin;Zhang, Hui-Zhong;Mai, Hai-Qiang;Chen, Min-Shan;Zheng, X. F. Steven;Wang, Hui-Yun
雄激素受体(AR)在人类前列腺癌的发生发展中起着重要作用。肝细胞癌也以男性为主，但AR在肝癌中的作用仍知之甚少。雷帕霉素复合体1的机制靶点(MTORC1)也被报道在肝细胞癌中高度激活。在本研究中，我们旨在探讨AR磷酸化在肝癌发生中的作用及其与mTORC1的关系。在体外实验中，我们观察到mTORC1与肝脏AR相互作用，并在S96响应于肝癌细胞的营养和有丝分裂刺激而将其磷酸化。S96的磷酸化促进了AR的稳定性、核定位和转录活性，促进了肝细胞的从头脂肪生成和增殖，并与雄激素单独和协同地诱导小鼠肝脏脂肪变性和肝癌发生。此外，在人类肝脏脂肪变性和肝细胞癌组织中观察到ARS96的高磷酸化，并与总生存期和无病生存期相关，这已被证明是肝细胞癌患者的独立生存预测因子。通过mTORC1AR-S96的磷酸化，可以独立地和雄激素协同作用推动肝脏脂肪变性和肝细胞癌的发生和发展，这不仅解释了为什么肝细胞癌偏重于男性，而且为预防和治疗肝细胞癌提供了靶分子，也为肝细胞癌患者提供了一个潜在的生存预测因子。
Androgen receptor (AR) has been reported to play an important role in the development and progression of man’s prostate cancer. Hepatocellular carcinoma (HCC) is also male‐dominant, but the role of AR in HCC remains poorly understood. Mechanistic target of rapamycin complex 1 (mTORC1) also has been reported to be highly activated in HCC. In this study, we aimed to explore the role of AR phosphorylation and its relationship with mTORC1 in hepatocarcinogenesis. In vitro experiment, we observed that mTORC1 interacts with hepatic AR and phosphorylates it at S96 in response to nutrient and mitogenic stimuli in HCC cells. S96 phosphorylation promotes the stability, nuclear localization, and transcriptional activity of AR, which enhances de novo lipogenesis and proliferation in hepatocytes and induces liver steatosis and hepatocarcinogenesis in mice independently and cooperatively with androgen. Furthermore, high ARS96 phosphorylation is observed in human liver steatotic and HCC tissues and is associated with overall survival and disease‐free survival, which has been proven as an independent survival predictor for patients with HCC. AR S96 phosphorylation by mTORC1 drives liver steatosis and HCC development and progression independently and cooperatively with androgen, which not only explains why HCC is man‐biased but also provides a target molecule for prevention and treatment of HCC and a potential survival predictor in patients with HCC.
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影响因子：
29.4
作者：
El-Serag HB
通讯作者：
El-Serag HB
影响因子：
5.8
作者：
SHECKTER, CB;MATSUMOTO, AM;BREMNER, WJ
通讯作者：
BREMNER, WJ
影响因子：
16
作者：
Düvel K;Yecies JL;Menon S;Raman P;Lipovsky AI;Souza AL;Triantafellow E;Ma Q;Gorski R;Cleaver S;Vander Heiden MG;MacKeigan JP;Finan PM;Clish CB;Murphy LO;Manning BD
通讯作者：
Manning BD
影响因子：
2
作者：
Kubrusly, Marcia Saldanha;Correa-Giannella, Maria Lucia;Carneiro D'Albuquerque, Luiz Augusto
通讯作者：
Carneiro D'Albuquerque, Luiz Augusto
影响因子：
25.7
作者：
Li L;Pilo GM;Li X;Cigliano A;Latte G;Che L;Joseph C;Mela M;Wang C;Jiang L;Ribback S;Simile MM;Pascale RM;Dombrowski F;Evert M;Semenkovich CF;Chen X;Calvisi DF
通讯作者：
Calvisi DF