Dampened VEPH1 activates mTORC1 signaling by weakening the TSC1/TSC2 association in hepatocellular carcinoma
Dampened VEPH1 activates mTORC1 signaling by weakening the TSC1/TSC2 association in hepatocellular carcinoma
复制标题
VEPH1 减弱通过削弱肝细胞癌中 TSC1/TSC2 关联来激活 mTORC1 信号传导
DOI：
10.1016/j.jhep.2020.06.027
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发表时间：
2020-12-01
影响因子：
25.7
通讯作者：
Chen, She
中科院分区：
文献类型：
--
作者：
Dong, Pingping;Wang, Xiaoxiao;Chen, She
背景与目的：mTORC 1信号异常激活在肝细胞癌（HCC）中发生频率很高。然而，这种异常激活的根本原因仍然难以捉摸。在这项研究中，我们确定了心室区表达pleckstrin同源结构域包含1（VEPH 1）作为一种新的肿瘤抑制剂，通过mTORC 1 axills.Methods的行为：我们进行了定量逆转录PCR（92对），蛋白质印迹（30对），免疫染色（225例）测定肝癌组织样本中，以评估VEPH 1的表达。我们探讨了VEPH 1对肿瘤生长和转移的功能作用。采用分子和生物化学方法对VEPH 1的抑瘤作用机制进行了研究。结果：VEPH 1在肝癌组织中经常被沉默，主要是由于let-7 d表达上调。VEPH 1表达降低与HCC患者预后不良和侵袭性肿瘤表型相关。VEPH 1通过调节细胞增殖、迁移和侵袭在体外和体内介导其肿瘤抑制活性。VEPH 1片段580- 625 aa和447-579 aa分别与TSC 1（719-1，164 aa）和TSC 2（1-420 aa）直接结合，增强TSC 1/TCS 2结合并促进TSC 2易位至膜，这导致TSC 2 Ser（1387）磷酸化增加。随后，Rheb被TSC 2的GTdR活性灭活，抑制mTORC 1信号传导并促进HCC癌变和转移的变化。mTOR抑制剂雷帕霉素可抑制VEPH 1敲低的促肿瘤发生作用。VEPH 1的缺失与HCC标本中TSC 2 Ser（1387）磷酸化的降低和mTOR活性的增加相关。（或雷帕霉素类似物）可以作为HCC患者和VEPH 1表达抑制的有效治疗选择。异常激活的哺乳动物雷帕霉素靶蛋白（mTOR）信号转导与肝细胞癌患者的肿瘤分化差、早期肿瘤复发和总生存率降低相关。在此，我们确定低VEPH 1表达是肝细胞癌组织中异常激活mTOR信号的潜在原因。因此，mTOR抑制剂可能是HCC和低VEPH 1表达患者的有效治疗选择。(C)2020年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Abnormal activation of mTORC1 signaling occurs at high frequency in hepatocellular carcinoma (HCC). However, the underlying causes of this aberrant activation remain elusive. In this study, we identified ventricular zone expressed pleckstrin homology domain-containing 1 (VEPH1) as a novel tumor suppressor that acts via the mTORC1 axis.Methods: We performed quantitative reverse-transcription PCR (92 pairs), western blot (30 pairs), and immunostaining (225 cases) assays in HCC tissue samples to evaluate VEPH1 expression. We explored the functional effects of VEPH1 on tumor growth and metastasis. Molecular and biochemical strategies were used to gain insight into mechanisms underlying the tumor-suppressive function of VEPH1.Results: VEPH1 is frequently silenced in HCC tissues, primarily resulting from let-7d upregulation. Decreased VEPH1 expression is associated with poor prognosis and aggressive tumor phenotypes in patients with HCC. VEPH1 mediates its tumor-suppressing activity through regulation of cell proliferation, migration and invasion in vitro and in vivo. The VEPH1 fragments 580-625aa and 447-579 aa bind directly to TSC1 (719-1,164aa) and TSC2 (1-420 aa), respectively, enhancing TSC1/TCS2 binding and promoting translocation of TSC2 to the membrane, which leads to increased TSC2 Ser(1387) phosphorylation. Subsequently, Rheb is inactivated by the GTPase activity of TSC2, inhibiting mTORC1 signaling and contributing to changes in HCC carcinogenesis and metastasis. Rapamycin, the mTOR inhibitor, can inhibit the pro-tumorigenic effect of VEPH1 knockdown. Loss of VEPH1 correlates with decreased TSC2 Ser(1387) phosphorylation and increased mTOR activity in HCC specimens.Conclusions: The loss of VEPH1 leads to aberrantly activated mTORC1 signaling in HCC; rapamycin (or rapalogs) may serve as an effective treatment option for patients with HCC and dampened VEPH1 expression.Lay summary: Abnormally activated mammalian target of rapamycin (mTOR) signaling is associated with poor tumor differentiation, early tumor recurrence and worse overall survival in patients with hepatocellular carcinoma. Herein, we identify low VEPH1 expression as a potential cause of abnormally activated mTOR signaling in hepatocellular carcinoma tissues. mTOR inhibitors could thus be an effective treatment option for patients with HCC and low VEPH1 expression. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.