文章：

CYP2E1依赖性SIRT7上调应对酒精介导的肝细胞癌转移

CYP2E1-dependent upregulation of SIRT7 is response to alcohol mediated metastasis in hepatocellular carcinoma 

原文发布日期：2022-07-28 

英文摘要：

Long-term alcohol use is a confirmed risk factor of liver cancer tumorigenesis and metastasis. Multiple mechanisms responsible for alcohol related tumorigenesis have been proposed, including toxic reactive metabolite production, oxidative stress and fat accumulation. However, mechanisms underlying alcohol-mediated liver cancer metastasis remain largely unknown. We have previously demonstrated that SIRT7 regulates chemosensitivity by altering a p53-dependent pathway in human HCC. In the current study, we further revealed that SIRT7 is a critical factor in promoting liver cancer metastasis. SIRT7 expression is associated with disease stage and high SIRT7 predicts worse overall and disease-free survival. Overexpression of SIRT7 promotes HCC cell migration and EMT while knockdown of SIRT7 showed opposite effects. Mechanistically, we found that SIRT7 suppresses E-Cadherin expression through FOXO3-dependent promoter binding and H3K18 deacetylation. Knockdown of FOXO3 abolished the suppressive effect of SIRT7 on E-cadherin transcription. More importantly, we identified that alcohol treatment upregulates SIRT7 and suppresses E-cadherin expression via a CYP2E/ROS axis in hepatocytes both in vitro and in vivo. Antioxidant treatment in primary hepatocyte or CYP2E1−/− mice fed with alcohol impaired those effects. Reducing SIRT7 activity completely abolished alcohol-mediated promotion of liver cancer metastasis in vivo. Taken together, our data reveal that SIRT7 is a pivotal regulator of alcohol-mediated HCC metastasis. 

摘要翻译： 

长期饮酒是肝癌发生与转移的明确风险因素。酒精相关肿瘤发生的多种机制已被提出，包括毒性反应代谢物产生、氧化应激和脂肪堆积。然而，酒精介导的肝癌转移机制仍很大程度上是未知的。我们先前研究表明，SIRT7通过改变人肝细胞癌（HCC）中p53依赖通路来调节化疗敏感性。本研究进一步揭示SIRT7是促进肝癌转移的关键因子。SIRT7表达与疾病分期相关，高SIRT7预示更差的总生存期和无病生存期。过表达SIRT7可促进HCC细胞迁移和上皮间质转化（EMT），而敲低SIRT7则呈现相反效果。机制上，我们发现SIRT7通过FOXO3依赖性启动子结合和H3K18去乙酰化抑制E-钙黏蛋白表达。敲低FOXO3可消除SIRT7对E-钙黏蛋白转录的抑制作用。更重要的是，我们发现酒精处理通过CYP2E/ROS轴在体外和体内肝细胞中上调SIRT7并抑制E-钙黏蛋白表达。在原代肝细胞或酒精喂养的CYP2E1−/−小鼠中进行抗氧化治疗可阻断这些效应。降低SIRT7活性完全消除了酒精介导的体内肝癌转移促进作用。综上所述，我们的数据表明SIRT7是酒精介导的HCC转移的关键调控因子。

原文链接：

CYP2E1-dependent upregulation of SIRT7 is response to alcohol mediated metastasis in hepatocellular carcinoma