ZHX2 inhibits SREBP1c-mediated de novo lipogenesis inhepatocellular carcinoma via miR-24-3p
ZHX2 inhibits SREBP1c-mediated de novo lipogenesis inhepatocellular carcinoma via miR-24-3p
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ZHX2 通过 miR-24-3p 抑制 SREBP1c 介导的肝细胞癌从头脂肪生成
DOI：
10.1002/path.5530
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发表时间：
2020
影响因子：
7.3
通讯作者：
Chunhong Ma
中科院分区：
文献类型：
--
作者：
Xiangguo Yu;Qinghai Lin;Zhuanchang Wu;Yankun Zhang;Tixiao Wang;Songbai Zhao;Xiaojia Song;Chaojia Chen;Zehua Wang;Leiqi Xu;Chunyang Li;Lifen Gao;Xiaohong Liang;Xuetian Yue;Chunhong Ma
肝细胞癌（HCC）是全球癌症相关死亡的主要原因之一。脂肪生成被认为是HCC发生和发展的关键因素。然而，其基本机制仍然没有完全理解。在这里，我们确定了锌指和同源异型盒2（ZHX 2），一个HCC相关的肿瘤抑制因子，作为一个重要的去新生脂肪生成抑制因子。ZHX 2的异位表达显著抑制HCC细胞中的新生血管生成，并降低FXR、ACL、ACC 1和SCD 1的表达。与此相一致，在HCC细胞系和人类样本中，ZHX 2与SREBP 1c（新生脂肪生成的主要调节因子）呈负相关。沉默和过表达的结果表明，ZHX 2通过抑制SREBP 1c来抑制癌细胞的发生和随后的HCC进展。此外，用SREBP 1c抑制剂法图他汀治疗抑制了肝特异性Zhx 2基因敲除小鼠中肿瘤的自发形成。从机制上讲，ZHX 2在转录上增加了miR-24 - 3 p的表达，这靶向了SREBP 1c并导致其降解。总之，我们的数据表明ZHX 2抑制HCC进展的新机制，这可能为HCC的治疗提供新的策略。© 2020大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer‐related death worldwide. Lipogenesis has been considered as a critical player in HCC initiation and progression. However, the underlying mechanism is still not fully understood. Here, we identified zinc fingers and homeoboxes 2 (ZHX2), an HCC‐associated tumor suppressor, as an important repressor ofde novolipogenesis. Ectopic expression of ZHX2 significantly inhibitedde novolipogenesis in HCC cells and decreased expression of FASN, ACL, ACC1, and SCD1. In accordance with this, ZHX2 was negatively associated with SREBP1c, the master regulator ofde novolipogenesis, in HCC cell lines and human specimens. Results from silencing and overexpression demonstrated that ZHX2 inhibitedde novolipogenesis and consequent HCC progression via repression of SREBP1c. Furthermore, treatment with the SREBP1c inhibitor fatostatin dampened the spontaneous formation of tumors in liver‐specificZhx2knockout mice. Mechanistically, ZHX2 increased expression of miR‐24‐3p transcriptionally, which targeted SREBP1c and led to its degradation. In conclusion, our data suggest a novel mechanism through which ZHX2 suppresses HCC progression, which may provide a new strategy for the treatment of HCC. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.