A novel mitochondrial amidoxime reducing component 2 is a favorable indicator of cancer and suppresses the progression of hepatocellular carcinoma by regulating the expression of p27
A novel mitochondrial amidoxime reducing component 2 is a favorable indicator of cancer and suppresses the progression of hepatocellular carcinoma by regulating the expression of p27
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一种新型线粒体偕胺肟还原成分 2 是癌症的有利指标，并通过调节 p27 的表达来抑制肝细胞癌的进展。
DOI：
10.1038/s41388-020-01417-6
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发表时间：
2020-08-18
期刊：
影响因子：
8
通讯作者：
Liu, Lianxin
中科院分区：
文献类型：
--
作者：
Wu, Dehai;Wang, Yan;Liu, Lianxin
肝细胞癌（HCC）是美国癌症相关死亡率的第五大原因。因此，深入研究肝癌的发病机制，寻找理想的治疗靶点至关重要。在本研究中，我们证明代谢功能障碍可能是HCC发生的关键因素。线粒体偕胺肟还原组分2（MARC 2）作为一种新发现的钼酶，在人肝癌组织和肝癌细胞中表达下调。MARC2表达下调与肝癌的临床病理特征如肿瘤大小、AFP水平和肿瘤分级显著相关，是预后不良的独立危险因素。体内外研究均提示MARC2通过调节p27蛋白表达水平抑制HCC的进展。Hippo信号通路和RNF123是这一过程所必需的。此外，MARC2通过Hippo信号通路调节HNF4A的表达。HNF4A被募集到MARC 2的启动子上，形成反馈环。MARC2水平通过甲基化下调。我们在这项研究中证实了MARC2在HCC中的预后价值，并确定了MARC2抑制HCC进展的机制。这些发现可能会为HCC带来新的治疗靶点。
Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related mortality in the United States. Exploring the mechanism of HCC and identifying ideal targets is critical. In the present study, we demonstrated metabolism dysfunction might be a key diver for the development of HCC. The mitochondrial amidoxime reducing component 2 (MARC2) as a newly discovered molybdenum enzyme was downregulated in human HCC tissues and HCC cells. Downregulated MARC2 was significantly associated with clinicopathological characteristics of HCC, such as tumor size, AFP levels, and tumor grade and was an independent risk factor of poor prognosis. Both in vitro and in vivo studies suggested that MARC2 suppressed the progression of HCC by regulating the protein expression level of p27. The Hippo signaling pathway and RNF123 were required for this process. Moreover, MARC2 regulated expression of HNF4A via the Hippo signaling pathway. HNF4A was recruited to the promoter of MARC2 forming a feedback loop. MARC2 levels were downregulated by methylation. We demonstrated the prognostic value of MARC2 in HCC and determined the mechanism by which MARC2 suppressed the progression of HCC in this study. These findings may lead to new therapeutic targets for HCC.