JMJD4-demethylated RIG-I prevents hepatic steatosis and carcinogenesis.
JMJD4-demethylated RIG-I prevents hepatic steatosis and carcinogenesis.
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JMJD4-去甲基化 RIG-I 预防肝脂肪变性和癌变
DOI：
10.1186/s13045-022-01381-6
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发表时间：
2022-11-04
影响因子：
28.5
通讯作者：
中科院分区：
文献类型：
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作者：
背景肝癌的发生是由坏死性炎症或代谢紊乱所驱动的，其潜在的机制仍然很难解释。我们以前发现，视黄酸诱导基因-I（RIG-I），识别RNA病毒在先天免疫细胞的传感器，主要是由肝实质肝细胞在肝脏中表达。然而，其在肝癌发生中的作用是未知的，这是深入调查在本study. MethodsDEN诱导的坏死性炎症驱动的肝癌发生和STAM NASH肝癌发生进行了肝细胞特异性RIG-I基因敲除小鼠。RIG-I的翻译后修饰通过质谱测定，并针对甲基化赖氨酸位点和RIG-I赖氨酸突变小鼠构建特异性抗体，以确定RIG-I甲基化的功能。ResultsWe有趣地发现，DEN诱导的肝癌发生增强，而NASH诱导的肝癌发生抑制肝细胞特异性RIG-I缺陷。此外，IL-6降低HCC祖细胞（HcPC）中RIG-I的表达，然后恶性促进IL-6效应信号传导并驱使HcPC完全建立HCC。RIG-I的表达增加，然后增加胆固醇的合成和脂肪变性，并反过来NASH和NASH诱导的肝癌发生。在机制上，RIG-I在K18和K146处组成性单甲基化，并且去甲基化酶JMJD 4介导的RIG-I去甲基化抑制IL-6-STAT 3信号传导。组成性甲基化RIG-I与AMPKα结合抑制HMGCR磷酸化，从而促进HMGCR酶活性和胆固醇合成。临床上，RIG-I在人肝癌前异型增生结节中减少，而在NAFLD肝脏中增加，这与小鼠models.ConclusionsDecreased RIG-I在HCPCs中促进坏死性炎症诱导的肝癌发生，而增加组成性甲基化RIG-I增强脂肪变性和NASH诱导的肝癌发生。JMJD 4-去甲基化RIG-I可预防坏死性炎症和NASH诱导的肝癌发生，这为预防HCC提供了机制见解和潜在靶点。
BackgroundHepatocarcinogenesis is driven by necroinflammation or metabolic disorders, and the underlying mechanisms remain largely elusive. We previously found that retinoic acid-inducible gene-I (RIG-I), a sensor for recognizing RNA virus in innate immune cells, is mainly expressed by parenchymal hepatocytes in the liver. However, its roles in hepatocarcinogenesis are unknown, which is intensively investigated in this study.MethodsDEN-induced necroinflammation-driven hepatocarcinogenesis and STAM NASH-hepatocarcinogenesis were carried out in hepatocyte-specific RIG-I knockout mice. The post-translational modification of RIG-I was determined by mass spectrometry, and specific antibodies against methylated lysine sites and the RIG-I lysine mutant mice were constructed to identify the functions of RIG-I methylation.ResultsWe interestingly found that DEN-induced hepatocarcinogenesis was enhanced, while NASH-induced hepatocarcinogenesis was suppressed by hepatocyte-specific RIG-I deficiency. Further, IL-6 decreased RIG-I expression in HCC progenitor cells (HcPCs), which then viciously promoted IL-6 effector signaling and drove HcPCs to fully established HCC. RIG-I expression was increased by HFD, which then enhanced cholesterol synthesis and steatosis, and the in-turn NASH and NASH-induced hepatocarcinogenesis. Mechanistically, RIG-I was constitutively mono-methylated at K18 and K146, and demethylase JMJD4-mediated RIG-I demethylation suppressed IL-6-STAT3 signaling. The constitutive methylated RIG-I associated with AMPKα to inhibit HMGCR phosphorylation, thus promoting HMGCR enzymatic activity and cholesterol synthesis. Clinically, RIG-I was decreased in human hepatic precancerous dysplastic nodules while increased in NAFLD livers, which were in accordance with the data in mouse models.ConclusionsDecreased RIG-I in HcPCs promotes necroinflammation-induced hepatocarcinogenesis, while increased constitutive methylated RIG-I enhances steatosis and NASH-induced hepatocarcinogenesis. JMJD4-demethylated RIG-I prevents both necroinflammation and NASH-induced hepatocarcinogenesis, which provides mechanistic insight and potential target for preventing HCC.
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影响因子：
64.5
作者：
He G;Dhar D;Nakagawa H;Font-Burgada J;Ogata H;Jiang Y;Shalapour S;Seki E;Yost SE;Jepsen K;Frazer KA;Harismendy O;Hatziapostolou M;Iliopoulos D;Suetsugu A;Hoffman RM;Tateishi R;Koike K;Karin M
通讯作者：
Karin M
影响因子：
64.8
作者：
Karin M;Clevers H
通讯作者：
Clevers H
microRNA-199a-3p 通过靶向 PDCD4 抑制肝细胞凋亡和肝癌发生。
影响因子：
6.2
作者：
Li Z;Zhou Y;Zhang L;Jia K;Wang S;Wang M;Li N;Yu Y;Cao X;Hou J
通讯作者：
Hou J
肝癌的发生需要通过 CD44 增强的生长因子信号传导抑制 p53
影响因子：
50.3
作者：
Dhar D;Antonucci L;Nakagawa H;Kim JY;Glitzner E;Caruso S;Shalapour S;Yang L;Valasek MA;Lee S;Minnich K;Seki E;Tuckermann J;Sibilia M;Zucman-Rossi J;Karin M
通讯作者：
Karin M
影响因子：
64.5
作者：
Qing, Hua;Desrouleaux, Reina;Wang, Andrew
通讯作者：
Wang, Andrew