m6A RNA methylation-mediated HNF3γ reduction rendershepatocellular carcinoma dedifferentiation and sorafenibresistance  

作　　者：Tengfei Zhou Shichao Li Daimin Xiang Junyu Liu Wen Sun Xiuliang Cui Beifang Ning Xiao Li Zhuo Cheng Weiqi Jiang Cheng Zhang Xijun Liang Liang Li Xin Cheng Liu Hui Hongyang Wang Jin Ding 

机构地区：[1]International Cooperation Laboratory on Signal Transduction,Eastern Hepatobiliary Surgery Hospital/Institute,The Second Military Medical University,Shanghai,China [2]Department of Gastroenterology,Changzheng Hospital,The Second Military Medical University,Shanghai,China [3]Shanghai Institutes for Biological Sciences,Chinese Academy of Sciences,Shanghai,China [4]The Third Department of Hepatic Surgery,Eastern Hepatobiliary Surgery Hospital,The Second Military Medical University,Shanghai,China [5]National Center for Liver Cancer,Shanghai,China [6]Tongji University School of Medicine,Shanghai,China

出　　处：《Signal Transduction and Targeted Therapy》2021年第1期144-157,共14页信号转导与靶向治疗（英文）

基　　金：This work was supported by Ministry of Education(MOE)Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer and Shanghai Key Laboratory of Hepatobiliary Tumor Biology;This work was supported by grants from the National Natural Science Foundation of China 81972222,81772582,and 81702736;National Key R&D Program of China(2017YFA0504503);Program of Shanghai Academic Research Leader(18XD1405400).

摘　　要：Hepatocyte nuclear factor 3γ(HNF3γ)is a hepatocyte nuclear factor,but its role and clinical significance in hepatocellular carcinoma(HCC)remain unclear.Herein,we report that HNF3γexpression is downregulated in patient HCC and inversely correlated with HCC malignancy and patient survival.Moreover,our data suggested that the HNF3γreduction in HCC could be mediated by METTL14-dependent m6A methylation of HNF3γmRNA.HNF3γexpression was increased during hepatic differentiation and decreased in dedifferentiated HCC cells.Interestingly,HNF3γdelivery promoted differentiation of not only HCC cells but also liver CSCs,which led to suppression of HCC growth.Mechanistic analysis suggested an HNF3γ-centered regulatory network that includes essential liver differentiation-associated transcription factors and functional molecules,which could synergistically facilitate HCC cell differentiation.More importantly,enforced HNF3γexpression sensitized HCC cells to sorafenib-induced growth inhibition and cell apoptosis through transactivation of OATP1B1 and OATP1B3 expression,which are major membrane transporters for sorafenib uptake.Clinical investigation showed that patient-derived HCC xenografts with high HNF3γexpression exhibited a sorafenib response and patients with high HCC HNF3γlevels benefited from sorafenib therapy.Together,these results suggest that HNF3γplays an essential role in HCC differentiation and may serve as a therapeutic target and predictor of sorafenib benefit in patients.

关 键 词：SORAFENIB HEPATOCELLULAR MEDIATED 

分 类 号：R735.7[医药卫生—肿瘤]