PID1 based connection of insulin resistance to hepatocellular carcinogenesis  

作　　者：Ming XIANG Qian-qian XU Sen-lin LI Bao-tian WANG Ya-li TUO 

机构地区：[1]Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

出　　处：《中国药理学与毒理学杂志》2018年第4期316-316,共1页Chinese Journal of Pharmacology and Toxicology

基　　金：supported by National Natural Science Foundation of China(81673440;81273521;91229114)

摘　　要：OBJECTIVE To investigate the effect of phosphotyrosine interaction domain containing1(PID1,NYGGF4) onpromotion of IR and HCC,and explore its underlying mechanisms.METHODS Lentivirus were used to mediate the knockdown of PID1 in HFD induced IR mouse model as well as ob/ob mice.Intraperitoneal glucose and insulin tolerance were performed 4 weeks after lentivirus injection.Hydrodynamics-based transfection was applied to induce the liver specific overexpression of PID1.Flow cytometry was exerted to detect the proportion and function of immune cells.qRT-PCR and Western blot were used to detect the expression of downstream pathways of PID1.Liquid chromatographymass spectrometry(LC-MS) and co-immunoprecipitation(Co-IP) were conducted to identify proteins interacting with PID1.Chromatin immunoprecipitation(ChIP) was operated to measure the modification of H3K4me3 of PID1 promoter.RESULTS PID1 restriction improved insulin resistance,hyperglycemia and fatty liver.Conversely,hepatic knockdown of PID1 attenuated liver xenografted tumor growth.Moreover,PID1 liver-specific protooncogenes via hydrodynamics-based transfection established a primary hepatocellular carcinoma mouse model,induced an immunosuppressive environment,with the reduction of CD3+,CD4+,CD8+T cells,retarded maturation of dendritic cells(DCs),pronounced differentiation of regulatory T cells(Tregs),and recruitment of MDSC.In addition,PID1 overexpression activated prolifer.ation related genes,promoted anti-inflammatory genes,suppressed pro-inflammatory genes,induced glycolysis and lipid metabolism genes to facilitate tumorigenesis in liver.Importantly,PID1 exerted its tumor-promoting function through binding to epidermal growth factor receptor(EGFR) and activation of downstream KRAS/ERK pathway.As such,PID1 exist trimethylation of histone H3 at lysine 4(H3K4me3)modification and IR up-regulated the expression of PID1 by activation the H3K4me3 modification.CONCLUSION PID1 is a new gene that exerts both liver cancer-promoting and insulin resistance inducing functionOBJECTIVE To investigate the effect of phosphotyrosine interaction domain containing1（PID1,NYGGF4） onpromotion of IR and HCC,and explore its underlying mechanisms.METHODS Lentivirus were used to mediate the knockdown of PID1 in HFD induced IR mouse model as well as ob/ob mice.Intraperitoneal glucose and insulin tolerance were performed 4 weeks after lentivirus injection.Hydrodynamics-based transfection was applied to induce the liver specific overexpression of PID1.Flow cytometry was exerted to detect the proportion and function of immune cells.qRT-PCR and Western blot were used to detect the expression of downstream pathways of PID1.Liquid chromatographymass spectrometry（LC-MS） and co-immunoprecipitation（Co-IP） were conducted to identify proteins interacting with PID1.Chromatin immunoprecipitation（ChIP） was operated to measure the modification of H3K4me3 of PID1 promoter.RESULTS PID1 restriction improved insulin resistance,hyperglycemia and fatty liver.Conversely,hepatic knockdown of PID1 attenuated liver xenografted tumor growth.Moreover,PID1 liver-specific protooncogenes via hydrodynamics-based transfection established a primary hepatocellular carcinoma mouse model,induced an immunosuppressive environment,with the reduction of CD3＋,CD4＋,CD8＋T cells,retarded maturation of dendritic cells（DCs）,pronounced differentiation of regulatory T cells（Tregs）,and recruitment of MDSC.In addition,PID1 overexpression activated prolifer.ation related genes,promoted anti-inflammatory genes,suppressed pro-inflammatory genes,induced glycolysis and lipid metabolism genes to facilitate tumorigenesis in liver.Importantly,PID1 exerted its tumor-promoting function through binding to epidermal growth factor receptor（EGFR） and activation of downstream KRAS/ERK pathway.As such,PID1 exist trimethylation of histone H3 at lysine 4（H3K4me3）modification and IR up-regulated the expression of PID1 by activation the H3K4me3 modification.CONCLUSION PID1 is a new gene that exerts both liver cancer-promoting an

关 键 词：磷酸酪氨酸 治疗方法 临床分析 药物治疗 

分 类 号：R378[医药卫生—病原生物学]