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 pati...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.展开更多
microRNAs(miRNAs),particularly the exosomal miRNAs have been widely used as biomarkers and promising therapeutic targets in cancer.However,a comprehensive analysis of miRNA-gene regulatory network with clinical signif...microRNAs(miRNAs),particularly the exosomal miRNAs have been widely used as biomarkers and promising therapeutic targets in cancer.However,a comprehensive analysis of miRNA-gene regulatory network with clinical significance remains scarce.The emergence of high-throughput multi-omics data over large,well-characterized patient cohorts provides an unprecedented opportunity to address this problem.Herein,we performed a clinic-centered analysis to identify cancer-associated miRNAs,miRNA-target axis.We first calculated the correlation among miRNA,mRNA and 75 unique clinico-pathological characteristics(CPCs)in 26 cancer types,and established an online resource(4CR).Interestingly,we found that the high expression of several DNA methylation-related enzymes was associated with adverse outcomes of cancer patients,and these genes were regulated by a cluster of miRNAs.Furthermore,by integrating exosomal miRNA and m RNA databases,we identified exosomal miRNA biomarkers for non-invasive cancer surveillance and therapy monitoring.Finally,we explored the role of CPC-related miRNAs for therapeutic effect prediction of drugs based on their shared targets.Our analysis pipeline illustrated the significance of clinic-centered analysis in miRNA-gene pair identification and provided helpful clues for future cancer studies.展开更多
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 pati...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.展开更多
基金supported by Ministry of Education(MOE)Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer and Shanghai Key Laboratory of Hepatobiliary Tumor Biologysupported 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).
文摘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.
基金supported by the National Natural Science Foundation of China(81602620,81700540 and 81770602)the State Key Project for Infectious Diseases(2015ZX09J15107)+1 种基金Shanghai Committee of Science and Technology(15431901600)Translational Application of Precision Medicine of Second Military Medical University(2017JZ52)。
文摘microRNAs(miRNAs),particularly the exosomal miRNAs have been widely used as biomarkers and promising therapeutic targets in cancer.However,a comprehensive analysis of miRNA-gene regulatory network with clinical significance remains scarce.The emergence of high-throughput multi-omics data over large,well-characterized patient cohorts provides an unprecedented opportunity to address this problem.Herein,we performed a clinic-centered analysis to identify cancer-associated miRNAs,miRNA-target axis.We first calculated the correlation among miRNA,mRNA and 75 unique clinico-pathological characteristics(CPCs)in 26 cancer types,and established an online resource(4CR).Interestingly,we found that the high expression of several DNA methylation-related enzymes was associated with adverse outcomes of cancer patients,and these genes were regulated by a cluster of miRNAs.Furthermore,by integrating exosomal miRNA and m RNA databases,we identified exosomal miRNA biomarkers for non-invasive cancer surveillance and therapy monitoring.Finally,we explored the role of CPC-related miRNAs for therapeutic effect prediction of drugs based on their shared targets.Our analysis pipeline illustrated the significance of clinic-centered analysis in miRNA-gene pair identification and provided helpful clues for future cancer studies.
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 BiologyThis work was supported by grants from the National Natural Science Foundation of China 81972222,81772582,and 81702736+1 种基金National Key R&D Program of China(2017YFA0504503)Program of Shanghai Academic Research Leader(18XD1405400).
文摘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.
