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Comprehensive analysis of miRNA-gene regulatory network with clinical significance in human cancers

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Science china(Life Sciences) 2020年第8期63卷 1201-1212页

作者： Xiuliang Cui yang Liu Wen Sun jin ding Xiaochen Bo hongyang wang National Center for Liver Cancer Shanghai 201805China international cooperation laboratory on signal transduction Shanghai Eastern Hepatobiliary Surgery HospitalShanghai 200438China Beijing institute of Radiation Medicine Beijing 100850China Research Center for Clinical and Translational Medicine Beijing 302 HospitalBeijing 100039China

microRNAs(miRNAs),particularly the exosomal miRNAs have been widely used as biomarkers and promising therapeutic targets in ***,a comprehensive analysis of miRNA-gene regulatory network with clinical significance remains *** emergence of high-throughput multi-omics data over large,well-characterized patient cohorts provides an unprecedented opportunity to address this ***,we performed a clinic-centered analysis to identify cancer-associated miRNAs,miRNA-target *** 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 ***,by integrating exosomal miRNA and m RNA databases,we identified exosomal miRNA biomarkers for non-invasive cancer surveillance and therapy ***,we explored the role of CPC-related miRNAs for therapeutic effect prediction of drugs based on their shared *** analysis pipeline illustrated the significance of clinic-centered analysis in miRNA-gene pair identification and provided helpful clues for future cancer studies.

关键词： exosomal miRNA biomarker clinical significance prognosis TCGA

Six2 is negatively correlated with prognosis and facilitates epithelial-mesenchymal transition via TGF-β/Smad signal pathway in hepatocellular carcinoma

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hepatobiliary & Pancreatic Diseases international 2019年第6期18卷 525-531页

作者： Zheng-Hua Wan yun-Han Ma Tian-Yi Jiang yun-Kai Lin Yuan-Yuan Shi Ye-Xiong Tan Li-Wei Dong hong-yang wang international cooperation laboratory on signal transduction Eastern Hepatobiliary Surgery InstituteThe Second Military Medical UniversityShanghai 200438China National Center for Liver Cancer The Second Military Medical UniversityShanghai 201805China No.971 Hospital of Peoples’Liberation Army Navy Qingdao 266071China State Key laboratory of Oncogenes and related Genes Shanghai Cancer InstituteRenji HospitalShanghai Jiaotong University School of MedicineShanghai 200127China

Background: Increasing evidence indicates that Six2 contributes to tumorigenesis in various tumor in- cluding hepatocellular carcinoma (HCC). This study aimed to determine the role of Six2 in HCC and to elucidate the association of Six2 with clinical pathological characteristics. Methods: The expressions of Six2 in HCC tumor, para-tumor tissue and portal vein tumor thrombus (PVTT) were detected by tissue microarray technique, immunohistochemistry, real-time RT-PCR and West- ern blotting. Chi-square and Kaplan-Meier analysis were used to analyze the correlation between Six2 expression and prognosis of HCC patients. Lentivirus mediated Six2 knockdown, spheroid formation as- say, proliferation assay and subcutaneous tumor implantation were performed to determine the function of Six2. Results: In 274 HCC samples, Six2 was strongly expressed. Kaplan-Meier analysis revealed that high ex- pression of Six2 was correlated with a shorter overall survival (OS) and disease-free survival (DFS). More- over, Six2 expression was associated with sex, alpha-fetoprotein, tumor size and portal vein invasion. Six2 was highly expressed in PVTT. Six2 knockdown inhibited HCC cell lines proliferation, migration, and self-renewal in vitro and in vivo. In addition, low-expression of Six2 weakened TGF-β induced Smad4 activation and epithelial-mesenchymal transition in HCC cell lines. Conclusions: Elevated Six2 expression in HCC tumor patients was associated with negative prognosis. Upregulated Six2 promoted tumor growth and facilitated HCC metastasis via TGF-β/Smad signal pathway.

关键词： Hepatocellular carcinoma Six2 Prognosis Metastasis

SOX9-transactived long non-coding RNA NEAT1 promotes the self-renewal of liver cancer stem cells through PKA/Hippo signaling

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signal transduction and Targeted Therapy 2021年第3期6卷 614-617页

作者： Zhuo Cheng Xijun Liang Cheng Zhang Ruoyu wang Tingting Wei Beifang Ning Elzbieta Poreba Liang Li hongyang wang jin ding international cooperation laboratory on signal transduction Eastern Hepatobiliary Surgery Hospital/InstituteThe Second Military Medical UniversityShanghaiChina Department of Hepatic surgery Eastern Hepatobiliary Surgery HospitalThe Second Military Medical UniversityShanghaiChina Department of laboratory Medicine Changzheng HospitalThe Second Military MedicaluniversityShanghaiChina Department of Gastroenterology Changzheng HospitalThe Second Military Medical UniversityShanghaiChina Department of Molecular Virology Institute of Experimental BiologyFaculty of BiologyAdam Mickiewicz UniversityPoznarPoland National Center for Liver Cancer ShanghaiChina Clinical Cancer institute Center for Translational MedicineSecond Military Medical UniversityShanghai 200433China

Dear Editor,Hepatocellular carcinoma(HCC),the most common pathological type of primary liver cancer,ranks as the third deadliest *** the progress of surgical resection in recent years,the 5-year survival of HCC patients is still unsatisfactory due to the frequent relapse and *** evidence has demonstrated that liver cancer stem cells(CSCs)are critical for HCC chemoresistance and ***,the molecular mechanisms of liver CSC regulation remain unclear,which hampers the development of the therapeutic strategy that targets liver CSCs.

关键词： cancer liver SOX9

Distinct Immune Signatures in Peripheral Blood Predict Chemosensitivity in Intrahepatic Cholangiocarcinoma Patients

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Engineering 2021年第10期7卷 1381-1392页

作者： Tong Wu Ying-Cheng yang Bo Zheng Xue-Bing Shi Wei Li Wen-Cong Ma Shan wang Zhi-Xuan Li Yan-jing Zhu Jian-Min Wu Kai-Ting wang Yan Zhao Rui Wu Cheng-Jun Sui Si-yun Shen Xuan Wu Lei Chen Zhen-Gang Yuan hong-yang wang international cooperation laboratory on signal transduction&Key laboratory of signaling Regulation and Targeting Therapy of Liver Cancer Ministry of Education&Shanghai Key Laboratory of Hepatobiliary Tumor BiologyEastern Hepatobiliary Surgery HospitalSecond Military Medical UniversityShanghai 200438China National Center for Liver Cancer Shanghai 201805China Department of hepatobiliary surgery Eastern Hepatobiliary Surgery HospitalSecond Military Medical UniversityShanghai 200438China Fudan university shanghai Cancer Center Shanghai 200032China institute of Metabolism and Integrative Biology Fudan UniversityShanghai 200433China Department of laboratory Medicine The Tenth People’s Hospital of ShanghaiTongji UniversityShanghai 200072China Key laboratory of signaling Regulation and Targeting Therapy of Liver Cancer Ministry of EducationShanghai 200438China Department of Oncology Eastern Hepatobiliary Surgery HospitalSecond Military Medical UniversityShanghai 200438China

Intrahepatic cholangiocarcinoma(ICC)is the second most common liver *** remains the main therapeutic strategy for advanced ICC patients,but chemosensitivity varies ***,we applied cytometry by time-of-flight(CyTOF)to establish the immune profile of peripheral blood mononuclear cells(PBMCs)on the single-cell level at indicated time points before,during,and after *** immunofluorescence staining was applied to examine the spatial distribution of certain immune *** microarrays(TMAs)were used for prognostic evaluation.A total of 20 ICC patients treated with gemcitabine(GEM)were enrolled in our study,including eight cases with good response(R)and 12 cases with non-response(NR).Tremendous changes in PBMC composition,including an increased level of CD4/CD8 double-positive T cells(DPT),were observed after *** with higher level of CD4^(+)CD45RO^(+)CXCR3^(+)T cells before treatment had a favorable response to *** study identified a positive correlation between the percentage of T cell subpopulations and clinical response after chemotherapy,which suggests that it is practical to predict the potential response before treatment by evaluating the proportions of the cell population in PBMCs.

关键词： Intrahepatic cholangiocarcinoma Gemcitabine Chemosensitivity Peripheral blood mononuclear cells

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

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signal transduction and Targeted Therapy 2021年第1期6卷 144-157页

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 international cooperation laboratory on signal transduction Eastern Hepatobiliary Surgery Hospital/InstituteThe Second Military Medical UniversityShanghaiChina Department of Gastroenterology Changzheng HospitalThe Second Military Medical UniversityShanghaiChina shanghai institutes for Biological Sciences Chinese Academy of SciencesShanghaiChina The Third Department of Hepatic surgery Eastern Hepatobiliary Surgery HospitalThe Second Military Medical UniversityShanghaiChina National Center for Liver Cancer ShanghaiChina Tongji university School of Medicine ShanghaiChina

Hepatocyte nuclear factor 3γ(HNF3γ)is a hepatocyte nuclear factor,but its role and clinical significance in hepatocellular carcinoma(HCC)remain ***,we report that HNF3γexpression is downregulated in patient HCC and inversely correlated with HCC malignancy and patient ***,our data suggested that the HNF3γreduction in HCC could be mediated by METTL14-dependent m6A methylation of HNF3γ***3γexpression was increased during hepatic differentiation and decreased in dedifferentiated HCC ***,HNF3γdelivery promoted differentiation of not only HCC cells but also liver CSCs,which led to suppression of HCC *** analysis suggested an HNF3γ-centered regulatory network that includes essential liver differentiation-associated transcription factors and functional molecules,which could synergistically facilitate HCC cell *** 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 *** investigation showed that patient-derived HCC xenografts with high HNF3γexpression exhibited a sorafenib response and patients with high HCC HNF3γlevels benefited from sorafenib ***,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

An RNA-RNA crosstalk network involving HMGB1 and RICTOR facilitates hepatocellular carcinoma tumorigenesis by promoting glutamine metabolism and impedes immunotherapy by PD-L1+ exosomes activity

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signal transduction and Targeted Therapy 2022年第1期7卷 282-294页

作者： Yanping Wei Xuewu Tang Yibin Ren yun yang fengliang Song jingbo Fu Shuowu Liu Miao Yu jing Chen Suyang wang Kecheng Zhang Yexiong Tan Zhipeng Han Lixjn Wei Baohua Zhang Zhangjun Cheng Liang Li hongyang wang international Co-operation laboratory on signal transduction Eastern Hepato-Biliary Surgery InstituteSecond Military Medical UniversityShanghaiChina National Center for Liver Cancer ShanghaiChina Hepato-Pancreato-biliary center Zhongda HospitalSchool of MedicineSoutheast UniversityNanjingChina The Third Department of Hepatic surgery Eastern Hepatobiliary Surgery HospitalShanghaiChina School of Medicine Nantong UniversityNantongJiangsu ProvinceChina Department of Biliary Tract surgery Eastern Hepatobiliary Surgery HospitalSecond Military Medical UniversityShanghaiChina Tumor Immunology and Gene Therapy Center Eastern Hepato-Biliary Surgery InstituteSecond Military Medical UniversityShanghaiChina National laboratory for Oncogenes and Related Genes Cancer InstituteRenJi HospitalShanghai Jiao Tong University200441 ShanghaiChina

Hepatocellular carcinoma(HCC)is the global leading cause of cancer-related deaths due to the deficiency of targets for precision therapy.A new modality of epigenetic regulation has emerged involving RNA-RNA crosstalk networks where two or more competing endogenous RNAs(ceRNAs)bind to the same ***,the contribution of such mechanisms in HCC has not been well ***,potential HMGB1-driven RNA-RNA crosstalk networks were evaluated at different HCC stages,identifying the mT0RC2 component RICTOR as a potential HMGB1 ceRNA in HBV^(+)early stage ***,elevated HMGB1 mRNA was found to promote the expressio n of RICTOR mRNA through competitively bin ding with the miR-200 family,especially *** nal assays emplo ying overexpressi on or in terference strategies dem on strated that the HMGB1 and RICTOR 3zuntra nslated regions(UTR)epigenetically promoted the malignant proliferation,self-renewal,and tumorigenesis in HCC ***,in terference agai nst HMGB1 and RICTOR in HCC cells promoted a stron ger an ti-PD-L1 immuno therapy resp on se,which appeared to associate with the production of PD-L1^(+)***,the HMGB1-driven RNA-RNA crosstalk network facilitated HCC cell glutamine metabolism via dual mechanisms,activating a positive feedback loop involving mT0RC2-AKT-C-MYC to upregulate glutamine synthetase(GS)expression,and inducing mTORCI signaling to derepress SIRT4 on glutamate dehydrogenase(GDH).Meanwhile,this crosstalk network could impede the efficacy of immunotherapy through mTORCI-P70S6K dependent PD-L1 production and PD-L1^(+)exosomes *** conclusion,our study highlights the non-coding regulatory role of HMGB1 with implicatio ns for RNA-based therapeutic targeting together with a predictio n of an ti-PD-L1 immuno therapy in HCC.

关键词： metabolism network crosstalk