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The Gut Microbiota, Tumorigenesis, and Liver Diseases

Engineering 2017年第1期3卷 110-114页

作者： Guishuai Lv Ningtao Cheng Hongyang Wang international cooperation laboratory on signal transduction Eastern Hepatobiliary Surgery Institute Second Military Medical University Shanghai 200438 China National Center for Liver Cancer Shanghai 201805 China

In recent decades, diseases concerning the gut microbiota have presented some of the most serious public health problems worldwide. The human host＇s physiological status is influenced by the intestinal microbiome, thus integrating external factors, such as diet, with genetic and immune signals. The notion that chronic inflammation drives carcinogenesis has been widely established for various tissues. It is surprising that the role of the microbiota in tumorigenesis has only recently been recognized, given that the presence of bacteria at tumor sites was first described more than a century ago. Extensive epidemiological studies have revealed that there is a strong link between the gut microbiota and some common cancers. However, the exact molecular mechanisms linking the gut microbiota and cancer are not yet fully understood. Changes to the gut microbiota are instrumental in determining the occurrence and progression of hepatocarcinoma, chronic liver diseases related to alcohol, nonalcoholic fatty liver disease （NAFLD）, and cirrhosis. To be specific, the gut milieu may play an important role in systemic inflammation, endotoxemia, and vasodilation, which leads to complications such as spontaneous bacterial peritonitis and hepatic encephalopathy. Relevant animal studies involving gut microbiota manipulations, combined with observational studies on patients with NAFLD, have provided ample evidence pointing to the contribution of dysbiosis to the pathogenesis of NAFLD. Given the poor prognosis of these clinical events, their prevention and early management are essential. Studies of the composition and function of the gut microbiota could shed some light on understanding the prognosis because the microbiota serves as an essential component of the gut milieu that can impact the aforementioned clinical events. As far as disease management is concerned, probiotics may provide a novel direction for therapeutics for hepatocellular carcinoma （HCC） and NAFLD, given that probioti

关键词： Gut microbiota Dysbiosis Tumorigenesis Hepatocellular carcinoma Nonalcoholic fatty liver disease

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Amino acid 1-209 is essential for PDX-1-mediated repression of human CMV IE promoter activity

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Acta Pharmacologica Sinica 2006年第11期27卷 1495-1503页

作者： Jing CHEN~1 Lei CHEN~2 Ge LI~1 Lu CHENG~1 Yin HUANG~1 Jia-xin ZHANG~1 Wei-wei FAN~1 Da-ru LU~(1,3)1 State Key laboratory of Genetic Engineering,Institute of Genetics,School of Life Sciences,Fudan University,Shanghai 200433,China 2 international cooperation laboratory on signal transduction,eastern hepatobiliary surgery Institute,Second Military Medical University,225 Changhai Road,Shanghai 200438,China. State Key laboratory of Genetic Engineering Institute of Genetics School of Life Sciences Fudan University Shanghai China international cooperation laboratory on signal transduction Eastern Hepatobiliary Surgery Institute Second Military Medical University Shanghai China

Aim:To explore the different roles of pancreatic duodenal homeobox factors-1(PDX-1)domains in PDX-1 mediated repression of human cytomegalovirus imme-diately early(CMV IE)***:A series of truncated PDX-1 mutantswere *** binding of PDX-1 and CMV IE promoter was identified byelectrophoretic mobility shift assay(EMSA).The dual-reporter assay was ap-plied to examine the repression activities of PDX-1 mutants on CMV IE *** addition,RNAi technology was used to specifically knock down the endog-enous PDX-1 ***:The reporter assay indicated that compared tothe mock controls(pEGFP-N2),overexpression of PDX-1 resulted in a 41% de-crease of CMV IE promoter activity in the 293 cells(P<0.05)and 43% decrease inHeLa cells(P<0.05),and the repression levels of various truncated mutants playedon CMV IE promoter were *** knock down of the endogenousPDX-1 expression significantly restored the activity of CMV IE *** that domain 3 is necessary for nuclear localization and DNA bind-ing activity of ***,binding of PDX-1 alone to CMV IE promoter wasnot sufficient to inhibit its transcriptional activity,and other domains of PDX-1presented were also ***:Our data suggested that the DNAbinding activity of PDX-1 domain 3 and the cooperative binding of PDX-1 domain1/2 with other proteins were required for PDX-1 mediated repression of CMV IEpromoter.

关键词： CMV Immediately Early promoter pancreatic duodenal homeobox factors-Ⅰ down regulation

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Microbiota transplantation reveals beneficial impact of berberine on hepatotoxicity by improving gut homeostasis

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Science China(Life Sciences) 2018年第12期61卷 1537-1544页

作者： Chenjie Qin Huilu Zhang Linghao Zhao Min Zeng Weijian Huang Gongbo Fu Weiping Zhou Hongyang Wang Hexin Yan international cooperation laboratory on signal transduction Eastern Hepatobiliary Surgery Institutethe Second Military Medical UniversityShanghai 200438China National Center for Liver Cancer Research Shanghai 201805China Department of Digestive Diseases Huashan HospitalFudan UniversityShanghai 200040China

Berberine has been shown to reduce acute liver injury although the underlying mechanism is not fully understood. Because of the anatomic connection, the liver is constantly exposed to gut-derived bacterial products and metabolites. In this study, we showed that berberine has beneficial effects on both hepatotoxicity and intestinal damage in a rat model of chronic or acute liver injury. Microbiota transplantation from the rats with chronic hepatotoxicity could aggravate acute hepatotoxicity in mice treated with diethylnitrosamine(DEN). In rat models with gut homeostasis disruption induced by penicillin or dextran sulfate sodium(DSS), their fecal microbiota could also cause an enhanced hepatotoxicity of recipient mice. When treated with berberine,the DSS-induced enteric dysbacteriosis could be mitigated and their fecal bacteria were able to reduce acute hepatotoxicity in recipient mice. This study indicates that berberine could improve intestinal dysbacteriosis, which reduces the hepatotoxicity caused by pathological or pharmacological intervention. Fecal microbiota transplantation might be a useful method to directly explore homeostatic alteration in gut microbiota.

关键词： berberine gut homeostasis fecal microbiota transplantation hepatotoxicity

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Contactin-associated protein-like 2(CNTNAP2)mutations impair the essentialα-secretase cleavages,leading to autism-like phenotypes

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signal transduction and Targeted Therapy 2024年第4期9卷 1625-1636页

作者： Qing Zhang Mengen Xing Zhengkai Bao Lu Xu Yang Bai Wanqi Chen Wenhao Pan Fang Cai Qunxian Wang Shipeng Guo Jing Zhang Zhe Wang Yili Wu Yun Zhang Jia-Da Li Weihong Song Oujiang laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)Zhejiang Key Laboratory of Alzheimer's DiseaseZhejiang Provincial Clinical Research Center for Mental DisordersSchool of Mental Health and Wenzhou Kangning HospitalThe Second Affiliated Hospital and Yuying Children's HospitalInstitute of AgingWenzhou Medical UniversityWenzhouZhejiang 325035China Townsend Family Laboratories Department of PsychiatryBrain Research CenterThe University of British Columbia2255 Wesbrook MallVancouverBC V6T 1Z3Canada Chongqing Key laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders Ministry of Education Key Laboratory of Child Development and DisordersChildren's Hospital of Chongqing Medical UniversityChongqing 400014China Center for Medical Genetics Hunan Key Laboratory of Animal Models for Human DiseasesHunan Key Laboratory of Medical GeneticsHunan International Scientific and Technological Cooperation Base of Animal Models for Human DiseasesSchool of Life SciencesCentral South UniversityChangsha 410078 HunanChina The National Clinical Research Center for Geriatric Disease Xuanwu HospitalCapital Medical UniversityBeijing 100053Chin

Mutations in the Contactin-associated protein-like 2(CNTNAP2)gene are associated with autism spectrum disorder(ASD),and ectodomain shedding of the CNTNAP2 protein plays a role in its ***,key enzymes involved in the C-terminal cleavage of CNTNAP2 remain largely unknown,and the effect of ASD-associated mutations on this process and its role in ASD pathogenesis remain *** this report we showed that CNTNAP2 undergoes sequential cleavages by furin,ADAM10/17-dependent a-secretase and presenilindependent *** identified that the cleavage sites of ADAM10 and ADAM17 in CNTNAP2 locate at its C-terminal residue I79 and L96,and the main a-cleavage product C79 by ADAM10 is required for the subsequent y-secretase cleavage to generate CNTNAP2 intracellular domain(CICD).ASD-associated CNTNAP2 mutations impair the a-cleavage to generate C79,and the inhibition leads to ASDIlike repetitive and social behavior abnormalties in the Cntnap2l1254T knock-in ***,exogenous expression of 79 improves autism-ike phenotypes in the Cntnap2^(11254T) knock-in and Cntnap2^(-/-)knockout *** data demonstrates that the a-secretase is essential for CNTNAP2 processing and its *** study indicates that inhibition of the cleavage by pathogenic mutations underlies ASD pathogenesis,and upregulation of its C-terminal fragments could have therapeutical potentials for ASD treatment.

关键词： NAP2 cleavage subsequent

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Prognostic significance of combining high mobility group Box-1 and OV-6 expression in hepatocellular carcinoma

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Science China(Life Sciences) 2018年第8期61卷 912-923页

作者： Jihui Zhu Han Yu Shuzhen Chen Pinghua Yang Zihui Dong Yan Ling Hao Tang Shilei Bai Wen Yang Liang Tang Feng Shen Hongyang Wang Wen Wen National Center for Liver Cancer Eastern Hepatobiliary Surgery Hospital Second Military Medical University Shanghai 200438 China international cooperation laboratory on signal transduction of eastern hepatobiliary surgery hospital Second Military Medical University Shanghai 200433 China Department of Hepatic surgery Eastern Hepatobiliary Surgery Hospital Second Military Medical University Shanghai 200433 China Department of Respiratory Medicine Changzheng Hospital Second Military Medical University Shanghai 200003 China Ministry of Education Key laboratory on signaling Regulation and Targeting Therapy of Liver Cancer Shanghai 200438 China

The inflammatory environment and existence of cancer stem cells are critical for progression and intrahepatic recurrence of hepatocellular carcinoma （HCC） after curative resections. Here, we investigated the prognostic significance of combining high mobility group box 1 （HMGB1） expression and hepatic progenitor marker OV6 in hepatocellular carcinoma. Expression of HMGB 1 and OV6 was evaluated using immunohistochemistry profiling in tissue microarrays containing samples from 208 HCC patients. Invasive clinical or pathological factors were found in patients with high expression of HMGB 1 or OV6. Higher HMGB1 was associated with poorer clinical outcomes, and independently related to elevated 5-year recurrence incidence （85.5% vs. 62.4%, P〈0.001）. We also found that more OV6 positive staining was correlated with poor prognosis of HCC patients （P〈0.001）. Notably, expression of HMGB 1 was positively correlated with OV6 in density （R2=0.032, P〈0.001） and reversely related to HCC outcomes. Abnormal expression of HMGBI in combination with positive staining of OV6 displayed poorer prognostic performance than single biomarker alone （area under curve （AUC） survival=0.696）. Therefore, HMGB 1 and OV6 positive staining are promising prognostic parameters for HCC, and we propose that HMGB1 and OV6 may cooperate with each other and predict poor prognosis of HCC.

关键词： hepatocellular carcinoma high mobility group box 1 hepatic progenitor marker OV6 prognosis

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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

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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

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Gender disparity in hepatocellular carcinoma(HCC):multiple underlying mechanisms

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Science China(Life Sciences) 2017年第6期60卷 575-584页

作者： Bo Zheng Yan-Jing Zhu Hong-Yang Wang Lei Chen international cooperation laboratory on signal transduction Eastern Hepatobiliary Surgery InstituteSecond Military Medical University Shanghai 200438China National Center for Liver Cancer Shanghai 201805China State Key laboratory of Oncogenes and related Genes Shanghai Cancer InstituteRenji HospitalShanghai Jiaotong University School of MedicineChina

On the global scale, hepatitis B virus(HBV) infection is the main cause of hepatocellular carcinoma(HCC) especially in regions of Asia where HBV infection is endemic. Epidemiological studies show that the incidence of inflammation-driven HCC in males is three times as high as in females. Recent studies suggest that sex hormones have a crucial role in the pathogenesis and development of HBV-induced HCC. We found that the estrogen/androgen signaling pathway is associated with decreased/increased transcription and replication of HBV genes and can promote the development of HBV infections by up/downregulating HBV RNA transcription and inflammatory cytokines levels, which in turn slow down the progression of HBV-induced HCC. Additionally, sex hormones can also affect HBV-related HCC by inducing epigenetic changes. The evidence that both morphology and function of the human liver are affected by sex hormones was found over 60 years ago. However,the underlying molecular mechanism largely remains to be elucidated. This review focuses mainly on the molecular mechanisms behind the sex difference in HCC associated with HBV and other factors. In addition, several potential treatment and therapeutic strategies for inflammation-driven HCC will be introduced in this review.

关键词： gender disparity hepatocarcinoma heptitis B virus

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An intelligent serological SERS test toward early-stage hepatocellular carcinoma diagnosis through ultrasensitive nanobiosensing

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Nano Research 2022年第6期15卷 5331-5339页

作者： Ningtao Cheng Bin Lou Hongyang Wang State Key laboratory of Oncogenes and Related Genes Shanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghai 200127China Department of laboratory Medicine the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310006China international cooperation laboratory on signal transduction Eastern Hepatobiliary Surgery HospitalShanghai 200438China National Center for Liver Cancer Shanghai 201805China

Early or very early detection of hepatocellular carcinoma(HCC)is an effective means to resolve the low cure rates,but there currently lacks a method that fulfills clinical *** of the most prospective approaches to detecting early-stage HCC is directly testing a compendium of disease-relevant biomolecules contained within human serum through surface-enhanced Raman scattering(SERS)nanobiosensing and recognizing the biomolecular *** report a novel Si-based bimetallic nanoensembles-functionalized SERS substrate(its analytical enhancement factor reaches 1.47×10^(12))and introduce an ultrasensitive nanobiosensing for capturing the subtle characteristic changes in SERS spectra caused by HCC,hepatitis B,or *** early diagnosis,we created an intelligent serological test with this nanobiosensing and the deep learning algorithm to gain key biomolecular phenotypes of early-stage *** clinical samples from four target populations(normal,HCC,cirrhosis,and hepatitis B),the proof-of-principle result indicates that the test yielded a predictive accuracy of 98.75%on a held-out dataset(randomly drew 4 out of 28 samples per population).On the same held-out dataset,the sensitivity and specificity of the test were both 100%for distinguishing *** a new-concept liquid biopsy could provide an opportunity for early diagnosis of HCC.

关键词： nanobiosensing intelligent serological SERS test SERS substrate early detection for liver cancer risk stratification for liver cancer screening

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MXR7 facilitates liver cancer metastasis via epithelial-mesenchymal transition

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Science China(Life Sciences) 2017年第11期60卷 1203-1213页

作者： guishuai lv yexiong tan hongwei lv tian fang changzheng wang ting li yanting yu congli hu wen wen hongyang wang wen yang international cooperation laboratory on signal transduction eastern hepatobiliary surgery institutesecond military medical universityShanghai 200438China national center for liver cancer Shanghai 201805China state key laboratory of oncogenes and related genes shanghai cancer institute renji hospitalshanghai jiaotong university school of medicineShanghai 200127China

MXR7 is a cell-surface protein and highly expressed in hepatocellular carcinoma(HCC). The aim of this study is to determine the expression profile of MXR7 in HCC and investigate the influence of MXR7 on invasion and metastasis of HCC cells. For this purpose, immunohistochemical assay was used to identify the differential expression of MXR7 in 94 HCC specimens. Expression of MXR7 in 4 pairs of HCC and portal vein tumor thrombus(PVTT) was also tested. The motility of HCC cells were characterized by transwell migration and matrigel invasion assays. In vivo metastasis potential was determined via tail vein injection ***, compared with noninvasive HCC tumors or human HCC cell lines with low metastatic potential, invasive HCC samples and HCC cell lines with high metastatic potential exhibited higher MXR7 expression. Furthermore, forced expression of MXR7 in SMMC-7721 promoted cell proliferation, migration and invasion in vitro and accelerated tumor growth and metastasis in vivo. Conversely, knockdown of MXR7 expression in HuH7 cells inhibited proliferation and motility of cells. Mechanically,overexpression of MXR7 promoted epithelial-mesenchymal transition(EMT) progress, and MXR7 depletion repressed the EMT phenotype. In conclusion, MXR7 is a mediator of EMT and metastasis in HCC and may serve as a novel therapeutic target.

关键词： hepatocellular carcinoma(HCC) MXR7 metastasis epithelial-mesenchymal transition(EMT)

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