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The role of gut microbiota in liver disease development and treatment

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Liver Research 2019年第1期3卷 3-18页

作者： Lijun wang Yu-Jui Yvonne Wan Department of Medical Pathology and Laboratory Medicine University of CaliforniaDavisSacramentoCAUSA The College of Life Science Yangtze UniversityJingzhouHubeiChina

Liver cancer is the sixth most common cancer worldwide,and the third most common cause of cancer-related death.Hepatocellular carcinoma(HCC),which accounts for more than 90%of primary liver cancers,is an important public health problem.In addition to cirrhosis caused by hepatitis B viral(HBV)or hepatitis C viral(HCV)infection,non-alcoholic fatty liver disease(NAFLD)is becoming a major risk factor for liver cancer because of the prevalence of obesity.Non-alcoholic steatohepatitis(NASH)will likely become the leading indication for liver transplantation in the future.It is well recognized that gut microbiota is a key environmental factor in the pathogenesis of liver disease and cancer.The interplay between gut microbiota and liver disease has been investigated in animal and clinical studies.In this article,we summarize the roles of gut microbiota in the development of liver disease as well as gut microbiota-targeted therapies.

关键词： Microorganism Hepatocellular carcinoma(HCC) Non-alcoholic fatty liver disease(NAFLD) Non-alcoholic steatohepatitis(NASH) Cirrhosis Probiotics Prebiotics Synbiotics

Regulation of bile acid receptor activity

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Liver Research 2018年第4期2卷 180-185页

作者： Yu-Jui Yvonne Wan Lili Sheng Department of Medical Pathology and Laboratory Medicine University of CaliforniaDavisSacramentoCAUSA

Many receptors can be activated by bile acids(BAs)and their derivatives.These include nuclear receptors farnesoid X receptor(FXR),pregnane X receptor(PXR),and vitamin D receptor(VDR),as well as membrane receptors Takeda G protein receptor 5(TGR5),sphingosine-1-phosphate receptor 2(S1PR2),and cholinergic receptor muscarinic 2(CHRM2).All of them are implicated in the development of metabolic and immunological diseases in response to endobiotic and xenobiotic exposure.Because epigenetic regulation is critical for organisms to adapt to constant environmental changes,this review article summarizes epigenetic regulation as well as post-transcriptional modification of bile acid re-ceptors.In addition,the focus of this review is on the liver and digestive tract although these receptors may have effects on other organs.Those regulatory mechanisms are implicated in the disease process and critically important in uncovering innovative strategy for prevention and treatment of metabolic and immunological diseases.

关键词： Bile acid receptor Farnesoid X receptor(FXR) G protein-coupled bile acid receptor Takeda G protein receptor 5(TGR5) Sphingosine-1-phosphate receptor 2 (S1PR2) Acetylation Methylation Glycosylation

Golgi protein 73, hepatocellular carcinoma and other types of cancers

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Liver Research 2020年第4期4卷 161-167页

作者： Yanan wang Yu-Jui Yvonne Wan Department of Pathology and Laboratory Medicine University of California DavisSacramentoCAUSA State Key Laboratory of Medical Molecular Biology Department of Physiolog

Hepatocellular carcinoma(HCC)is one of the most common malignant tumors with a low survival rate.The identification of mechanisms underlying the development of HCC helps uncover cellular and mo-lecular targets for the diagnosis,prevention,and treatment of HCC.Golgi protein 73(GP73)level is up-regulated in HCC patients and potentially can be a therapeutic target.Despite many studies devoted to GP73 as a marker for HCC early diagnosis,there is little discussion about the function of GP73 in HCC tumorigenesis.Given the poor response to currently available HCC therapies,a better understanding of the role of GP73 in HCC may provide a new therapeutic target for HCC.The current paper summarizes the role of GP73 as a diagnostic marker as well as its roles in liver carcinogenesis.Its roles in other types of cancer are also discussed.

关键词： Liver cancer Hepatocellular carcinoma(HCC) Diagnostic markers Golgi protein 73(GP73) Alpha-fetoprotein(AFP) Gamma-glutamyl transferase(GGT) Hepatitis C virus(HCV) Hepatitis B virus(HBV)

Targeting stroma and tumor,silencing galectin 1 treats orthotopic mouse hepatocellular carcinoma

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Acta Pharmaceutica Sinica B 2024年第1期14卷 292-303页

作者： Tahereh Setayesh Ying Hu Farzam Vaziri Xin Chen Jinping Lai Dongguang Wei Yu-Jui Yvonne Wan Department of Medical Pathology and Laboratory Medicine University of CaliforniaDavisSacramentoCA 95817USA Cancer Biology Program the University of Hawaii Cancer CenterHonoluluHI 96813USA Department of Pathology and Laboratory Medicine Kaiser Permanente Sacramento Medical CenterSacramentoCA 95825USA

This study examines inhibiting galectin 1(Gal1)as a treatment option for hepatocellular carcinoma(HCC).Gal1 has immunosuppressive and cancer-promoting roles.Our data showed that Gal1 was highly expressed in human and mouse HCC.The levels of Gal1 positively correlated with the stages of human HCC and negatively with survival.The roles of Gal1 in HCC were studied using overexpression(OE)or silencing using Igals1 siRNA delivered by AAV9.Prior to HCC initiation induced by RAS and AKT mutations,lgals1-OE and silencing had opposite impacts on tumor load.The treatment effect of lgals1 siRNAwas further demonstrated by intersecting HCC at different time points when the tumor load had already reached 9%or even 42%of the body weight.Comparing spatial transcriptomic profiles of Gal1 silenced and OE HCC,inhibiting matrix formation and recognition of foreign antigen in CD45t cell-enriched areas located at tumor-margin likely contributed to the anti-HCC effects of Gal1 silencing.Within the tumors,silencing Gal1 inhibited translational initiation,elongation,and termination.Furthermore,Gal1 silencing increased immune cells as well as expanded cytotoxic T cells within the tumor,and the anti-HCC effect of lgals1 siRNAwas CD8-dependent.Overall,Gal1 silencing has a promising potential for HCC treatment.

关键词： Liver Hepatocellular carcinoma Carbohydrate-binding lectin Galectin 1 Extracellular matrix Translation Spatial transcriptomics Tumor-margin

The contributions of bacteria metabolites to the development of hepatic encephalopathy

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Liver Research 2023年第4期7卷 296-303页

作者： Miranda Claire Gilbert Tahereh Setayesh Yu-Jui Yvonne Wan Department of Pathology and Laboratory Medicine University of CaliforniaDavisSacramentoCAUSA

Over 20%of mortality during acute liver failure is associated with the development of hepatic encephalopathy(HE).Thus,HE is a complication of acute liver failure with a broad spectrum of neuropsychiatric abnormalities ranging from subclinical alterations to coma.HE is caused by the diversion of portal blood into systemic circulation through portosystemic collateral vessels.Thus,the brain is exposed to intestinal-derived toxic substances.Moreover,the strategies to prevent advancement and improve the prognosis of such a liver-brain disease rely on intestinal microbial modulation.This is supported by the findings that antibiotics such as rifaximin and laxative lactulose can alleviate hepatic cirrhosis and/or prevent HE.Together,the significance of the gut-liver-brain axis in human health warrants attention.This review paper focuses on the roles of bacteria metabolites,mainly ammonia and bile acids(BAs)as well as BA receptors in HE.The literature search conducted for this review included searches for phrases such as BA receptors,BAs,ammonia,farnesoid X receptor(FXR),G protein-coupled bile acid receptor 1(GPBAR1 or TGR5),sphingosine-1-phosphate receptor 2(S1PR2),and cirrhosis in conjunction with the phrase hepatic encephalopathy and portosystemic encephalopathy.PubMed,as well as Google Scholar,was the search engines used to find relevant publications.

关键词： Liver Gut-liver-brain axis Bile acids(BAs) Bile acid(BA)receptors Farnesoid X receptor(FXR) Takeda G protein-coupled receptor 5(TGR5) Sphingosine-1-phosphate receptor 2 (S1PR2) Brain

Hepatocellular carcinoma immunotherapy:The impact of epigenetic drugs and the gut microbiome

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Liver Research 2020年第4期4卷 191-198页

作者： Farzam Vaziri Steven D.Colquhoun Yu-Jui Yvonne Wan Department of Pathology and Laboratory Medicine University of California DavisSacramentoCAUSA Department of Surgery University of California DavisSacramentoCAUSA

The incidence of hepatocellular carcinoma(HCC)has been increasing for decades.This disease has now risen to become the sixth most common malignancy overall,while ranking as the third most frequent cause of cancer mortality.While several surgical interventions and loco-regional treatment options are available,up to 80%of patients present with advanced disease not amenable to standard therapies.Indeed,traditional cytotoxic chemotherapeutic agents are notoriously ineffective and essentially play no role in the management of affected patients.This has led to an enormous need for more effective sys-temic therapeutic options.In recent years,immunotherapy has emerged as a potentially viable and exciting new alternative for the treatment of HCC.Although the current immunotherapeutic options remain imperfect,various strategies can be employed to further improve their efficacy.New findings have revealed epigenetic modulation can be effective as a new approach for improving HCC immuno-therapy.Studying the gut microbiome(gut-liver axis)can also be an interesting subject in this regard.Here,we explore the latest insights into the role of immunotherapy treating HCC,both mono and in combination with other agents.We also focus on the impact of epigenetic drugs and the microbiome in the overall effectiveness of HCC immunotherapy.

关键词： Hepatocellular carcinoma(HCC) Immunotherapy Gut microbiota Epigenetic drugs Combination therapy

Overexpression of Galectin-1 and Galectin-3 in hepatocellular carcinoma

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Liver Research 2020年第4期4卷 173-179页

作者： Tahereh Setayesh Steven D.Colquhoun Yu-Jui Yvonne Wan Department of Pathology and Laboratory Medicine University of California DavisSacramentoCAUSA Department of Surgery University of California DavisSacramentoCAUSA

Galectins(Gals)are evolutionarily conserved proteins that bind to b-galactoside containing glycans.Abnormal expression of Gals is associated with the development,progression,and metastasis of different types of cancer.Among the 11 Gals identified in humans,the roles of Gal-1 and Gal-3 have been extensively investigated in various tumors.Here,we summarize the roles of overly expressed Gal-1 and Gal-3 in the pathogenesis of hepatocellular carcinoma(HCC).The overexpression of Gal-1 and Gal-3 correlates with tumor growth,HCC cell migration and invasion,tumor aggressiveness,metastasis,and poor prognosis.A potentially promising future treatment strategy for HCC may include the combination of immunotherapy with Gal-1 inhibition.Additional research is warranted to investigate targeting Gal-1 and Gal-3 for HCC treatment.

关键词： Galectin-1(Gal-1) Galectin-3(Gal-3) Liver cancer Hepatocellular carcinoma(HCC) Fibrosis Cirrhosis Non-alcoholic steatohepatitis(NASH) Metastasis Epithelial-mesenchymal transition(EMT)

MiR-22 as a metabolic silencer and liver tumor suppressor

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Liver Research 2020年第2期4卷 74-80页

作者： Lijun wang yu-Shiuan wang Eko Mugiyanto Wei-Chiao Chang Yu-Jui Yvonne Wan Department of Pathology and Laboratory Medicine University of California DavisSacramentoCA The College of Life Science Yangtze UniversityJingzhouHubei PhD Program in Clinical Drug Development of Chinese Herbal Medicine College of PharmacyTaipei Medical UniversityTaipei Department of Clinical Pharmacy School of PharmacyTaipei Medical UniversityTaipei

With obesity rate consistently increasing,a strong relationship between obesity and fatty liver disease has been discovered.More than 90%of bariatric surgery patients also have non-alcoholic fatty liver diseases(NAFLDs).NAFLD and non-alcoholic steatohepatitis(NASH),which are the hepatic manifesta-tions of metabolic syndrome,can lead to liver carcinogenesis.Unfortunately,there is no effective medicine that can be used to treat NASH or liver cancer.Thus,it is critically important to understand the mechanism underlying the development of these diseases.Extensive evidence suggests that microRNA 22(miR-22)can be a diagnostic marker for liver diseases as well as a treatment target.This review paper focuses on the roles of miR-22 in metabolism,steatosis,and liver carcinogenesis.Literature search is limited based on the publications included in the PubMed database in the recent 10 years.

关键词： MicroRNA-22(miR-22) Cancer Liver Metabolism Steatosis Non-alcoholic steatohepatitis Hepatitis

Glypican-3: A molecular marker for the detection and treatment of hepatocellular carcinoma

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Liver Research 2020年第4期4卷 168-172页

作者： Tsung-Chieh Shih Lijun wang Hsiao-Chi wang Yu-Jui Yvonne Wan Department of Biochemistry and Molecular Medicine University of California DavisSacramentoCAUSA Department of Pathology and Laboratory Medicine University of California DavisSacramentoCAUSA Department of Internal Medicine University of California DavisDavisCAUSA

Hepatocellular carcinoma(HCC)is a malignant tumor with a fairly poor prognosis(5-year survival of less than 50%).Using sorafenib,the only food and drug administration(FDA)-approved drug,HCC cannot be effectively treated;it can only be controlled at most for a couple of months.There is a great need to develop efficacious treatment against this debilitating disease.Glypican-3(GPC3),a member of the glypican family that attaches to the cell surface by a glycosylphosphatidylinositol anchor,is overex-pressed in HCC cases and is elevated in the serum of a large proportion of patients with HCC.GPC3 expression contributes to HCC growth and metastasis.Furthermore,several different types of antibodies targeting GPC3 have been developed.The aim of this review is to summarize the current literatures on the GPC3 expression in human HCC,molecular mechanisms of GPC3 regulation and antibodies targeting GPC3.

关键词： Glypican-3(GPC3) Wnt signaling Hepatocellular carcinoma(HCC)