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1
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Nayak A, Streiff H, Gonzalez I, Adekoya OO, Silva I, Shenoy AK. Wnt Pathway-Targeted Therapy in Gastrointestinal Cancers: Integrating Benchside Insights with Bedside Applications. Cells 2025; 14:178. [PMID: 39936971 PMCID: PMC11816596 DOI: 10.3390/cells14030178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 01/05/2025] [Accepted: 01/07/2025] [Indexed: 02/13/2025] Open
Abstract
The Wnt signaling pathway is critical in the onset and progression of gastrointestinal (GI) cancers. Anomalies in this pathway, often stemming from mutations in critical components such as adenomatous polyposis coli (APC) or β-catenin, lead to uncontrolled cell proliferation and survival. In the case of colorectal cancer, dysregulation of the Wnt pathway drives tumor initiation and growth. Similarly, aberrant Wnt signaling contributes to tumor development, metastasis, and resistance to therapy in other GI cancers, such as gastric, pancreatic, and hepatocellular carcinomas. Targeting the Wnt pathway or its downstream effectors has emerged as a promising therapeutic strategy for combating these highly aggressive GI malignancies. Here, we review the dysregulation of the Wnt signaling pathway in the pathogenesis of GI cancers and further explore the therapeutic potential of targeting the various components of the Wnt pathway. Furthermore, we summarize and integrate the preclinical evidence supporting the therapeutic efficacy of potent Wnt pathway inhibitors with completed and ongoing clinical trials in GI cancers. Additionally, we discuss the challenges of Wnt pathway-targeted therapies in GI cancers to overcome these concerns for effective clinical translation.
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Ferrell LD, Kakar S, Terracciano LM, Wee A. Tumours and Tumour-Like Lesions. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:842-946. [DOI: 10.1016/b978-0-7020-8228-3.00013-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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3
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Milosevic I, Todorovic N, Filipovic A, Simic J, Markovic M, Stevanovic O, Malinic J, Katanic N, Mitrovic N, Nikolic N. HCV and HCC Tango-Deciphering the Intricate Dance of Disease: A Review Article. Int J Mol Sci 2023; 24:16048. [PMID: 38003240 PMCID: PMC10671156 DOI: 10.3390/ijms242216048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 10/12/2023] [Accepted: 10/25/2023] [Indexed: 11/26/2023] Open
Abstract
Hepatitis C virus (HCV) is a major cause of hepatocellular carcinoma (HCC) accounting for around one-third of all HCC cases. Prolonged inflammation in chronic hepatitis C (CHC), maintained through a variety of pro- and anti-inflammatory mediators, is one of the aspects of carcinogenesis, followed by mitochondrial dysfunction and oxidative stress. Immune response dysfunction including the innate and adaptive immunity also plays a role in the development, as well as in the recurrence of HCC after treatment. Some of the tumor suppressor genes inhibited by the HCV proteins are p53, p73, and retinoblastoma 1. Mutations in the telomerase reverse transcriptase promoter and the oncogene catenin beta 1 are two more important carcinogenic signaling pathways in HCC associated with HCV. Furthermore, in HCV-related HCC, numerous tumor suppressor and seven oncogenic genes are dysregulated by epigenetic changes. Epigenetic regulation of gene expression is considered as a lasting "epigenetic memory", suggesting that HCV-induced changes persist and are associated with liver carcinogenesis even after cure. Epigenetic changes and immune response dysfunction are recognized targets for potential therapy of HCC.
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Affiliation(s)
- Ivana Milosevic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Nevena Todorovic
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Ana Filipovic
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Jelena Simic
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Marko Markovic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Olja Stevanovic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Jovan Malinic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Natasa Katanic
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
- Faculty of Medicine, University of Pristina Situated in Kosovska Mitrovica, 28000 Kosovska Mitrovica, Serbia
| | - Nikola Mitrovic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Natasa Nikolic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
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Przybyszewski EM, Chung RT. Unmet Needs in the Post-Direct-Acting Antiviral Era: Hepatocarcinogenesis After Hepatitis C Virus Eradication. J Infect Dis 2023; 228:S226-S231. [PMID: 37703341 PMCID: PMC10499186 DOI: 10.1093/infdis/jiac447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/15/2023] Open
Abstract
Infection with chronic hepatitis C virus (HCV) is an important risk factor for hepatocellular carcinoma (HCC). Direct-acting antiviral therapy has transformed care for patients with HCV and reduces the risk of HCC. Despite HCV cure, a residual HCC risk remains in patients with advanced fibrosis and cirrhosis, with multiple mechanisms underlying subsequent hepatocarcinogenesis. Transcriptomic and proteomic signatures demonstrate the capacity for HCC risk stratification, and chemoprevention strategies are emerging. For now, pending more precise stratification, HCC surveillance of patients with cured HCV and advanced fibrosis or cirrhosis should continue.
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Affiliation(s)
- Eric M Przybyszewski
- Liver Center and Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Raymond T Chung
- Liver Center and Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
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5
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Zou G, Park JI. Wnt signaling in liver regeneration, disease, and cancer. Clin Mol Hepatol 2023; 29:33-50. [PMID: 35785913 PMCID: PMC9845677 DOI: 10.3350/cmh.2022.0058] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 06/30/2022] [Indexed: 02/02/2023] Open
Abstract
The liver exhibits the highest recovery rate from acute injuries. However, in chronic liver disease, the long-term loss of hepatocytes often leads to adverse consequences such as fibrosis, cirrhosis, and liver cancer. The Wnt signaling plays a pivotal role in both liver regeneration and tumorigenesis. Therefore, manipulating the Wnt signaling has become an attractive approach to treating liver disease, including cancer. Nonetheless, given the crucial roles of Wnt signaling in physiological processes, blocking Wnt signaling can also cause several adverse effects. Recent studies have identified cancer-specific regulators of Wnt signaling, which would overcome the limitation of Wnt signaling target approaches. In this review, we discussed the role of Wnt signaling in liver regeneration, precancerous lesion, and liver cancer. Furthermore, we summarized the basic and clinical approaches of Wnt signaling blockade and proposed the therapeutic prospects of cancer-specific Wnt signaling blockade for liver cancer treatment.
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Affiliation(s)
- Gengyi Zou
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA,Corresponding author : Gengyi Zou Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Blvd Unit 1054, Houston, TX 77030, USA Tel: +1-713-792-3659, Fax: +1-713-794-5369, E-mail:
| | - Jae-Il Park
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA,Genetics and Epigenetics Program, The University of Texas MD Anderson Cancer Center Graduate School of Biomedical Sciences, Houston, TX, USA,Jae-Il Park Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Blvd. Unit 1052, Houston, TX 77030, USA Tel: +1-713-792-3659, Fax: +1-713-794-5369, E-mail:
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6
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Xu Y, Yu X, Sun Z, He Y, Guo W. Roles of lncRNAs Mediating Wnt/β-Catenin Signaling in HCC. Front Oncol 2022; 12:831366. [PMID: 35356220 PMCID: PMC8959654 DOI: 10.3389/fonc.2022.831366] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Accepted: 02/14/2022] [Indexed: 11/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is considered the second most deadly cancer worldwide. Due to the absence of early diagnostic markers and effective therapeutic approaches, distant metastasis and increasing recurrence rates are major difficulties in the clinical treatment of HCC. Further understanding of its pathogenesis has become an urgent goal in HCC research. Recently, abnormal expression of long noncoding RNAs (lncRNAs) was identified as a vital regulator involved in the initiation and development of HCC. Activation of the Wnt/β-catenin pathway has been reported to obviously impact cell proliferation, invasion, and migration of HCC. This article reviews specific interactions, significant mechanisms and molecules related to HCC initiation and progression to provide promising strategies for treatment.
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Affiliation(s)
- Yating Xu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Open and Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China.,Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation Medicine, Zhengzhou, China
| | - Xiao Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Open and Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China.,Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation Medicine, Zhengzhou, China
| | - Zongzong Sun
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yuting He
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Open and Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China.,Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation Medicine, Zhengzhou, China
| | - Wenzhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Open and Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China.,Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation Medicine, Zhengzhou, China
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HCV Proteins Modulate the Host Cell miRNA Expression Contributing to Hepatitis C Pathogenesis and Hepatocellular Carcinoma Development. Cancers (Basel) 2021; 13:cancers13102485. [PMID: 34069740 PMCID: PMC8161081 DOI: 10.3390/cancers13102485] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 05/12/2021] [Accepted: 05/17/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary According to the last estimate by the World Health Organization (WHO), more than 71 million individuals have chronic hepatitis C worldwide. The persistence of HCV infection leads to chronic hepatitis, which can evolve into liver cirrhosis and ultimately into hepatocellular carcinoma (HCC). Although the pathogenic mechanisms are not fully understood, it is well established that an interplay between host cell factors, including microRNAs (miRNA), and viral components exist in all the phases of the viral infection and replication. Those interactions establish a complex equilibrium between host cells and HCV and participate in multiple mechanisms characterizing hepatitis C pathogenesis. The present review aims to describe the role of HCV structural and non-structural proteins in the modulation of cellular miRNA during HCV infection and pathogenesis. Abstract Hepatitis C virus (HCV) genome encodes for one long polyprotein that is processed by cellular and viral proteases to generate 10 polypeptides. The viral structural proteins include the core protein, and the envelope glycoproteins E1 and E2, present at the surface of HCV particles. Non-structural (NS) proteins consist of NS1, NS2, NS3, NS4A, NS4B, NS5a, and NS5b and have a variable function in HCV RNA replication and particle assembly. Recent findings evidenced the capacity of HCV virus to modulate host cell factors to create a favorable environment for replication. Indeed, increasing evidence has indicated that the presence of HCV is significantly associated with aberrant miRNA expression in host cells, and HCV structural and non-structural proteins may be responsible for these alterations. In this review, we summarize the recent findings on the role of HCV structural and non-structural proteins in the modulation of host cell miRNAs, with a focus on the molecular mechanisms responsible for the cell re-programming involved in viral replication, immune system escape, as well as the oncogenic process. In this regard, structural and non-structural proteins have been shown to modulate the expression of several onco-miRNAs or tumor suppressor miRNAs.
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Lin D, Reddy V, Osman H, Lopez A, Koksal AR, Rhadhi SM, Dash S, Aydin Y. Additional Inhibition of Wnt/β-Catenin Signaling by Metformin in DAA Treatments as a Novel Therapeutic Strategy for HCV-Infected Patients. Cells 2021; 10:790. [PMID: 33918222 PMCID: PMC8065725 DOI: 10.3390/cells10040790] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/24/2021] [Accepted: 03/27/2021] [Indexed: 12/17/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection causes hepatocellular carcinoma (HCC). Although HCV clearance has been improved by the advent of direct-acting antiviral agents (DAA), retrospective studies have shown that the risk of subsequent HCC, while considerably decreased compared with active HCV infection, persists after DAA regimens. However, either the mechanisms of how chronic HCV infection causes HCC or the factors responsible for HCC development after viral eradication in patients with DAA treatments remain elusive. We reported an in vitro model of chronic HCV infection and determined Wnt/β-catenin signaling activation due to the inhibition of GSK-3β activity via serine 9 phosphorylation (p-ser9-GSK-3β) leading to stable non-phosphorylated β-catenin. Immunohistochemical staining demonstrated the upregulation of both β-catenin and p-Ser9-GSK-3β in HCV-induced HCC tissues. Chronic HCV infection increased proliferation and colony-forming ability, but knockdown of β-catenin decreased proliferation and increased apoptosis. Unexpectedly, Wnt/β-catenin signaling remained activated in chronic HCV-infected cells after HCV eradication by DAA, but metformin reversed it through PKA/GSK-3β-mediated β-catenin degradation, inhibited colony-forming ability and proliferation, and increased apoptosis, suggesting that DAA therapy in combination with metformin may be a novel therapy to treat HCV-associated HCC where metformin suppresses Wnt/β-catenin signaling for HCV-infected patients.
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Affiliation(s)
- Dong Lin
- Laboratory Medicine and Department of Pathology, Tulane University School of Medicine, New Orleans, LA 70112, USA; (V.R.); (H.O.); (A.L.); (A.R.K.); (S.M.R.); (S.D.)
| | | | | | | | | | | | | | - Yucel Aydin
- Laboratory Medicine and Department of Pathology, Tulane University School of Medicine, New Orleans, LA 70112, USA; (V.R.); (H.O.); (A.L.); (A.R.K.); (S.M.R.); (S.D.)
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9
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Jung YS, Stratton SA, Lee SH, Kim MJ, Jun S, Zhang J, Zheng B, Cervantes CL, Cha JH, Barton MC, Park JI. TMEM9-v-ATPase Activates Wnt/β-Catenin Signaling Via APC Lysosomal Degradation for Liver Regeneration and Tumorigenesis. Hepatology 2021; 73:776-794. [PMID: 32380568 PMCID: PMC7647947 DOI: 10.1002/hep.31305] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 04/07/2020] [Accepted: 04/08/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS How Wnt signaling is orchestrated in liver regeneration and tumorigenesis remains elusive. Recently, we identified transmembrane protein 9 (TMEM9) as a Wnt signaling amplifier. APPROACH AND RESULTS TMEM9 facilitates v-ATPase assembly for vesicular acidification and lysosomal protein degradation. TMEM9 is highly expressed in regenerating liver and hepatocellular carcinoma (HCC) cells. TMEM9 expression is enriched in the hepatocytes around the central vein and acutely induced by injury. In mice, Tmem9 knockout impairs hepatic regeneration with aberrantly increased adenomatosis polyposis coli (Apc) and reduced Wnt signaling. Mechanistically, TMEM9 down-regulates APC through lysosomal protein degradation through v-ATPase. In HCC, TMEM9 is overexpressed and necessary to maintain β-catenin hyperactivation. TMEM9-up-regulated APC binds to and inhibits nuclear translocation of β-catenin, independent of HCC-associated β-catenin mutations. Pharmacological blockade of TMEM9-v-ATPase or lysosomal degradation suppresses Wnt/β-catenin through APC stabilization and β-catenin cytosolic retention. CONCLUSIONS Our results reveal that TMEM9 hyperactivates Wnt signaling for liver regeneration and tumorigenesis through lysosomal degradation of APC.
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Affiliation(s)
- Youn-Sang Jung
- Department of Experimental Radiation OncologyDivision of Radiation OncologyThe University of Texas MD Anderson Cancer CenterHoustonTX.,Department of Life ScienceChung-Ang UniversitySeoulSouth Korea
| | - Sabrina A Stratton
- Department of Epigenetics and Molecular CarcinogenesisThe University of Texas MD Anderson Cancer CenterHoustonTX
| | - Sung Ho Lee
- Department of Experimental Radiation OncologyDivision of Radiation OncologyThe University of Texas MD Anderson Cancer CenterHoustonTX
| | - Moon-Jong Kim
- Department of Experimental Radiation OncologyDivision of Radiation OncologyThe University of Texas MD Anderson Cancer CenterHoustonTX
| | - Sohee Jun
- Department of Experimental Radiation OncologyDivision of Radiation OncologyThe University of Texas MD Anderson Cancer CenterHoustonTX
| | - Jie Zhang
- Department of Experimental Radiation OncologyDivision of Radiation OncologyThe University of Texas MD Anderson Cancer CenterHoustonTX
| | - Biyun Zheng
- Department of Experimental Radiation OncologyDivision of Radiation OncologyThe University of Texas MD Anderson Cancer CenterHoustonTX
| | - Christopher L Cervantes
- Department of Experimental Radiation OncologyDivision of Radiation OncologyThe University of Texas MD Anderson Cancer CenterHoustonTX
| | - Jong-Ho Cha
- Department of Biomedical SciencesCollege of MedicineInha UniversityIncheonSouth Korea
| | - Michelle C Barton
- Department of Epigenetics and Molecular CarcinogenesisThe University of Texas MD Anderson Cancer CenterHoustonTX.,Graduate School of Biomedical SciencesThe University of Texas MD Anderson Cancer CenterHoustonTX
| | - Jae-Il Park
- Department of Experimental Radiation OncologyDivision of Radiation OncologyThe University of Texas MD Anderson Cancer CenterHoustonTX.,Graduate School of Biomedical SciencesThe University of Texas MD Anderson Cancer CenterHoustonTX.,Program in Genetics and EpigeneticsThe University of Texas MD Anderson Cancer CenterHoustonTX
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Hashempour T, Dehghani B, Musavi Z, Moayedi J, Hasanshahi Z, Sarvari J, Hosseini SY, Hosseini E, Moeini M, Merat S. Impact of IL28 Genotypes and Modeling the Interactions of HCV Core Protein on Treatment of Hepatitis C. Interdiscip Sci 2020; 12:424-437. [PMID: 32656614 DOI: 10.1007/s12539-020-00382-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 05/02/2020] [Accepted: 07/01/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Mutations in the core CVR region of hepatitis C virus (HCV) and polymorphisms of interleukin 28B (IL28B) are associated with progression toward liver disease and in response to therapy. In addition, interactions of the core protein with some cell interactors can be related to HCV liver damage. AIM This study aimed to evaluate the effect of core mutations as well as IL28B polymorphism on clinical features, sustained virological response (SVR) in 1a and 3a HCV genotypes amongst Iranian HCV infected patients, and the impact of mutations on core protein properties, antigenic properties, and interactions with HCV inhibitors, using several bioinformatics tools. METHODS Seventy-nine Iranian patients infected with HCV genotypes 1a and 3a and diagnosed with chronic active hepatitis were examined. Plasma viral RNA was used to amplify and sequence the HCV Core gene; also, HCV viral load, molecular genotyping, and the liver enzymes were determined for all samples. The sequencing results were analyzed by several reliable bioinformatics tools to determine the physicochemical properties, B cell epitopes, post-modification changes, and secondary/tertiary structures; and evaluate the interactions with 4 drugs by docking method. RESULT There were some substitutions in core CVR related to ALT and AST enzymes that can lead to HCV advanced liver disease. The most prevalent mutation for 3a genotypes was a substitution in aa 162 (I to V) while we did not find any mutation in 1a responder group. Polymorphism of the rs8099917 showed that the majority of patients had TG heterozygous and carried CT genotype at the rs12979860. Analysis indicated several phosphorylation sits for core protein as well as two important disulfide bonds. Immunogenic prediction showed that core protein can strongly induce the immune system. Interaction analysis, using the docking method revealed two potential interactors (Vitronectin and SETD2). CONCLUSION Generally, mutations in all core CVR regions in all patients showed a relationship between such substitutions and higher liver enzymes that can result in advanced liver disease progression in HCV infected patients. Furthermore, immunoinformatics analysis determined the possible immunodominant regions to be considered in HCV vaccine designs. Furthermore, no association between SVR and IL28B polymorphism was shown. In silico analysis determined modification sites, structures, B-cell epitopes of core protein and interactions with several interactors can lead to persistent HCV infection in the cell and the progress of liver diseases.
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Affiliation(s)
- Tayebeh Hashempour
- Clinical Microbiology Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Behzad Dehghani
- Shiraz HIV/AIDS Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Musavi
- Clinical Microbiology Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Javad Moayedi
- Clinical Microbiology Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Hasanshahi
- Shiraz HIV/AIDS Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Jamal Sarvari
- Bacteriology and Virology Department, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Younes Hosseini
- Bacteriology and Virology Department, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ebrahim Hosseini
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Maryam Moeini
- Gastroenterology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shahin Merat
- Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
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11
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Ljungberg JK, Kling JC, Tran TT, Blumenthal A. Functions of the WNT Signaling Network in Shaping Host Responses to Infection. Front Immunol 2019; 10:2521. [PMID: 31781093 PMCID: PMC6857519 DOI: 10.3389/fimmu.2019.02521] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 10/10/2019] [Indexed: 12/15/2022] Open
Abstract
It is well-established that aberrant WNT expression and signaling is associated with developmental defects, malignant transformation and carcinogenesis. More recently, WNT ligands have emerged as integral components of host responses to infection but their functions in the context of immune responses are incompletely understood. Roles in the modulation of inflammatory cytokine production, host cell intrinsic innate defense mechanisms, as well as the bridging of innate and adaptive immunity have been described. To what degree WNT responses are defined by the nature of the invading pathogen or are specific for subsets of host cells is currently not well-understood. Here we provide an overview of WNT responses during infection with phylogenetically diverse pathogens and highlight functions of WNT ligands in the host defense against infection. Detailed understanding of how the WNT network orchestrates immune cell functions will not only improve our understanding of the fundamental principles underlying complex immune response, but also help identify therapeutic opportunities or potential risks associated with the pharmacological targeting of the WNT network, as currently pursued for novel therapeutics in cancer and bone disorders.
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Affiliation(s)
- Johanna K Ljungberg
- The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Jessica C Kling
- The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Thao Thanh Tran
- The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Antje Blumenthal
- The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia
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12
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Guo L, Sharma SD, Debes JD, Beisang D, Rattenbacher B, Louis IVS, Wiesner DL, Cameron CE, Bohjanen PR. The hepatitis C viral nonstructural protein 5A stabilizes growth-regulatory human transcripts. Nucleic Acids Res 2019; 46:2537-2547. [PMID: 29385522 PMCID: PMC5861452 DOI: 10.1093/nar/gky061] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Accepted: 01/22/2018] [Indexed: 12/11/2022] Open
Abstract
Numerous mammalian proto-oncogene and other growth-regulatory transcripts are upregulated in malignancy due to abnormal mRNA stabilization. In hepatoma cells expressing a hepatitis C virus (HCV) subgenomic replicon, we found that the viral nonstructural protein 5A (NS5A), a protein known to bind to viral RNA, also bound specifically to human cellular transcripts that encode regulators of cell growth and apoptosis, and this binding correlated with transcript stabilization. An important subset of human NS5A-target transcripts contained GU-rich elements, sequences known to destabilize mRNA. We found that NS5A bound to GU-rich elements in vitro and in cells. Mutation of the NS5A zinc finger abrogated its GU-rich element-binding and mRNA stabilizing activities. Overall, we identified a molecular mechanism whereby HCV manipulates host gene expression by stabilizing host transcripts in a manner that would promote growth and prevent death of virus-infected cells, allowing the virus to establish chronic infection and lead to the development of hepatocellular carcinoma.
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Affiliation(s)
- Liang Guo
- Department of Medicine, Division of Infectious Diseases and International Medicine, Program in Infection and Immunity, University of Minnesota, Minneapolis, MN 55455, USA
- Institute for Molecular Virology Training Program, University of Minnesota, Minneapolis, MN 55455, USA
- Graduate Program in Comparative and Molecular Bioscience, University of Minnesota, Minneapolis, MN 55455, USA
| | - Suresh D Sharma
- Department of Biochemistry & Molecular Biology, The Pennsylvania State University 201 Althouse Laboratory, University Park, PA 16802, USA
| | - Jose D Debes
- Department of Medicine, Division of Infectious Diseases and International Medicine, Program in Infection and Immunity, University of Minnesota, Minneapolis, MN 55455, USA
| | - Daniel Beisang
- Department of Medicine, Division of Infectious Diseases and International Medicine, Program in Infection and Immunity, University of Minnesota, Minneapolis, MN 55455, USA
- Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Bernd Rattenbacher
- Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Irina Vlasova-St Louis
- Department of Medicine, Division of Infectious Diseases and International Medicine, Program in Infection and Immunity, University of Minnesota, Minneapolis, MN 55455, USA
| | - Darin L Wiesner
- Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Craig E Cameron
- Department of Biochemistry & Molecular Biology, The Pennsylvania State University 201 Althouse Laboratory, University Park, PA 16802, USA
- Correspondence may also be addressed to Craig E. Cameron.
| | - Paul R Bohjanen
- Department of Medicine, Division of Infectious Diseases and International Medicine, Program in Infection and Immunity, University of Minnesota, Minneapolis, MN 55455, USA
- Institute for Molecular Virology Training Program, University of Minnesota, Minneapolis, MN 55455, USA
- Graduate Program in Comparative and Molecular Bioscience, University of Minnesota, Minneapolis, MN 55455, USA
- Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USA
- To whom correspondence should be addressed.
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13
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Wang W, Smits R, Hao H, He C. Wnt/β-Catenin Signaling in Liver Cancers. Cancers (Basel) 2019; 11:E926. [PMID: 31269694 PMCID: PMC6679127 DOI: 10.3390/cancers11070926] [Citation(s) in RCA: 118] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 06/24/2019] [Accepted: 06/25/2019] [Indexed: 12/12/2022] Open
Abstract
Liver cancer is among the leading global healthcare issues associated with high morbidity and mortality. Liver cancer consists of hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), hepatoblastoma (HB), and several other rare tumors. Progression has been witnessed in understanding the interactions between etiological as well as environmental factors and the host in the development of liver cancers. However, the pathogenesis remains poorly understood, hampering the design of rational strategies aiding in preventing liver cancers. Accumulating evidence demonstrates that aberrant activation of the Wnt/β-catenin signaling pathway plays an important role in the initiation and progression of HCC, CCA, and HB. Targeting Wnt/β-catenin signaling potentiates a novel avenue for liver cancer treatment, which may benefit from the development of numerous small-molecule inhibitors and biologic agents in this field. In this review, we discuss the interaction between various etiological factors and components of Wnt/β-catenin signaling early in the precancerous lesion and the acquired mechanisms to further enhance Wnt/β-catenin signaling to promote robust cancer formation at later stages. Additionally, we shed light on current relevant inhibitors tested in liver cancers and provide future perspectives for preclinical and clinical liver cancer studies.
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Affiliation(s)
- Wenhui Wang
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing 211198, China
| | - Ron Smits
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam 3015 CN, The Netherlands
| | - Haiping Hao
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing 211198, China.
| | - Chaoyong He
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing 211198, China.
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14
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Liu Y, Song Y, Ye M, Hu X, Wang ZP, Zhu X. The emerging role of WISP proteins in tumorigenesis and cancer therapy. J Transl Med 2019; 17:28. [PMID: 30651114 PMCID: PMC6335850 DOI: 10.1186/s12967-019-1769-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Accepted: 01/02/2019] [Indexed: 12/14/2022] Open
Abstract
Accumulated evidence has demonstrated that WNT1 inducible signaling pathway protein (WISP) genes, which belong to members of the CCN growth factor family, play a pivotal role in tumorigenesis and progression of a broad spectrum of human cancers. Mounting studies have identified that WISP proteins (WISP1-3) exert different biological functions in various human malignancies. Emerging evidence indicates that WISP proteins are critically involved in cell proliferation, apoptosis, invasion and metastasis in cancers. Because the understanding of a direct function of WISP proteins in cancer development and progression has begun to emerge, in this review article, we describe the physiological function of WISP proteins in a variety of human cancers. Moreover, we highlight the current understanding of how the WISP protein is involved in tumorigenesis and cancer progression. Furthermore, we discuss that targeting WISP proteins could be a promising strategy for the treatment of human cancers. Hence, the regulation of WISP proteins could improve treatments for cancer patients.
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Affiliation(s)
- Yi Liu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan Xi Road, Wenzhou, 325027 Zhejiang China
| | - Yizuo Song
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan Xi Road, Wenzhou, 325027 Zhejiang China
| | - Miaomiao Ye
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan Xi Road, Wenzhou, 325027 Zhejiang China
| | - Xiaoli Hu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan Xi Road, Wenzhou, 325027 Zhejiang China
| | - Z. Peter Wang
- Center of Scientific Research, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027 Zhejiang China
- Department of Biochemistry and Molecular Biology, School of Laboratory Medicine, Bengbu Medical College, Bengbu, 233030 Anhui China
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215 USA
| | - Xueqiong Zhu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan Xi Road, Wenzhou, 325027 Zhejiang China
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15
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Villani R, Vendemiale G, Serviddio G. Molecular Mechanisms Involved in HCC Recurrence after Direct-Acting Antiviral Therapy. Int J Mol Sci 2018; 20:ijms20010049. [PMID: 30583555 PMCID: PMC6337751 DOI: 10.3390/ijms20010049] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 12/18/2018] [Accepted: 12/19/2018] [Indexed: 12/14/2022] Open
Abstract
Chronic hepatitis C is associated with a high risk of developing hepatocellular carcinoma (HCC) because of a direct effect of the Hepatitis C Virus (HCV) proteins and an indirect oncogenic effect of chronic inflammation and impaired immune response. The treatment of chronic hepatitis C markedly reduces all-cause mortality; in fact, interferon-based treatment has shown a reduction of HCC incidence of more than 70%. The recent introduction of the highly effective direct-acting antivirals (DAAs) has completely changed the scenario of chronic hepatitis C (CHC) with rates of HCV cure over 90%. However, an unexpectedly high incidence of HCC recurrence was observed in patients after DAA treatment (27% versus 0.4–2% in patients who received interferon treatment). The mechanism that underlies the high rate of tumor relapse is currently unknown and is one of the main issues in hepatology. We reviewed the possible mechanisms involved in HCC recurrence after DAA treatment.
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MESH Headings
- Animals
- Antiviral Agents/therapeutic use
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/epidemiology
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/virology
- Hepacivirus/drug effects
- Hepacivirus/immunology
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/epidemiology
- Hepatitis C, Chronic/immunology
- Hepatitis C, Chronic/virology
- Humans
- Incidence
- Interferons/therapeutic use
- Liver Neoplasms/drug therapy
- Liver Neoplasms/epidemiology
- Liver Neoplasms/immunology
- Liver Neoplasms/virology
- Macrophages/drug effects
- Monocytes/drug effects
- Neoplasm Recurrence, Local/drug therapy
- Neoplasm Recurrence, Local/epidemiology
- Neoplasm Recurrence, Local/immunology
- Neoplasm Recurrence, Local/virology
- Neutrophils/drug effects
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Affiliation(s)
- Rosanna Villani
- C.U.R.E. University Centre for Liver Disease Research and Treatment, Department of Medical and Surgical Sciences, Institute of Internal Medicine, University of Foggia, 71122 Foggia, Italy.
| | - Gianluigi Vendemiale
- C.U.R.E. University Centre for Liver Disease Research and Treatment, Department of Medical and Surgical Sciences, Institute of Internal Medicine, University of Foggia, 71122 Foggia, Italy.
| | - Gaetano Serviddio
- C.U.R.E. University Centre for Liver Disease Research and Treatment, Department of Medical and Surgical Sciences, Institute of Internal Medicine, University of Foggia, 71122 Foggia, Italy.
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16
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Virzì A, Roca Suarez AA, Baumert TF, Lupberger J. Oncogenic Signaling Induced by HCV Infection. Viruses 2018; 10:v10100538. [PMID: 30279347 PMCID: PMC6212953 DOI: 10.3390/v10100538] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 09/29/2018] [Accepted: 09/30/2018] [Indexed: 02/07/2023] Open
Abstract
The liver is frequently exposed to toxins, metabolites, and oxidative stress, which can challenge organ function and genomic stability. Liver regeneration is therefore a highly regulated process involving several sequential signaling events. It is thus not surprising that individual oncogenic mutations in hepatocytes do not necessarily lead to cancer and that the genetic profiles of hepatocellular carcinomas (HCCs) are highly heterogeneous. Long-term infection with hepatitis C virus (HCV) creates an oncogenic environment by a combination of viral protein expression, persistent liver inflammation, oxidative stress, and chronically deregulated signaling events that cumulate as a tipping point for genetic stability. Although novel direct-acting antivirals (DAA)-based treatments efficiently eradicate HCV, the associated HCC risk cannot be fully eliminated by viral cure in patients with advanced liver disease. This suggests that HCV may persistently deregulate signaling pathways beyond viral cure and thereby continue to perturb cancer-relevant gene function. In this review, we summarize the current knowledge about oncogenic signaling pathways derailed by chronic HCV infection. This will not only help to understand the mechanisms of hepatocarcinogenesis but will also highlight potential chemopreventive strategies to help patients with a high-risk profile of developing HCC.
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Affiliation(s)
- Alessia Virzì
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.
- Université de Strasbourg, 67000 Strasbourg, France.
| | - Armando Andres Roca Suarez
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.
- Université de Strasbourg, 67000 Strasbourg, France.
| | - Thomas F Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.
- Université de Strasbourg, 67000 Strasbourg, France.
- Pôle Hépato-digestif, Institut Hospitalo-universitaire, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France.
| | - Joachim Lupberger
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.
- Université de Strasbourg, 67000 Strasbourg, France.
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17
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Zhu X, Wen L, Sheng S, Wang W, Xiao Q, Qu M, Hu Y, Liu C, He K. Porcine Circovirus-Like Virus P1 Inhibits Wnt Signaling Pathway in Vivo and in Vitro. Front Microbiol 2018; 9:390. [PMID: 29593670 PMCID: PMC5857601 DOI: 10.3389/fmicb.2018.00390] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 02/20/2018] [Indexed: 11/13/2022] Open
Abstract
Porcine circovirus-like virus P1 is an important pathogen of the current pig industry, the infection mechanism is not entirely clear. Wnt signaling pathway plays an important role in the growth of young animals and infection of some viruses. This study was designed to demonstrate the effects of P1 infection on the Wnt signaling pathway. In vivo experiments, we demonstrated the down-regulatory effects of P1 infection in piglets and mice on the downstream components expression levels of Wnt signaling pathway, and the effects of Wnt signaling pathway activation on the pathogenesis of P1. In vitro studies, we found P1 infection down-regulated protein level of β-catenin and mRNA level of mmp2, prevented the β-catenin from entering into nucleus, abolished the TCF/LEF promoter activity, proved that P1 could inhibit the activation of Wnt signaling pathway in vitro. Finally, we found that VP1 of P1 virus also had the inhibitory effects on Wnt signaling pathway in vitro, elucidated the mechanism of P1’s inhibitory effects on the Wnt signaling pathway and offered the possibility that the suppression of Wnt signaling pathway was involved in the post-weaning multisystemic wasting syndrome (PMWS), laying a foundation for elucidating the pathogenesis of P1.
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Affiliation(s)
- Xuejiao Zhu
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences - Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Nanjing, China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China.,Jiangsu Key Laboratory for Food Quality and Safety - State Key Laboratory Cultivation Base of Ministry of Science and Technology, Nanjing, China
| | - Libin Wen
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences - Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Nanjing, China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China.,Jiangsu Key Laboratory for Food Quality and Safety - State Key Laboratory Cultivation Base of Ministry of Science and Technology, Nanjing, China
| | - Shaoyang Sheng
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences - Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Nanjing, China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China
| | - Wei Wang
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences - Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Nanjing, China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China.,Jiangsu Key Laboratory for Food Quality and Safety - State Key Laboratory Cultivation Base of Ministry of Science and Technology, Nanjing, China
| | - Qi Xiao
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences - Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Nanjing, China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China.,Jiangsu Key Laboratory for Food Quality and Safety - State Key Laboratory Cultivation Base of Ministry of Science and Technology, Nanjing, China
| | - Meng Qu
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences - Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Nanjing, China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China
| | - Yiyi Hu
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences - Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Nanjing, China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China.,Jiangsu Key Laboratory for Food Quality and Safety - State Key Laboratory Cultivation Base of Ministry of Science and Technology, Nanjing, China
| | - Chuanmin Liu
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences - Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Nanjing, China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China.,Jiangsu Key Laboratory for Food Quality and Safety - State Key Laboratory Cultivation Base of Ministry of Science and Technology, Nanjing, China
| | - Kongwang He
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences - Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Nanjing, China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China.,Jiangsu Key Laboratory for Food Quality and Safety - State Key Laboratory Cultivation Base of Ministry of Science and Technology, Nanjing, China
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18
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Ferrell LD, Kakar S, Terracciano LM, Wee A. Tumours and Tumour-like Lesions of the Liver. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:780-879. [DOI: 10.1016/b978-0-7020-6697-9.00013-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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19
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Swamy SG, Kameshwar VH, Shubha PB, Looi CY, Shanmugam MK, Arfuso F, Dharmarajan A, Sethi G, Shivananju NS, Bishayee A. Targeting multiple oncogenic pathways for the treatment of hepatocellular carcinoma. Target Oncol 2017; 12:1-10. [PMID: 27510230 DOI: 10.1007/s11523-016-0452-7] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common forms of liver cancer diagnosed worldwide. HCC occurs due to chronic liver disease and is often diagnosed at advanced stages. Chemotherapeutic agents such as doxorubicin are currently used as first-line agents for HCC therapy, but these are non-selective cytotoxic molecules with significant side effects. Sorafenib, a multi-targeted tyrosine kinase inhibitor, is the only approved targeted drug for HCC patients. However, due to adverse side effects and limited efficacy, there is a need for the identification of novel pharmacological drugs beyond sorafenib. Several agents that target and inhibit various signaling pathways involved in HCC are currently being assessed for HCC treatment. In the present review article, we summarize the diverse signal transduction pathways responsible for initiation as well as progression of HCC and also the potential anticancer effects of selected targeted therapies that can be employed for HCC therapy.
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Affiliation(s)
- Supritha G Swamy
- Department of Biotechnology, JSS Science and Technology University, JSS Technical Institutions Campus, Mysore, Karnataka, 570006, India
| | - Vivek H Kameshwar
- Department of Biotechnology, JSS Science and Technology University, JSS Technical Institutions Campus, Mysore, Karnataka, 570006, India
| | - Priya B Shubha
- Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, 570 006, Karnataka, India
| | - Chung Yeng Looi
- Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, 50603, Malaysia
| | - Muthu K Shanmugam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | - Frank Arfuso
- School of Biomedical Sciences, Curtin Health Innovation Research Institute, Biosciences Research Precinct, Curtin University, Bentley, Western Australia, 6009, Australia
| | - Arunasalam Dharmarajan
- School of Biomedical Sciences, Curtin Health Innovation Research Institute, Biosciences Research Precinct, Curtin University, Bentley, Western Australia, 6009, Australia
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
- School of Biomedical Sciences, Curtin Health Innovation Research Institute, Biosciences Research Precinct, Curtin University, Bentley, Western Australia, 6009, Australia
| | - Nanjunda Swamy Shivananju
- Department of Biotechnology, JSS Science and Technology University, JSS Technical Institutions Campus, Mysore, Karnataka, 570006, India.
| | - Anupam Bishayee
- Department of Pharmaceutical Sciences, College of Pharmacy, Larkin Health Sciences Institute, 18301 N. Miami Avenue, Miami, FL, 33169, USA.
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20
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Kwak J, Choi JH, Jang KL. Hepatitis C virus Core overcomes all- trans retinoic acid-induced apoptosis in human hepatoma cells by inhibiting p14 expression via DNA methylation. Oncotarget 2017; 8:85584-85598. [PMID: 29156743 PMCID: PMC5689633 DOI: 10.18632/oncotarget.20337] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 07/25/2017] [Indexed: 01/15/2023] Open
Abstract
All-trans retinoic acid (ATRA), the most biologically active metabolite of vitamin A, is known to induce p14 expression via promoter hypomethylation to activate the p14-MDM2-p53 pathway, which leads to activation of the p53-dependent apoptotic pathway and subsequent induction of apoptosis in human hepatoma cells. In the present study, we found that hepatitis C virus (HCV) Core derived from ectopic expression or HCV infection overcomes ATRA-induced apoptosis in p53-positive hepatoma cells. For this effect, HCV Core upregulated both protein levels and enzyme activities of DNA methyltransferase 1 (DNMT1), DNMT3a, and DNMT3b and thereby repressed p14 expression via promoter hypermethylation, resulting in inactivation of the pathway leading to p53 accumulation in the presence of ATRA. As a result, HCV Core prevented ATRA from activating several apoptosis-related molecules, including Bax, p53 upregulated modulator of apoptosis, caspase-9, caspase-3, and poly (ADP-ribose) polymerase. In addition, complementation of p14 in the Core-expressing cells by either ectopic expression or treatment with 5-Aza-2′dC almost completely abolished the potential of HCV Core to suppress ATRA-induced apoptosis. Based on these observations, we conclude that HCV Core executes its oncogenic potential by suppressing the p53-dependent apoptosis induced by ATRA in human hepatoma cells.
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Affiliation(s)
- Juri Kwak
- Department of Microbiology, College of Natural Sciences, Pusan National University, Busan 609-735, Republic of Korea
| | - Jung-Hye Choi
- Department of Microbiology, College of Natural Sciences, Pusan National University, Busan 609-735, Republic of Korea
| | - Kyung Lib Jang
- Department of Microbiology, College of Natural Sciences, Pusan National University, Busan 609-735, Republic of Korea
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21
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The Path to Cancer and Back: Immune Modulation During Hepatitis C Virus Infection, Progression to Fibrosis and Cancer, and Unexpected Roles of New Antivirals. Transplantation 2017; 101:910-915. [PMID: 28045877 DOI: 10.1097/tp.0000000000001623] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) infection affects over 130 million individuals worldwide, and it is the number 1 reason for liver transplantation in the United States. HCV infection progresses in a slow chronic fashion eliciting a strong but ineffective immune response, mainly characterized by NK cell dysfunction and T cell exhaustion. The chronic hepatic inflammation leads to liver fibrosis, cirrhosis, and cancer in a significant number of patients. In recent years, groundbreaking research has led to the discovery of new HCV-specific direct-acting antivirals (DAAs), which have an unprecedented efficacy to clear the virus, and establish a sustained virological response. Indeed, curing HCV infection with an oral medication is now reality. The effects of DAAs in mitigating the HCV-related complications of liver fibrosis and cancer are yet largely unknown. Nonetheless, recent controversial reports suggest a potential increase in liver cancer recurrence upon use of DAAs. In the current article, we review the most important immune-mediated mechanisms underlying HCV chronicity and the development of liver fibrosis and cancer. Furthermore, we discuss recent concern on use of the new agents.
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22
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Della Corte CM, Viscardi G, Papaccio F, Esposito G, Martini G, Ciardiello D, Martinelli E, Ciardiello F, Morgillo F. Implication of the Hedgehog pathway in hepatocellular carcinoma. World J Gastroenterol 2017; 23:4330-4340. [PMID: 28706416 PMCID: PMC5487497 DOI: 10.3748/wjg.v23.i24.4330] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2017] [Revised: 04/13/2017] [Accepted: 05/19/2017] [Indexed: 02/06/2023] Open
Abstract
The prognosis for patients who are diagnosed with advanced stage hepatocellular carcinoma (HCC) is poor because there are few treatment options. Recent research has focused on the identification of novel molecular entities that can be targeted to inhibit oncogenic signals that are involved in the carcinogenesis, proliferation and progression of HCC. Among all of the pathways that are involved in the development of HCC, Hedgehog (HH) signalling has demonstrated a substantial role in hepatocarcinogenesis and HCC progression. HH plays a physiological role in embryogenesis, through the induction of the differentiation of hepatocytes from endodermal progenitors. The re-activation of the HH pathway in chronic damaged liver is a mechanism of fibrotic degeneration and is implicated in various stages of HCC development. HH activation sustains the sub-population of immature liver epithelial cells that are involved in the pathogenesis of cirrhosis and HCC, and HH itself is a mediator of the alcohol-derived malignant transformation of liver cells. High levels of expression of HH protein markers in liver tumour tissues are correlated with aggressive histological and biological features and a poor clinical outcome. In vitro and in vivo inhibition models of the HH pathway confirm that HH is essential in maintaining tumour growth, metastasis and a mesenchymal phenotype.
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23
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Jiang XH, Xie YT, Cai YP, Ren J, Ma T. Effects of hepatitis C virus core protein and nonstructural protein 4B on the Wnt/β-catenin pathway. BMC Microbiol 2017; 17:124. [PMID: 28545480 PMCID: PMC5445264 DOI: 10.1186/s12866-017-1032-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Accepted: 05/15/2017] [Indexed: 12/21/2022] Open
Abstract
Background Hepatitis C virus (HCV) core protein and nonstructural protein 4B (NS4B) are potentially oncogenic. Aberrant activation of the Wnt/β-catenin signaling pathway is closely associated with hepatocarcinogenesis. We investigated the effects of HCV type 1b core protein and NS4B on Wnt/β-catenin signaling in various liver cells, and explored the molecular mechanism underlying HCV-related hepatocarcinogenesis. Results Compared with the empty vector control, HCV core protein and NS4B demonstrated the following characteristics in the Huh7 cells: significantly enhanced β-catenin/Tcf-dependent transcriptional activity (F = 40.87, P < 0.01); increased nuclear translocation of β-catenin (F = 165.26, P < 0.01); upregulated nuclear β-catenin, cytoplasmic β-catenin, Wnt1, c-myc, and cyclin D1 protein expression (P < 0.01); and promoted proliferation of Huh7 cells (P < 0.01 or P < 0.05). Neither protein enhanced β-catenin/Tcf-dependent transcriptional activity in the LO2 cells (F = 0.65, P > 0.05), but they did significantly enhance Wnt3a-induced β-catenin/Tcf-dependent transcriptional activity (F = 64.25, P < 0.01), and promoted the nuclear translocation of β-catenin (F = 66.54, P < 0.01) and the Wnt3a-induced proliferation of LO2 cells (P < 0.01 or P < 0.05). Moreover, activation of the Wnt/β-catenin signaling pathway was greater with the core protein than with NS4B (P < 0.01 or P < 0.05). Conclusions HCV core protein and NS4B directly activate the Wnt/β-catenin signaling pathway in Huh7 cells and LO2 cells induced by Wnt3a. These data suggest that HCV core protein and NS4B contribute to HCV-associated hepatocellular carcinogenesis. Electronic supplementary material The online version of this article (doi:10.1186/s12866-017-1032-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xiao-Hua Jiang
- Department of Infectious Diseases, the First Affiliated Hospital of the University of South China, Hengyang, 421001, China
| | - Yu-Tao Xie
- Department of Infectious Diseases, Xiangya Hospital of Central South University, Changsha, 410087, China.
| | - Ya-Ping Cai
- Department of Epidemiology and Health Statistics, the University of South China, Hengyang, 421001, China
| | - Jing Ren
- Department of Infectious Diseases, the First Affiliated Hospital of the University of South China, Hengyang, 421001, China
| | - Tao Ma
- Department of Infectious Diseases, the First Affiliated Hospital of the University of South China, Hengyang, 421001, China
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24
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Liu JL, Kaddour N, Chowdhury S, Li Q, Gao ZH. Role of CCN5 (WNT1 inducible signaling pathway protein 2) in pancreatic islets. J Diabetes 2017; 9:462-474. [PMID: 27863006 DOI: 10.1111/1753-0407.12507] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Accepted: 11/07/2016] [Indexed: 12/15/2022] Open
Abstract
In search of direct targets of insulin-like growth factor (IGF)-1 action, we discovered CCN5 (WNT1 inducible signaling pathway protein 2 [WISP2]) as a novel protein expressed in pancreatic β-cells. As a member of the "CCN" ( C ysteine-rich angiogenic inducer 61 [Cyr61], C onnective tissue growth factor [CTGF in humans], and N ephroblastoma overexpressed [Nov; in chickens]) family, the expression of CCN5/WISP2 is stimulated by IGF-1 together with Wnt signaling. When overexpressed in insulinoma cells, CCN5 promotes cell proliferation and cell survival against streptozotocin-induced cell death. The cell proliferation effect seems to be caused by AKT phosphorylation and increased cyclin D1 levels. These properties resemble those of CCN2/CTGF, another isoform of the CCN family, although CCN5 is the only one within the family of six proteins that lacks the C-terminal repeat. Treatment of primary mouse islets with recombinant CCN5 protein produced similar effects to those of gene transfection, indicating that either as a matricellular protein or a secreted growth factor, CCN5 stimulates β-cell proliferation and regeneration in a paracrine fashion. This review also discusses the regulation of CCN5/WISP2 by estrogen and its involvement in angiogenesis and tumorigenesis.
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Affiliation(s)
- Jun-Li Liu
- Fraser Laboratories, Department of Medicine, The Research Institute of McGill University Health Centre, Montreal, Canada
| | - Nancy Kaddour
- Fraser Laboratories, Department of Medicine, The Research Institute of McGill University Health Centre, Montreal, Canada
| | - Subrata Chowdhury
- Fraser Laboratories, Department of Medicine, The Research Institute of McGill University Health Centre, Montreal, Canada
| | - Qing Li
- Fraser Laboratories, Department of Medicine, The Research Institute of McGill University Health Centre, Montreal, Canada
| | - Zu-Hua Gao
- Department of Pathology, The Research Institute of McGill University Health Centre, Montreal, Canada
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25
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Wang W, Pan Q, Fuhler GM, Smits R, Peppelenbosch MP. Action and function of Wnt/β-catenin signaling in the progression from chronic hepatitis C to hepatocellular carcinoma. J Gastroenterol 2017; 52:419-431. [PMID: 28035485 PMCID: PMC5357489 DOI: 10.1007/s00535-016-1299-5] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 12/17/2016] [Indexed: 02/04/2023]
Abstract
Hepatitis C virus (HCV) infection is one of the leading causes of hepatocellular carcinoma (HCC) worldwide but the mechanistic basis as to how chronic HCV infection furthers the HCC process remains only poorly understood. Accumulating evidence indicates that HCV core and nonstructural proteins provoke activation of the Wnt/β-catenin signaling pathway, and the evidence supporting a role of Wnt/β-catenin signaling in the onset and progression of HCC is compelling. Convincing molecular explanations as to how expression of viral effectors translates into increased activity of the Wnt/β-catenin signaling machinery are still largely lacking, hampering the design of rational strategies aimed at preventing HCC. Furthermore, how such increased signaling is especially associated with HCC oncogenesis in the context of HCV infection remains obscure as well. Here we review the body of contemporary biomedical knowledge on the role of the Wnt/β-catenin pathway in the progression from chronic hepatitis C to cirrhosis and HCC and explore potential hypotheses as to the mechanisms involved.
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Affiliation(s)
- Wenhui Wang
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, ’s Gravendijkwal 230, 3015 CE Rotterdam, Netherlands
| | - Qiuwei Pan
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, ’s Gravendijkwal 230, 3015 CE Rotterdam, Netherlands
| | - Gwenny M. Fuhler
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, ’s Gravendijkwal 230, 3015 CE Rotterdam, Netherlands
| | - Ron Smits
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, ’s Gravendijkwal 230, 3015 CE Rotterdam, Netherlands
| | - Maikel P. Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, ’s Gravendijkwal 230, 3015 CE Rotterdam, Netherlands
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26
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Bal M, Verma A, Ramadwar M, Deodhar K, Patil P, Goel M. Clinicopathologic characteristics of Wnt/β-catenin-deregulated hepatocellular carcinoma. Indian J Cancer 2017; 54:634-639. [DOI: 10.4103/ijc.ijc_655_17] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
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27
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Zhou L, Wen J, Huang Z, Nice EC, Huang C, Zhang H, Li Q. Redox proteomics screening cellular factors associated with oxidative stress in hepatocarcinogenesis. Proteomics Clin Appl 2016; 11. [PMID: 27763721 DOI: 10.1002/prca.201600089] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 10/10/2016] [Accepted: 10/18/2016] [Indexed: 02/05/2023]
Abstract
Liver cancer is a major global health problem being the sixth most common cancer and the third cause of cancer-related death, with hepatocellular carcinoma (HCC) representing more than 90% of primary liver cancers. Mounting evidence suggests that, compared with their normal counterparts, many types of cancer cell have increased levels of ROS. Therefore, cancer cells need to combat high levels of ROS, especially at early stages of tumor development. Recent studies have revealed that ROS-mediated regulation of redox-sensitive proteins (redox sensors) is involved in the pathogenesis and/or progression of many human diseases, including cancer. Unraveling the altered functions of redox sensors and the underlying mechanisms in hepatocarcinogenesis is critical for the development of novel cancer therapeutics. For this reason, redox proteomics has been developed for the high-throughput screening of redox sensors, which will benefit the development of novel therapeutic strategies for the treatment of HCC. In this review, we will briefly introduce several novel redox proteomics techniques that are currently available to study various oxidative modifications in hepatocarcinogenesis and summarize the most important discoveries in the study of redox processes related to the development and progression of HCC.
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Affiliation(s)
- Li Zhou
- Key Laboratory of Tropical Diseases and Translational Medicine of Ministry of Education & Department of Neurology, the First Affiliated Hospital of Hainan Medical University, Haikou, P. R. China.,State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, P. R. China
| | - Ji Wen
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, P. R. China
| | - Zhao Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, P. R. China
| | - Edouard C Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia.,Visiting professor, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, P. R. China
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, P. R. China
| | - Haiyuan Zhang
- Key Laboratory of Tropical Diseases and Translational Medicine of Ministry of Education & Department of Neurology, the First Affiliated Hospital of Hainan Medical University, Haikou, P. R. China
| | - Qifu Li
- Key Laboratory of Tropical Diseases and Translational Medicine of Ministry of Education & Department of Neurology, the First Affiliated Hospital of Hainan Medical University, Haikou, P. R. China
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28
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Sun W, Han Y, Li Z, Ge K, Zhang J. Bone-Targeted Mesoporous Silica Nanocarrier Anchored by Zoledronate for Cancer Bone Metastasis. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2016; 32:9237-9244. [PMID: 27531422 DOI: 10.1021/acs.langmuir.6b02228] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Once bone metastasis occurs, the chances of survival and quality of life for cancer patients decrease significantly. With the development of nanomedicine, nanocarriers loading bisphosphonates have been built to prevent cancer metastasis based on their enhanced permeability and retention (EPR) effects; however, as a passive mechanism, the EPR effects cannot apply to the metastatic sites because of their lack of leaky vasculature. In this study, we fabricated 40 nm-sized mesoporous silica nanoparticles (MSNs) anchored by zoledronic acid (ZOL) for targeting bone sites and delivered the antitumor drug doxorubicin (DOX) in a spatiotemporally controlled manner. The DOX loading and release behaviors, bone-targeting ability, cellular uptake and its mechanisms, subcellular localization, cytotoxicity, and the antimigration effect of this drug delivery system (DDS) were investigated. The results indicated that MSNs-ZOL had better bone-targeting ability compared with that of the nontargeted MSNs. The maximum loading capacity of DOX into MSNs and MSNs-ZOL was about 1671 and 1547 mg/g, with a loading efficiency of 83.56 and 77.34%, respectively. DOX@MSNs-ZOL had obvious pH-sensitive DOX release behavior. DOX@MSNs-ZOL entered into cells through an ATP-dependent pathway and then localized in the lysosome to achieve effective intracellular DOX release. The antitumor results indicated that DOX@MSNs-ZOL exhibited the best cytotoxicity against A549 cells and significantly decreased cell migration in vitro. This DDS is promising for the treatment of cancer bone metastasis in the future.
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Affiliation(s)
- Wentong Sun
- Key Laboratory of Chemical Biology of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, College of Chemistry & Environmental Science, Hebei University , Baoding 071002, China
| | - Yu Han
- Key Laboratory of Chemical Biology of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, College of Chemistry & Environmental Science, Hebei University , Baoding 071002, China
| | - Zhenhua Li
- Key Laboratory of Chemical Biology of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, College of Chemistry & Environmental Science, Hebei University , Baoding 071002, China
| | - Kun Ge
- Key Laboratory of Chemical Biology of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, College of Chemistry & Environmental Science, Hebei University , Baoding 071002, China
- Affiliated Hospital of Hebei University , Baoding 071000, China
| | - Jinchao Zhang
- Key Laboratory of Chemical Biology of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, College of Chemistry & Environmental Science, Hebei University , Baoding 071002, China
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29
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Liu LJ, Xie SX, Chen YT, Xue JL, Zhang CJ, Zhu F. Aberrant regulation of Wnt signaling in hepatocellular carcinoma. World J Gastroenterol 2016; 22:7486-7499. [PMID: 27672271 PMCID: PMC5011664 DOI: 10.3748/wjg.v22.i33.7486] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Revised: 06/07/2016] [Accepted: 07/20/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies in the world. Several signaling pathways, including the wingless/int-1 (Wnt) signaling pathway, have been shown to be commonly activated in HCC. The Wnt signaling pathway can be triggered via both catenin β1 (CTNNB1)-dependent (also known as "canonical") and CTNNB1-independent (often referred to as "non-canonical") pathways. Specifically, the canonical Wnt pathway is one of those most frequently reported in HCC. Aberrant regulation from three complexes (the cell-surface receptor complex, the cytoplasmic destruction complex and the nuclear CTNNB1/T-cell-specific transcription factor/lymphoid enhancer binding factor transcriptional complex) are all involved in HCC. Although the non-canonical Wnt pathway is rarely reported, two main non-canonical pathways, Wnt/planar cell polarity pathway and Wnt/Ca(2+) pathway, participate in the regulation of hepatocarcinogenesis. Interestingly, the canonical Wnt pathway is antagonized by non-canonical Wnt signaling in HCC. Moreover, other signaling cascades have also been demonstrated to regulate the Wnt pathway through crosstalk in HCC pathogenesis. This review provides a perspective on the emerging evidence that the aberrant regulation of Wnt signaling is a critical mechanism for the development of HCC. Furthermore, crosstalk between different signaling pathways might be conducive to the development of novel molecular targets of HCC.
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30
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van Zuylen WJ, Rawlinson WD, Ford CE. The Wnt pathway: a key network in cell signalling dysregulated by viruses. Rev Med Virol 2016; 26:340-55. [PMID: 27273590 DOI: 10.1002/rmv.1892] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Revised: 05/04/2016] [Accepted: 05/12/2016] [Indexed: 12/19/2022]
Abstract
Viruses are obligate parasites dependent on host cells for survival. Viral infection of a cell activates a panel of pattern recognition receptors that mediate antiviral host responses to inhibit viral replication and dissemination. Viruses have evolved mechanisms to evade and subvert this antiviral host response, including encoding proteins that hijack, mimic and/or manipulate cellular processes such as the cell cycle, DNA damage repair, cellular metabolism and the host immune response. Currently, there is an increasing interest whether viral modulation of these cellular processes, including the cell cycle, contributes to cancer development. One cellular pathway related to cell cycle signalling is the Wnt pathway. This review focuses on the modulation of this pathway by human viruses, known to cause (or associated with) cancer development. The main mechanisms where viruses interact with the Wnt pathway appear to be through (i) epigenetic modification of Wnt genes; (ii) cellular or viral miRNAs targeting Wnt genes; (iii) altering specific Wnt pathway members, often leading to (iv) nuclear translocation of β-catenin and activation of Wnt signalling. Given that diverse viruses affect this signalling pathway, modulating Wnt signalling could be a generalised critical process for the initiation or maintenance of viral pathogenesis, with resultant dysregulation contributing to virus-induced cancers. Further study of this virus-host interaction may identify options for targeted therapy against Wnt signalling molecules as a means to reduce virus-induced pathogenesis and the downstream consequences of infection. Copyright © 2016 John Wiley & Sons, Ltd.
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Affiliation(s)
- Wendy J van Zuylen
- Serology and Virology Division, SEALS Microbiology, Prince of Wales Hospital, Sydney, Australia.,School of Medical Sciences, University of New South Wales, Sydney, Australia
| | - William D Rawlinson
- Serology and Virology Division, SEALS Microbiology, Prince of Wales Hospital, Sydney, Australia.,School of Medical Sciences, University of New South Wales, Sydney, Australia.,School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia
| | - Caroline E Ford
- Metastasis Research Group, School of Women's and Children's Health, University of New South Wales, Sydney, Australia.
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31
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Tu KS, Yao YM. Epithelial-mesenchymal transition and related signaling pathways in hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2016; 24:2131-2142. [DOI: 10.11569/wcjd.v24.i14.2131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common forms of liver cancer and the third leading cause of cancer-related mortality in the world. Although numerous therapeutic strategies have been employed to treat this fatal disease, the prognosis of HCC patients remains dismal with a low 5-year survival rate of approximately 30%. Postoperative recurrence and metastasis of HCC are the leading cause of poor prognosis. Metastasis has been thought to rely on non-motile epithelial tumor cells acquiring characteristics of mesenchymal cells, which are more migratory. This change is known as the epithelial-to-mesenchymal transition (EMT). EMT has been considered one of the main reasons for the invasion and metastasis of HCC. Notably, increasing evidence indicates that several signaling pathways participate in the regulation of EMT in HCC. In the current review, we will discuss the current progress in research of EMT and its related signaling pathways in HCC.
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32
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Macaluso FS, Calvaruso V, Craxì A. Residual risk of hepatocellular carcinoma after HCV eradication: more than meets the eye. Future Microbiol 2016; 10:977-88. [PMID: 26059621 DOI: 10.2217/fmb.15.31] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Eradication of HCV in patients with advanced liver fibrosis or cirrhosis reduces, but does not altogether abolish, the risk of development of hepatocellular carcinoma. The reasons underlying this residual risk remain elusive. Even if HCV clearance eliminates its direct and indirect carcinogenic effects, the persistence of cirrhosis and the possible coexistence of metabolic factors (diabetes, obesity and insulin resistance) and of alcohol abuse can promote the development of hepatocellular carcinoma acting as autonomous, nonviral carcinogenic factors. Lessons learned in the IFN era may still assist in predicting the forthcoming scenario, when IFN-free regimens will obtain high rates of viral clearance even at the most advanced stages of liver disease.
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Affiliation(s)
| | - Vincenza Calvaruso
- Sezione di Gastroenterologia & Epatologia, DiBiMIS, University of Palermo, Italy
| | - Antonio Craxì
- Sezione di Gastroenterologia & Epatologia, DiBiMIS, University of Palermo, Italy
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33
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Kao CC, Yi G, Huang HC. The core of hepatitis C virus pathogenesis. Curr Opin Virol 2016; 17:66-73. [PMID: 26851516 DOI: 10.1016/j.coviro.2016.01.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Revised: 01/05/2016] [Accepted: 01/14/2016] [Indexed: 02/06/2023]
Abstract
Capsid proteins form protective shells around viral genomes and mediate viral entry. However, many capsid proteins have additional and important roles for virus infection and in modulating cellular response to infection, with important consequences on pathogenesis. Infection by the Hepatitis C virus (HCV) can lead to liver steatosis, cirrhosis, and hepatocellular carcinoma. Herein, we focus on the role in pathogenesis of Core, the capsid protein of the HCV.
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Affiliation(s)
- C Cheng Kao
- Dept of Molecular & Cellular Biochemistry, Indiana University, Bloomington, IN 47405, United States.
| | - Guanghui Yi
- Dept of Molecular & Cellular Biochemistry, Indiana University, Bloomington, IN 47405, United States
| | - Hsuan-Cheng Huang
- Inst. of Biomedical Informatics, National Yang-Ming University, Taipei 11221, Taiwan
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34
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Jia Q, Dong Q, Qin L. CCN: core regulatory proteins in the microenvironment that affect the metastasis of hepatocellular carcinoma? Oncotarget 2016; 7:1203-1214. [PMID: 26497214 PMCID: PMC4811454 DOI: 10.18632/oncotarget.6209] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2015] [Accepted: 10/09/2015] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) results from an underlying chronic liver inflammatory disease, such as chronic hepatitis B or C virus infections, and the general prognosis of patients with HCC still remains extremely dismal because of the high frequency of HCC metastases. Throughout the process of tumor metastasis, tumor cells constantly communicate with the surrounding microenvironment and improve their malignant phenotype. Therefore, there is a strong rationale for targeting the tumor microenvironment as primary treatment of HCC therapies. Recently, CCN family proteins have emerged as localized multitasking signal integrators in the inflammatory microenvironment. In this review, we summarize the current knowledge of CCN family proteins in inflammation and the tumor. We also propose that the CCN family proteins may play a central role in signaling the tumor microenvironment and regulating the metastasis of HCC.
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Affiliation(s)
- Qingan Jia
- Cancer Center, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
- Department of General Surgery, Huashan Hospital, Fudan University; Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Qiongzhu Dong
- Cancer Center, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Lunxiu Qin
- Cancer Center, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
- Department of General Surgery, Huashan Hospital, Fudan University; Cancer Metastasis Institute, Fudan University, Shanghai, China
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35
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Waisberg J, Saba GT. Wnt-/-β-catenin pathway signaling in human hepatocellular carcinoma. World J Hepatol 2015; 7:2631-2635. [PMID: 26609340 PMCID: PMC4651907 DOI: 10.4254/wjh.v7.i26.2631] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 08/11/2015] [Accepted: 11/04/2015] [Indexed: 02/06/2023] Open
Abstract
The molecular basis of the carcinogenesis of hepatocellular carcinoma (HCC) has not been adequately clarified, which negatively impacts the development of targeted therapy protocols for this overwhelming neoplasia. The aberrant activation of signaling in the HCC is primarily due to the deregulated expression of the components of the Wnt-/-β-catenin. This leads to the activation of β-catenin/T-cell factor-dependent target genes that control cell proliferation, cell cycle, apoptosis, and cell motility. The deregulation of the Wnt pathway is an early event in hepatocarcinogenesis. An aggressive phenotype was associated with HCC, since this pathway is implicated in the proliferation, migration, and invasiveness of cancer cells, regarding the cell’s own survival. The disruption of the signaling cascade Wnt-/-β-catenin has shown anticancer properties in HCC’s clinical evaluations of therapeutic molecules targeted for blocking the Wnt signaling pathway for the treatment of HCC, and it represents a promising perspective. The key to bringing this strategy in to clinical practice is to identify new molecules that would be effective only in tumor cells with aberrant signaling β-catenin.
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36
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Yamaguchi M. Involvement of regucalcin as a suppressor protein in human carcinogenesis: insight into the gene therapy. J Cancer Res Clin Oncol 2015; 141:1333-41. [PMID: 25230901 DOI: 10.1007/s00432-014-1831-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2014] [Accepted: 09/09/2014] [Indexed: 12/18/2022]
Abstract
Regucalcin, which its gene is located on the X chromosome, plays a multifunctional role as a suppressor protein in cell signal transduction in various types of cells and tissues. The suppression of regucalcin gene expression has been shown to involve in carcinogenesis. Regucalcin gene expression was uniquely downregulated in carcinogenesis of rat liver in vivo, although the expression of other many genes was upregulated, indicating that endogenous regucalcin plays a suppressive role in the development of hepatocarcinogenesis. Overexpression of endogenous regucalcin was found to suppress proliferation of rat cloned hepatoma cells in vitro. Moreover, the regucalcin gene and its protein levels were demonstrated specifically to downregulate in human hepatocellular carcinoma by analysis with multiple gene expression profiles and proteomics. Regucalcin gene expression was also found to suppress in human tumor tissues including kidney, lung, brain, breast and prostate, suggesting that repressed regucalcin gene expression leads to the development of carcinogenesis in various tissues. Regucalcin may play a role as a suppressor protein in carcinogenesis. Overexpression of endogenous regucalcin is suggested to reveal preventive and therapeutic effects on carcinogenesis. Delivery of the regucalcin gene may be a novel useful tool in the gene therapy of carcinogenesis. This review will discuss regarding to an involvement of regucalcin as a suppressor protein in human carcinogenesis in insight into the gene therapy.
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Affiliation(s)
- Masayoshi Yamaguchi
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, 1365 C Clifton Road NE, Atlanta, GA, 30322, USA,
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37
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Yong X, Tang B, Li BS, Xie R, Hu CJ, Luo G, Qin Y, Dong H, Yang SM. Helicobacter pylori virulence factor CagA promotes tumorigenesis of gastric cancer via multiple signaling pathways. Cell Commun Signal 2015; 13:30. [PMID: 26160167 PMCID: PMC4702319 DOI: 10.1186/s12964-015-0111-0] [Citation(s) in RCA: 139] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2015] [Accepted: 07/03/2015] [Indexed: 12/12/2022] Open
Abstract
Helicobacter pylori (H. pylori) infection is strongly associated with the development of gastric diseases but also with several extragastric diseases. The clinical outcomes caused by H. pylori infection are considered to be associated with a complex combination of host susceptibility, environmental factors and bacterial isolates. Infections involving H. pylori strains that possess the virulence factor CagA have a worse clinical outcome than those involving CagA-negative strains. It is remarkable that CagA-positive H. pylori increase the risk for gastric cancer over the risk associated with H. pylori infection alone. CagA behaves as a bacterial oncoprotein playing a key role in H. pylori-induced gastric cancer. Activation of oncogenic signaling pathways and inactivation of tumor suppressor pathways are two crucial events in the development of gastric cancer. CagA shows the ability to affect the expression or function of vital protein in oncogenic or tumor suppressor signaling pathways via several molecular mechanisms, such as direct binding or interaction, phosphorylation of vital signaling proteins and methylation of tumor suppressor genes. As a result, CagA continuously dysregulates of these signaling pathways and promotes tumorigenesis. Recent research has enriched our understanding of how CagA effects on these signaling pathways. This review summarizes the results of the most relevant studies, discusses the complex molecular mechanism involved and attempts to delineate the entire signaling pathway.
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Affiliation(s)
- Xin Yong
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, P.R. China.
| | - Bo Tang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, P.R. China.
| | - Bo-Sheng Li
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, P.R. China.
| | - Rui Xie
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, P.R. China.
| | - Chang-Jiang Hu
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, P.R. China.
| | - Gang Luo
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, P.R. China.
| | - Yong Qin
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, P.R. China.
| | - Hui Dong
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, P.R. China.
| | - Shi-Ming Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, P.R. China.
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Abstract
Hepatitis C virus (HCV) is a leading etiology of hepatocellular carcinoma (HCC). The interaction of HCV with its human host is complex and multilayered; stemming in part from the fact that HCV is a RNA virus with no ability to integrate in the host's genome. Direct and indirect mechanisms of HCV-induced HCC include activation of multiple host pathways such as liver fibrogenic pathways, cellular and survival pathways, interaction with the immune and metabolic systems. Host factors also play a major role in HCV-induced HCC as evidenced by genomic studies identifying polymorphisms in immune, metabolic, and growth signaling systems associated with increased risk of HCC. Despite highly effective direct-acting antiviral agents, the morbidity and incidence of liver-related complications of HCV, including HCC, is likely to persist in the near future. Clinical markers to selectively identify HCV subjects at higher risk of developing HCC have been reported however they require further validation, especially in subjects who have experienced sustained virological response. Molecular biomarkers allowing further refinement of HCC risk are starting to be implemented in clinical platforms, allowing objective stratification of risk and leading to individualized therapy and surveillance for HCV individuals. Another role for molecular biomarker-based stratification could be enrichment of HCC chemoprevention clinical trials leading to smaller sample size, shorter trial duration, and reduced costs.
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Affiliation(s)
- Nicolas Goossens
- Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
- Division of Gastroenterology and Hepatology, Geneva University Hospital, Geneva, Switzerland
| | - Yujin Hoshida
- Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
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Abstract
About 80% of hepatocellular carcinoma (HCC) is caused by hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections especially in the setting of established cirrhosis or advanced fibrosis, making HCC prevention a major goal of antiviral therapy. HCC tumors are highly complex and heterogeneous resulting from the aberrant function of multiple molecular pathways. The roles of HCV or HBV in promoting HCC development are still either directly or indirectly are still speculative, but the evidence for both effects is compelling. In patients with chronic hepatitis viral infection, cirrhosis is not a prerequisite for tumorigenesis.
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Affiliation(s)
- Ziv Ben Ari
- Liver Disease Center, Sheba Medical Center, Derech Sheba No 1, Ramat Gan 52621, Israel; Liver Research Laboratory, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
| | - Ella Weitzman
- Liver Disease Center, Sheba Medical Center, Derech Sheba No 1, Ramat Gan 52621, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Michal Safran
- Liver Disease Center, Sheba Medical Center, Derech Sheba No 1, Ramat Gan 52621, Israel; Liver Research Laboratory, Sheba Medical Center, Ramat Gan, Israel
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Jiang XH, Xie YT, Jiang B, Tang MY, Ma T, Peng H. Inhibition of expression of hepatitis C virus 1b genotype core and NS4B genes in HepG2 cells using artificial microRNAs. Mol Med Rep 2015; 12:1905-13. [PMID: 25847260 DOI: 10.3892/mmr.2015.3571] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Accepted: 02/05/2015] [Indexed: 11/06/2022] Open
Abstract
The present study aimed to evaluate the silencing effect of artificial microRNAs (amiRNAs) against the hepatitis C virus (HCV) 1b (HCV1b) genotype core (C) and non-structural protein 4B (NS4B) genes. pDsRed-monomer-Core and pDsRed-monomer-NS4B plasmids, containing the target genes were constructed. A total of eight artificial micro RNA (amiRNA)-expressing plasmids, namely, pmiRE-C-mi1 to -mi4 and pmiRE-NS4B-mi1 to -mi4, were designed and constructed to interfere with various sites of the core and NS4B genes, and the amiRNA interfering plasmid and the corresponding target gene-expressing plasmid were co-transfected into HepG2 cells. At 48 h after transfection, HCV core and NS4B gene expression levels were detected using fluorescence microscopy, flow cytometry, reverse transcription quantitative polymerase chain reaction and western blot analysis. Fluorescence microscopy revealed that the target gene-transfected cells expressed red fluorescent protein, whereas the interfering plasmid-transfected cells exhibited expression of green fluorescent protein. The percentage of red fluorescent proteins and mean fluorescence intensity, as well as protein expression levels of the core and NS4B genes within the cells, which were co-transfected by the amiRNA interfering plasmid and the target gene, were significantly decreased. The results of the present study confirmed that amiRNAs may effectively and specifically inhibit the expression of HCV1b core and NS4B genes in HepG2 cells, potentially providing a novel therapeutic strategy for the treatment of HCV.
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Affiliation(s)
- Xiao-Hua Jiang
- Department of Infectious Diseases, Xiangya Hospital of Central South University, Changsha, Hunan 410087, P.R. China
| | - Yu-Tao Xie
- Department of Infectious Diseases, Xiangya Hospital of Central South University, Changsha, Hunan 410087, P.R. China
| | - Bo Jiang
- Department of Infectious Diseases, The First Affiliated Hospital of The University of South China, Hengyang, Hunan 421001, P.R. China
| | - Meng-Ying Tang
- Department of Infectious Diseases, The First Affiliated Hospital of The University of South China, Hengyang, Hunan 421001, P.R. China
| | - Tao Ma
- Department of Infectious Diseases, The First Affiliated Hospital of The University of South China, Hengyang, Hunan 421001, P.R. China
| | - Hua Peng
- Department of Infectious Diseases, The First Affiliated Hospital of The University of South China, Hengyang, Hunan 421001, P.R. China
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41
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Moreau M, Rivière B, Vegna S, Aoun M, Gard C, Ramos J, Assenat E, Hibner U. Hepatitis C viral proteins perturb metabolic liver zonation. J Hepatol 2015; 62:278-85. [PMID: 25220251 DOI: 10.1016/j.jhep.2014.09.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 08/22/2014] [Accepted: 09/01/2014] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS The metabolic identity of a hepatocyte is determined by its position along the porto-centrilobular axis of a liver lobule. Altered patterns of metabolic liver zonation are associated with several pathologies. In hepatitis C, although only a minority of hepatocytes harbour the virus, the liver undergoes major systemic metabolic changes. We have investigated the HCV-driven mechanisms that allow the systemic loss of metabolic zonation. METHODS Transgenic mice with hepatocyte-targeted expression of all HCV proteins (FL-N/35 model) and needle biopsies from hepatitis C patients were studied with respect to patterns of lipid deposition in the context of metabolic zonation of the liver lobule. RESULTS We report that low levels of viral proteins are sufficient to drive striking alterations of hepatic metabolic zonation. In mice, a major lipogenic enzyme, fatty acid synthase, was redistributed from its normal periportal expression into the midzone of the lobule, coinciding with a highly specific midzone accumulation of lipids. Strikingly, alteration of zonation was not limited to lipogenic enzymes and appeared to be driven by systemic signalling via the Wnt/β-catenin pathway. Importantly, we show that similarly perturbed metabolic zonation appears to precede steatosis in early stages of human disease associated with HCV infection. CONCLUSIONS Our results rationalize systemic effects on liver metabolism, triggered by a minority of infected cells, thus opening new perspectives for the investigation of HCV-related pathologies.
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Affiliation(s)
- Marie Moreau
- CNRS, UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France; Université de Montpellier 2, Montpellier, France; Université de Montpellier 1, Montpellier, France
| | - Benjamin Rivière
- Département de Biopathologie Cellulaire et Tissulaire des Tumeurs, Hôpital Saint Eloi-Gui de Chauliac, Centre Hospitalier Universitaire, Montpellier, France; Université de Montpellier 1, Montpellier, France
| | - Serena Vegna
- CNRS, UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France; Université de Montpellier 2, Montpellier, France; Université de Montpellier 1, Montpellier, France
| | - Manar Aoun
- Départment de Biochimie, CHU, Université Montpellier I, France
| | - Christopher Gard
- CNRS, UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France; Université de Montpellier 2, Montpellier, France; Université de Montpellier 1, Montpellier, France; University of Manchester, Manchester, UK
| | - Jeanne Ramos
- Département de Biopathologie Cellulaire et Tissulaire des Tumeurs, Hôpital Saint Eloi-Gui de Chauliac, Centre Hospitalier Universitaire, Montpellier, France; Université de Montpellier 1, Montpellier, France
| | - Eric Assenat
- CNRS, UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France; Université de Montpellier 2, Montpellier, France; Université de Montpellier 1, Montpellier, France; Service d'Oncologie Médicale, CHU St Eloi, Montpellier, France
| | - Urszula Hibner
- CNRS, UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France; Université de Montpellier 2, Montpellier, France; Université de Montpellier 1, Montpellier, France.
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microRNAs: novel players in hepatitis C virus infection. Clin Res Hepatol Gastroenterol 2014; 38:664-75. [PMID: 24875730 DOI: 10.1016/j.clinre.2014.04.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Revised: 03/23/2014] [Accepted: 04/15/2014] [Indexed: 02/04/2023]
Abstract
Hepatitis C virus (HCV) is a single-stranded, positive-sense RNA virus. About 70% of patients exposed to HCV develop a chronic infection, which can lead to scarring of the liver and ultimately to cirrhosis, liver failure, and hepatocellular carcinoma. For the past decade, the standard therapy for HCV infection has been a combination of interferon-α and ribavirin. In recent years, direct-acting antiviral agents, boceprevir and telaprevir, have been added to the therapeutic regimen and considerably improve the cure rates for HCV infection. However, the treatment continues to cause substantial side effects and is associated with drug resistance due to frequent mutations in the HCV RNA genome resulting from the low fidelity of its RNA polymerase. MicroRNAs (miRNAs) are a class of small, non-coding RNAs approximately 22 nucleotides in length. They are derived from cellular or viral transcripts and bind to their target mRNAs in a sequence-specific manner, resulting in either mRNA cleavage or translational repression and subsequent modulation of the expression of the majority of the protein-coding genes. miRNAs have been implicated in regulating multiple aspects of HCV life cycles and certain miRNAs serve as essential mediators for the interferon-based antiviral therapy. Furthermore, recent studies have documented the potential values of miRNAs as novel therapeutic targets against hepatitis C infectivity.
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43
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Abstract
Hepatitis C virus (HCV) is one of the major etiologic agents of liver cancer. HCV is an RNA virus that, unlike hepatitis B virus, is unable to integrate into the host genome. Through complex interactions between viral and host proteins that induce host responses and promote inflammation, fibrosis, and ultimately cirrhosis, HCV infection can result in the development of hepatocellular carcinoma (HCC). The HCV oncogenic process involves genetic and epigenetic alterations and oncogenic effects mediated by viral proteins in the activation of cellular oncogenes, inactivation of tumor-suppressor genes, and dysregulation of multiple signal-transduction pathways. Advances in genetics and gene expression profiling have enhanced our current understanding of the pathways involved in HCV-associated liver cancer development. In this review, we summarize the current understanding of mechanisms of hepatocarcinogenesis induced by HCV infection.
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Affiliation(s)
- Ming V Lin
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114; , ,
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44
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Hoshida Y, Fuchs BC, Bardeesy N, Baumert TF, Chung RT. Pathogenesis and prevention of hepatitis C virus-induced hepatocellular carcinoma. J Hepatol 2014; 61:S79-90. [PMID: 25443348 PMCID: PMC4435677 DOI: 10.1016/j.jhep.2014.07.010] [Citation(s) in RCA: 153] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Revised: 07/03/2014] [Accepted: 07/10/2014] [Indexed: 02/08/2023]
Abstract
Hepatitis C virus (HCV) is one of the major aetiologic agents that causes hepatocellular carcinoma (HCC) by generating an inflammatory, fibrogenic, and carcinogenic tissue microenvironment in the liver. HCV-induced HCC is a rational target for cancer preventive intervention because of the clear-cut high-risk condition, cirrhosis, associated with high cancer incidence (1% to 7% per year). Studies have elucidated direct and indirect carcinogenic effects of HCV, which have in turn led to the identification of candidate HCC chemoprevention targets. Selective molecular targeted agents may enable personalized strategies for HCC chemoprevention. In addition, multiple experimental and epidemiological studies suggest the potential value of generic drugs or dietary supplements targeting inflammation, oxidant stress, or metabolic derangements as possible HCC chemopreventive agents. While the successful use of highly effective direct-acting antiviral agents will make important inroads into reducing long-term HCC risk, there will remain an important role for HCC chemoprevention even after viral cure, given the persistence of HCC risk in persons with advanced HCV fibrosis, as shown in recent studies. The successful development of cancer preventive therapies will be more challenging compared to cancer therapeutics because of the requirement for larger and longer clinical trials and the need for a safer toxicity profile given its use as a preventive agent. Molecular biomarkers to selectively identify high-risk population could help mitigate these challenges. Genome-wide, unbiased molecular characterization, high-throughput drug/gene screening, experimental model-based functional analysis, and systems-level in silico modelling are expected to complement each other to facilitate discovery of new HCC chemoprevention targets and therapies.
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Affiliation(s)
- Yujin Hoshida
- Liver Cancer Program, Tisch Cancer Institute, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, United States.
| | - Bryan C Fuchs
- Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, United States
| | - Nabeel Bardeesy
- Cancer Center, Massachusetts General Hospital, Harvard Medical School, United States
| | - Thomas F Baumert
- INSERM Unité 1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, and Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, France; Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, United States
| | - Raymond T Chung
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, United States.
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45
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Abstract
Abundant evidence supports the belief of a causal relationship between cirrhosis and hepatocellular carcinoma, but one that differs between high- and low-incidence regions of the tumor. In high-incidence regions, the cirrhosis is of the macronodular variety, is typically asymptomatic, and is caused predominantly by chronic hepatitis B virus infection, whereas in low-incidence regions, the cirrhosis, although usually macronodular, may be micronodular, is commonly symptomatic and of long-standing, and is caused by chronic hepatitis C virus infection, alcohol abuse over many years, the metabolic syndrome, or hereditary hemochromatosis. In a minority of patients, hepatocellular carcinoma develops in the absence of cirrhosis, supporting a direct hepatocarcinogenic effect of some of the causal agents. Cirrhosis is the major risk factor for tumor formation in patients with chronic hepatitis C virus infection. This virus does not integrate into cellular DNA, and malignant transformation results from increased liver cell turnover induced by recurring injury and regeneration of cells in the context of persisting inflammation, oxidative DNA damage, fibrosis, cirrhosis, and changes induced by the virus at a DNA level that have yet to be fully defined. Hepatitis B virus causes malignant transformation by both direct and indirect routes. The direct route results, in part, from integration of the viral DNA into host cellular DNA; transcriptional activation of host growth regulatory genes by hepatitis B virus-encoded proteins; and effects on apoptosis, cell signaling, and DNA repair. The direct route may share some similarities with that of hepatitis C virus infection. The metabolic syndrome may cause malignant transformation by production of oxidative stress and the induction of a variety of mutations, including some in the p53 gene.
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Affiliation(s)
- Michael C Kew
- Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa,
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46
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Mikhail S, Cosgrove D, Zeidan A. Hepatocellular carcinoma: systemic therapies and future perspectives. Expert Rev Anticancer Ther 2014; 14:1205-18. [PMID: 25199765 DOI: 10.1586/14737140.2014.949246] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma is (HCC) the most common primary malignancy of the liver in adults. It is also the fifth most common solid cancer worldwide and the third leading cause of cancer-related deaths. Treatment options for HCC include liver transplantation, surgical resection, locoregional therapies and chemotherapy. The median survival time of patients following the diagnosis of unresectable disease is approximately 6-20 months, whereas the 5-year survival is less than 5%. Given the projected increase in incidence of HCC due to hepatitis C virus infection and obesity related cirrhosis, there is an urgent need for more intensive research in this cancer. In this article, we review the systemic options available for patients with HCC, its molecular pathogenesis and future therapeutic directions with special emphasis on immune-based and molecularly-targeted therapy.
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Affiliation(s)
- Sameh Mikhail
- Wexner Medical Center, Ohio State University, 320 W.10th Street, Columbus, Ohio, 43210, USA
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47
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Li HC, Ma HC, Yang CH, Lo SY. Production and pathogenicity of hepatitis C virus core gene products. World J Gastroenterol 2014; 20:7104-7122. [PMID: 24966583 PMCID: PMC4064058 DOI: 10.3748/wjg.v20.i23.7104] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 12/05/2013] [Accepted: 04/03/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is a major cause of chronic liver diseases, including steatosis, cirrhosis and hepatocellular carcinoma, and its infection is also associated with insulin resistance and type 2 diabetes mellitus. HCV, belonging to the Flaviviridae family, is a small enveloped virus whose positive-stranded RNA genome encoding a polyprotein. The HCV core protein is cleaved first at residue 191 by the host signal peptidase and further cleaved by the host signal peptide peptidase at about residue 177 to generate the mature core protein (a.a. 1-177) and the cleaved peptide (a.a. 178-191). Core protein could induce insulin resistance, steatosis and even hepatocellular carcinoma through various mechanisms. The peptide (a.a. 178-191) may play a role in the immune response. The polymorphism of this peptide is associated with the cellular lipid drop accumulation, contributing to steatosis development. In addition to the conventional open reading frame (ORF), in the +1 frame, an ORF overlaps with the core protein-coding sequence and encodes the alternative reading frame proteins (ARFP or core+1). ARFP/core+1/F protein could enhance hepatocyte growth and may regulate iron metabolism. In this review, we briefly summarized the current knowledge regarding the production of different core gene products and their roles in viral pathogenesis.
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48
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Hepatitis C virus and microRNAs: miRed in a host of possibilities. Curr Opin Virol 2014; 7:1-10. [PMID: 24721496 DOI: 10.1016/j.coviro.2014.03.004] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Revised: 03/09/2014] [Accepted: 03/10/2014] [Indexed: 12/17/2022]
Abstract
It is well-established that the host microRNA (miRNA) milieu has a significant influence on the etiology of disease. In the context of viruses, such as hepatitis C virus (HCV), microRNAs have been shown to influence viral life cycles both directly, through interactions with the viral genome, and indirectly, through regulation of critical virus-associated host pathways. Several miRNA profiling studies have demonstrated that HCV infection aberrantly regulates a significant number of human miRNA. However, the biological relevance of these modulations remains poorly understood. In this review, we summarize recent research that has shed light on the pro-viral and anti-viral roles of HCV-induced changes in human miRNA expression and their significance in the development of HCV related sequelae and response to therapy.
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49
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Georgopoulou U, Dimitriadis A, Foka P, Karamichali E, Mamalaki A. Hepcidin and the iron enigma in HCV infection. Virulence 2014; 5:465-76. [PMID: 24626108 PMCID: PMC4063809 DOI: 10.4161/viru.28508] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
An estimated 30-40% of patients with chronic hepatitis C have elevated serum iron, transferrin saturation, and ferritin levels. Clinical data suggest that iron is a co-morbidity factor for disease progression following HCV infection. Iron is essential for a number of fundamental metabolic processes in cells and organisms. Mammalian iron homeostasis is tightly regulated and this is maintained through the coordinated action of sensory and regulatory networks that modulate the expression of iron-related proteins at the transcriptional and/or posttranscriptional levels. Disturbances of iron homeostasis have been implicated in infectious disease pathogenesis. Viruses, similarly to other pathogens, can escape recognition by the immune system, but they need iron from their host to grow and spread. Hepcidin is a 25-aa peptide, present in human serum and urine and represents the key peptide hormone, which modulates iron homeostasis in the body. It is synthesized predominantly by hepatocytes and its mature form is released in circulation. In this review, we discuss recent advances in the exciting crosstalk of molecular mechanisms and cell signaling pathways by which iron and hepcidin production influences HCV-induced liver disease.
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Affiliation(s)
- Urania Georgopoulou
- Laboratory of Molecular Virology; Hellenic Pasteur Institute; Athens, Greece
| | - Alexios Dimitriadis
- Laboratory of Molecular Biology and Immunobiotechnology; Hellenic Pasteur Institute; Athens, Greece
| | - Pelagia Foka
- Laboratory of Molecular Virology; Hellenic Pasteur Institute; Athens, Greece; Laboratory of Molecular Biology and Immunobiotechnology; Hellenic Pasteur Institute; Athens, Greece
| | - Eirini Karamichali
- Laboratory of Molecular Virology; Hellenic Pasteur Institute; Athens, Greece
| | - Avgi Mamalaki
- Laboratory of Molecular Biology and Immunobiotechnology; Hellenic Pasteur Institute; Athens, Greece
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50
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Zhou JJ, Chen RF, Deng XG, Zhou Y, Ye X, Yu M, Tang J, He XY, Cheng D, Zeng B, Zhou QB, Li ZH. Hepatitis C virus core protein regulates NANOG expression via the stat3 pathway. FEBS Lett 2014; 588:566-73. [PMID: 24462277 DOI: 10.1016/j.febslet.2013.11.041] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2013] [Revised: 11/20/2013] [Accepted: 11/25/2013] [Indexed: 12/20/2022]
Abstract
HCV Core plays a role in the development of hepatocellular carcinoma. Aberrant expression of NANOG has been observed in many types of human malignancies. However, relationship between Core and NANOG has not been clarified. In this study, we found that Core is capable of up-regulating NANOG expression. Core-induced NANOG expression was accompanied by enforced expression of phosphorylated stat3 protein and was attenuated by inhibition of stat3 phosphorylation. ChIP showed that phosphorylated stat3 directly binds to the NANOG promoter. Core-induced NANOG expression resulted in enhanced cell growth and cell cycle progression. Knockdown of NANOG blocked the cell cycle at the G0/G1 phases and inhibited the cyclin D1 expression. Our findings provide a new insight into the mechanism of hepatocarcinogenesis by HCV infection.
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Affiliation(s)
- Jia-Jia Zhou
- Department of Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
| | - Ru-Fu Chen
- Department of Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China; Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Xiao-Geng Deng
- Department of Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Yu Zhou
- Department of Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Xiao Ye
- Department of Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Min Yu
- Department of Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Jing Tang
- Department of Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Xiao-Yu He
- Laboratory of Biomechanics and Physiology, Guangdong Provincial Institute of Sports Science, Guangzhou, Guangdong Province, China
| | - Di Cheng
- Department of Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Bing Zeng
- Department of Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Quan-bo Zhou
- Department of Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China; Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Zhi-hua Li
- Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
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