|
1
|
Xu L, Xu Y, Zhang F, Xu P, Wang L. Immunological pathways in viral hepatitis-induced hepato-cellular carcinoma. Zhejiang Da Xue Xue Bao Yi Xue Ban 2024; 53:64-72. [PMID: 38426692 PMCID: PMC10945487 DOI: 10.3724/zdxbyxb-2023-0481] [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: 10/08/2023] [Accepted: 12/25/2023] [Indexed: 03/02/2024]
Abstract
Hepatocellular carcinoma (HCC) is a serious neoplastic disease with increasing incidence and mortality, accounting for 90% of all liver cancers. Hepatitis viruses are the major causative agents in the development of HCC. Hepatitis A virus (HAV) primarily causes acute infections, which is associated with HCC to a certain extent, as shown by clinicopathological studies. Chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections lead to persistent liver inflammation and cirrhosis, disrupt multiple pathways associated with cellular apoptosis and proliferation, and are the most common viral precursors of HCC. Mutations in the HBV X protein (HBx) gene are closely associated with the incidence of HCC, while the expression of HCV core proteins contributes to hepatocellular lipid accumulation, thereby promoting tumorigenesis. In the clinical setting, hepatitis D virus (HDV) frequently co-infects with HBV, increasing the risk of chronic hepatitis. Hepatitis E virus (HEV) usually causes acute infections. However, chronic infections of HEV have been increasing recently, particularly in immuno-compromised patients and organ transplant recipients, which may increase the risk of progression to cirrhosis and the occurrence of HCC. Early detection, effective intervention and vaccination against these viruses may significantly reduce the incidence of liver cancer, while mechanistic insights into the interplay between hepatitis viruses and HCC may facilitate the development of more effective intervention strategies. This article provides a comprehensive overview of hepatitis viruses and reviews recent advances in research on aberrant hepatic immune responses and the pathogenesis of HCC due to viral infection.
Collapse
Affiliation(s)
- Lingdong Xu
- Laboratory Animal Center, Zhejiang University, Hangzhou 310058, China.
- Zhejiang University School of Medicine, Hangzhou 310058, China.
| | - Yifan Xu
- Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Fei Zhang
- Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
- Institute of Intelligent Medicine, Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou 311200, China
| | - Pinglong Xu
- Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
- Institute of Intelligent Medicine, Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou 311200, China.
- Key Laboratory of Biosystems Homeostasis and Protection, Ministry of Education, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Zhejiang University, Hangzhou 310058, China.
- Cancer Center, Zhejiang University, Hangzhou 310058, China.
| | - Lie Wang
- Laboratory Animal Center, Zhejiang University, Hangzhou 310058, China.
- Zhejiang University School of Medicine, Hangzhou 310058, China.
| |
Collapse
|
|
2
|
Volovat SR, Scripcariu DV, Vasilache IA, Stolniceanu CR, Volovat C, Augustin IG, Volovat CC, Ostafe MR, Andreea-Voichița SG, Bejusca-Vieriu T, Lungulescu CV, Sur D, Boboc D. Oncolytic Virotherapy: A New Paradigm in Cancer Immunotherapy. Int J Mol Sci 2024; 25:1180. [PMID: 38256250 PMCID: PMC10816814 DOI: 10.3390/ijms25021180] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 01/10/2024] [Accepted: 01/12/2024] [Indexed: 01/24/2024] Open
Abstract
Oncolytic viruses (OVs) are emerging as potential treatment options for cancer. Natural and genetically engineered viruses exhibit various antitumor mechanisms. OVs act by direct cytolysis, the potentiation of the immune system through antigen release, and the activation of inflammatory responses or indirectly by interference with different types of elements in the tumor microenvironment, modification of energy metabolism in tumor cells, and antiangiogenic action. The action of OVs is pleiotropic, and they show varied interactions with the host and tumor cells. An important impediment in oncolytic virotherapy is the journey of the virus into the tumor cells and the possibility of its binding to different biological and nonbiological vectors. OVs have been demonstrated to eliminate cancer cells that are resistant to standard treatments in many clinical trials for various cancers (melanoma, lung, and hepatic); however, there are several elements of resistance to the action of viruses per se. Therefore, it is necessary to evaluate the combination of OVs with other standard treatment modalities, such as chemotherapy, immunotherapy, targeted therapies, and cellular therapies, to increase the response rate. This review provides a comprehensive update on OVs, their use in oncolytic virotherapy, and the future prospects of this therapy alongside the standard therapies currently used in cancer treatment.
Collapse
Affiliation(s)
- Simona Ruxandra Volovat
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania; (S.R.V.); (M.-R.O.); (S.-G.A.-V.); (T.B.-V.)
| | - Dragos Viorel Scripcariu
- Department of Surgery, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania;
| | - Ingrid Andrada Vasilache
- Department of Obstetrics and Gynecology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Cati Raluca Stolniceanu
- Department of Biophysics and Medical Physics—Nuclear Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania;
| | - Constantin Volovat
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania; (S.R.V.); (M.-R.O.); (S.-G.A.-V.); (T.B.-V.)
| | | | | | - Madalina-Raluca Ostafe
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania; (S.R.V.); (M.-R.O.); (S.-G.A.-V.); (T.B.-V.)
| | - Slevoacă-Grigore Andreea-Voichița
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania; (S.R.V.); (M.-R.O.); (S.-G.A.-V.); (T.B.-V.)
| | - Toni Bejusca-Vieriu
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania; (S.R.V.); (M.-R.O.); (S.-G.A.-V.); (T.B.-V.)
| | | | - Daniel Sur
- 11th Department of Medical Oncology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania;
| | - Diana Boboc
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania; (S.R.V.); (M.-R.O.); (S.-G.A.-V.); (T.B.-V.)
| |
Collapse
|
|
3
|
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.
Collapse
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.)
| |
Collapse
|
|
4
|
Computational identification of bioactive compounds from Cydonia oblonga Mill. against hepatocellular carcinoma by targeting pTEN and HBx-interacting protein. J Mol Model 2022; 28:191. [PMID: 35711004 DOI: 10.1007/s00894-022-05170-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 05/25/2022] [Indexed: 10/18/2022]
Abstract
Phytochemicals derived from Cydonia oblonga have been investigated for their anti-oxidant and anti-cancer activities in various cancer cell lines. The reported bioactive compounds are evaluated in silico to develop a novel antagonist against pTEN (phosphatase and tensin homolog) and HBx (hepatitis B X-interacting protein) to target hepatocellular carcinoma. Lower expression of pTEN or higher expression of HBx represents the progression of hepatocellular carcinoma. This research is intended to identify the best candidate who interacts with our target proteins (pTEN and HBx) from the quince seeds by using computational methodologies. The ternary structures of the proteins and phytochemicals are retrieved from the online databases (RCSB and PubChem). The drug likeness analysis of the reported seventeen compounds was done, but only five follow the selection criteria. ADMET profiling of these five compounds was done, followed by docking analysis and molecular dynamics study of the best complexes to determine the stability of the complexes. A docking study revealed that caffeoylquinic acids (CQA) derivatives have the significant inhibitory potential of 3-O-caffeoylquinic acid (3CQA) and 5-O-caffeoylquinic acid (5CQA) with binding affinity of - 7.53 and - 7.49 against pTEN and - 5.94 and - 6.01 against HBx in comparison to the doxorubicin. The average root mean square deviation and root mean square fluctuation values for protein-ligand complexes were found quite stable compared to the standard, while parameters like gyration and SASA (solvent-accessible surface area) supported the complexes significant binding and stability. The results obtained from the evaluation show that 3CQA and 5CQA have the best stability, especially with the pTEN protein target. Hence, these compounds have to be considered for detailed experimental studies to understand their biological function against hepato-carcinoma.
Collapse
|
|
5
|
Kellogg C, Kouznetsova VL, Tsigelny IF. Implications of viral infection in cancer development. Biochim Biophys Acta Rev Cancer 2021; 1876:188622. [PMID: 34478803 DOI: 10.1016/j.bbcan.2021.188622] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 08/27/2021] [Accepted: 08/28/2021] [Indexed: 12/12/2022]
Abstract
Since the identification of the first human oncogenic virus in 1964, viruses have been studied for their potential role in aiding the development of cancer. Through the modulation of cellular pathways associated with proliferation, immortalization, and inflammation, viral proteins can mimic the effect of driver mutations and contribute to transformation. Aside from the modulation of signaling pathways, the insertion of viral DNA into the host genome and the deregulation of cellular miRNAs represent two additional mechanisms implicated in viral oncogenesis. In this review, we will discuss the role of twelve different viruses on cancer development and how these viruses utilize the abovementioned mechanisms to influence oncogenesis. The identification of specific mechanisms behind viral transformation of human cells could further elucidate the process behind cancer development.
Collapse
Affiliation(s)
- Caroline Kellogg
- REHS Program, San Diego Supercomputer Center, University of California, San Diego, CA, USA
| | - Valentina L Kouznetsova
- San Diego Supercomputer Center, University of California, San Diego, CA, USA; BiAna San Diego, CA, USA
| | - Igor F Tsigelny
- San Diego Supercomputer Center, University of California, San Diego, CA, USA; Department of Neurosciences, University of California, San Diego, CA, USA; BiAna San Diego, CA, USA.
| |
Collapse
|
|
6
|
Diao P, Jia F, Wang X, Hu X, Kimura T, Nakajima T, Aoyama T, Moriya K, Koike K, Tanaka N. Mechanisms of Steatosis-Derived Hepatocarcinogenesis: Lessons from HCV Core Gene Transgenic Mice. ENGINEERING 2021; 7:1797-1805. [DOI: 10.1016/j.eng.2021.08.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/11/2025]
|
|
7
|
Aftab A, Afzal S, Idrees M, Shahid AA. p53 and rb promoter methylation in hepatitis C virus-related chronic hepatitis and hepatocellular carcinoma. Future Virol 2021. [DOI: 10.2217/fvl-2020-0154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Aim: To identify methylation in p53 and rb during hepatitis C virus (HCV) infection in individuals in Pakistan. Materials & methods: Methylation-specific PCR was used on liver biopsies from hepatocellular carcinoma and chronic hepatitis C patients and on blood samples from healthy individuals. Real-time PCR was used to assess changes in the expression of p53 and rb in Huh-7 cells transfected with HCV-3a. Results: The p53 and rb promoters were methylated in hepatocellular carcinoma patients. The presence of HCV-3a- Core (p = 0.03), HCV-3a- NS-3 (p = 0.01) and HCV-3a- NS-5a (p = 0.02) downregulated p53 expression. Exposure to HCV-3a- Core (p = 0.04) downregulated rb expression. Conclusion: It can be hypothesized that HCV-induced epigenetic modifications may lead to the development of hepatic cancer that in turn inactivates p53 and rb.
Collapse
Affiliation(s)
- Ayma Aftab
- Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Samia Afzal
- Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Muhammad Idrees
- Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Ahmad Ali Shahid
- Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| |
Collapse
|
|
8
|
Morrell BC, Zhang L, Schütz LF, Perego MC, Maylem ERS, Spicer LJ. Regulation of the transcription factor E2F8 gene expression in bovine ovarian cells. Mol Cell Endocrinol 2019; 498:110572. [PMID: 31493442 DOI: 10.1016/j.mce.2019.110572] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2019] [Revised: 09/01/2019] [Accepted: 09/03/2019] [Indexed: 12/31/2022]
Abstract
Overexpression of the transcription factor, E2F8, has been associated with ovarian cancer. Objectives of this study were to determine: 1) if E2F8 gene expression in granulosa cells (GC) and theca cells (TC) change with follicular development, and 2) if E2F8 mRNA abundance in TC and GC is hormonally regulated. Using real-time PCR, E2F8 mRNA abundance in GC and TC was greater (P < 0.05) in small than large follicles. FGF9 induced an increase (P < 0.05) in E2F8 mRNA abundance by 1.6- to 7-fold in large-follicle (8-20 mm) TC and GC as well as in small-follicle (1-5 mm) GC. Abundance of E2F8 mRNA in TC was increased (P < 0.05) with FGF2, FGF9 or VEGFA treatments alone in vitro, and concomitant treatment of VEGFA with FGF9 increased (P < 0.05) abundance of E2F8 mRNA above any of the singular treatments; BMP4, WNT3A and LH were without effect. IGF1 amplified the stimulatory effect of FGF9 on E2F8 mRNA abundance by 2.7-fold. Collectively, our studies show for the first time that follicular E2F8 is developmentally and hormonally regulated indicating that E2F8 may be involved in follicular development.
Collapse
Affiliation(s)
- Breanne C Morrell
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK, 74078, USA
| | - Lingna Zhang
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK, 74078, USA
| | - Luis F Schütz
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK, 74078, USA
| | - M Chiara Perego
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK, 74078, USA
| | - Excel Rio S Maylem
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK, 74078, USA
| | - Leon J Spicer
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK, 74078, USA.
| |
Collapse
|
|
9
|
Non-Coding RNAs and Hepatitis C Virus-Induced Hepatocellular Carcinoma. Viruses 2018; 10:v10110591. [PMID: 30380697 PMCID: PMC6265700 DOI: 10.3390/v10110591] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 10/27/2018] [Accepted: 10/29/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is a worldwide health problem and is one of the main causes of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Despite recent improvements, effective treatments for HCC are still missing and new tools for early detection are needed. Non-coding RNAs (ncRNAs) have emerged as important regulators of gene expression and key players in human carcinogenesis, including HCC. Aberrant expression of ncRNAs is associated with HCC metastasis, invasion, dissemination, and recurrence. This review will focus on the recent advances in ncRNA expression profiles, their dysregulation in HCV-related HCC, and the clinical perspective of ncRNA signatures for the early detection of HCC.
Collapse
|
|
10
|
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.
Collapse
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.
| |
Collapse
|
|
11
|
Suhail M, Sohrab SS, Qureshi A, Tarique M, Abdel-Hafiz H, Al-Ghamdi K, Qadri I. Association of HCV mutated proteins and host SNPs in the development of hepatocellular carcinoma. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2018; 60:160-172. [PMID: 29501636 DOI: 10.1016/j.meegid.2018.02.034] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2017] [Revised: 02/14/2018] [Accepted: 02/28/2018] [Indexed: 12/13/2022]
Abstract
Hepatitis C virus plays a significant role in the development of hepatocellular carcinoma (HCC) globally. The pathogenic mechanisms of hepatocellular carcinoma with HCV infection are generally linked with inflammation, cytokines, fibrosis, cellular signaling pathways, and liver cell proliferation modulating pathways. HCV encoded proteins (Core, NS3, NS4, NS5A) interact with a broad range of hepatocytes derived factors to modulate an array of activities such as cell signaling, DNA repair, transcription and translational regulation, cell propagation, apoptosis, membrane topology. These four viral proteins are also implicated to show a strong conversion potential in tissue culture. Furthermore, Core and NS5A also trigger the accretion of the β-catenin pathway as a common target to contribute viral induced transformation. There is a strong association between HCV variants within Core, NS4, and NS5A and host single nucleotide polymorphisms (SNPs) with the HCC pathogenesis. Identification of such viral mutants and host SNPs is very critical to determine the risk of HCC and response to antiviral therapy. In this review, we highlight the association of key variants, mutated proteins, and host SNPs in development of HCV induced HCC. How such viral mutants may modulate the interaction with cellular host machinery is also discussed.
Collapse
Affiliation(s)
- Mohd Suhail
- King Fahd Medical Research Center, King Abdulaziz University, PO Box 80216, Jeddah 21589, Saudi Arabia
| | - Sayed Sartaj Sohrab
- Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, PO Box 80216, Jeddah 21589, Saudi Arabia
| | - Abid Qureshi
- Biomedical Informatics Centre, Sher-i-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, J&K, India
| | - Mohd Tarique
- Department of Surgery, Sylvester Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, United States
| | - Hany Abdel-Hafiz
- Dept of Medicine, University of Colorado Denver, Aurora, CO 80045, United States
| | - Khalid Al-Ghamdi
- Department of Biological Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ishtiaq Qadri
- Department of Biological Science, King Abdulaziz University, Jeddah, Saudi Arabia.
| |
Collapse
|
|
12
|
Abstract
Hepatitis C virus (HCV) consists of envelope proteins, core proteins, and genome RNA. The structural genes and non-structural genes in the open reading frame of its genome encode functional proteins essential to viral life cycles, ranging from virus attachment to progeny virus secretion. After infection, the host cells suffer damage from virus-induced oxidative stress, steatosis, and activation of proto-oncogenes. Every process during the viral life cycle can be considered as targets for direct acting antivirals. However, protective immunity cannot be easily acquired for the volatility in HCV antigenic epitopes. Understanding its molecular characteristics, especially pathogenesis and targets the drugs act on, not only helps professionals to make optimal therapeutic decisions, but also helps clinicians who do not specialize in infectious diseases/hepatology to provide better management for patients. This review serves to provide an insight for clinicians and this might provide a possible solution for any possible collision.
Collapse
Affiliation(s)
- Lingyao Du
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China. E-mail.
| | | |
Collapse
|
|
13
|
Khalid A, Hussain T, Manzoor S, Saalim M, Khaliq S. PTEN: A potential prognostic marker in virus-induced hepatocellular carcinoma. Tumour Biol 2017. [DOI: 10.1177/1010428317705754] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Ayesha Khalid
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied BioSciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Tabinda Hussain
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied BioSciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Sobia Manzoor
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied BioSciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Muhammad Saalim
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied BioSciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Saba Khaliq
- University of Health Sciences, Lahore, Pakistan
| |
Collapse
|
|
14
|
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.
Collapse
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
| |
Collapse
|
|
15
|
Ezzat WM, Amr KS. Insights for hepatitis C virus related hepatocellular carcinoma genetic biomarkers: Early diagnosis and therapeutic intervention. World J Hepatol 2016; 8:1251-1261. [PMID: 27843535 PMCID: PMC5084054 DOI: 10.4254/wjh.v8.i30.1251] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 07/15/2016] [Accepted: 09/08/2016] [Indexed: 02/06/2023] Open
Abstract
The current review explores the role of emerging molecular contributing factors in liver carcinogenesis on top of hepatitis C virus (HCV). Here we will try to discuss the role genetic and epigenetic factors in pathogenesis of hepatocellular carcinoma. Understanding the role of these factors will help in discovering the mystery of liver carcinogenesis on top of chronic HCV infection. Moreover, use of the studied molecular factors will provide the hepatologists with tailored diagnostic promising biomarkers and flatten the way for establishment of emerging molecular treatment based on exploring the molecular subscription of this aggressive liver cancer.
Collapse
|
|
16
|
Pikor LA, Bell JC, Diallo JS. Oncolytic Viruses: Exploiting Cancer's Deal with the Devil. Trends Cancer 2015; 1:266-277. [PMID: 28741515 DOI: 10.1016/j.trecan.2015.10.004] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2015] [Revised: 10/18/2015] [Accepted: 10/20/2015] [Indexed: 12/12/2022]
Abstract
Tumor cells harbor tens to thousands of genetic and epigenetic alterations that disrupt cellular pathways, providing them with growth and survival advantages. However, these benefits come at a cost, with uncontrolled cell growth, defective apoptosis, sustained pathological angiogenesis, immune evasion, and a metastatic phenotype occurring at the expense of the antiviral response of the individual tumor cell. Oncolytic virotherapy is an emerging therapeutic strategy that uses replication-competent viruses to selectivity kill cancer cells by exploiting their impaired antiviral response. In this review, we outline our understanding of the alterations in signaling pathways that simultaneously contribute to the malignant phenotype and virus-mediated killing of cancer cells.
Collapse
Affiliation(s)
- Larissa A Pikor
- Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ONT, Canada
| | - John C Bell
- Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ONT, Canada; Department of Biochemistry, Immunology and Microbiology, University of Ottawa, Ottawa, ONT, Canada
| | - Jean-Simon Diallo
- Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ONT, Canada.
| |
Collapse
|
|
17
|
Mileo AM, Mattarocci S, Matarrese P, Anticoli S, Abbruzzese C, Catone S, Sacco R, Paggi MG, Ruggieri A. Hepatitis C virus core protein modulates pRb2/p130 expression in human hepatocellular carcinoma cell lines through promoter methylation. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2015; 34:140. [PMID: 26576645 PMCID: PMC4650920 DOI: 10.1186/s13046-015-0255-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Accepted: 11/09/2015] [Indexed: 12/14/2022]
Abstract
Background Hepatitis C Virus (HCV) infection is associated with chronically evolving disease and development of hepatocellular carcinoma (HCC), albeit the mechanism of HCC induction by HCV is still controversial. The nucleocapsid (core) protein of HCV has been shown to be directly implicated in cellular transformation and immortalization, enhancing the effect of oncogenes and decreasing the one of tumor suppressor genes, as RB1 and its protein product pRB. With the aim of identifying novel molecular mechanisms of hepatocyte transformation by HCV, we examined the effect of HCV core protein on the expression of the whole Retinoblastoma (RB) family of tumor and growth suppressor factors, i.e. pRb, p107 and pRb2/p130. Methods We used a model system consisting of the HuH-7, HCV-free, human hepatocellular carcinoma cell line and of the HuH-7-CORE cells derived from the former and constitutively expressing the HCV core protein. We determined pRb, p107 and pRb2/p130 protein and mRNA amount of the respective genes RB1, RBL1 and RBL2, RBL2 promoter activity and methylation as well as DNA methyltransferase 1 (DNMT1) and 3b (DNMT3b) expression level. The effect of pRb2/p130 over-expression on the HCV core-expressing HuH-7-CORE cells was also evaluated. Results We found that the HCV core protein expression down-regulated pRb2/p130 protein and mRNA levels in HuH-7-CORE cells by inducing promoter hyper-methylation with the concomitant up-regulation of DNMT1 and DNMT3b expression. When pRb2/p130 expression was artificially re-established in HuH-7-CORE cells, cell cycle analysis outlined an accumulation in the G0/G1 phase, as expected. Conclusions HCV core appears indeed able to significantly down-regulate the expression and the function of two out of three RB family tumor and growth suppressor factors, i.e. pRb and pRb2/p130. The functional consequences at the level of cell cycle regulation, and possibly of more complex cell homeostatic processes, may represent a plausible molecular mechanism involved in liver transformation by HCV.
Collapse
Affiliation(s)
- Anna Maria Mileo
- Experimental Oncology, "Regina Elena" National Cancer Institute, IRCCS, Via Elio Chianesi, 53, 00144, Rome, Italy
| | - Stefano Mattarocci
- Department of Molecular Biology, University of Geneva, 1211, Geneva, Switzerland
| | - Paola Matarrese
- Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, 00161, Rome, Italy
| | - Simona Anticoli
- National AIDS Center, Istituto Superiore di Sanità, 00161, Rome, Italy
| | - Claudia Abbruzzese
- Experimental Oncology, "Regina Elena" National Cancer Institute, IRCCS, Via Elio Chianesi, 53, 00144, Rome, Italy
| | - Stefania Catone
- Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, 00161, Rome, Italy
| | - Rodolfo Sacco
- Gastroenterology and Metabolic Diseases, Department of Gastroenterology, 56124 Pisa University Hospital, Pisa, Italy
| | - Marco G Paggi
- Experimental Oncology, "Regina Elena" National Cancer Institute, IRCCS, Via Elio Chianesi, 53, 00144, Rome, Italy.
| | - Anna Ruggieri
- Department of Veterinary Public Health & Food Safety, Istituto Superiore di Sanità, 00161, Rome, Italy
| |
Collapse
|
|
18
|
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.
Collapse
Affiliation(s)
- Ming V Lin
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114; , ,
| | | | | |
Collapse
|
|
19
|
Blum HE. Hepatitis C and Hepatocellular Carcinoma. VIRAL HEPATITIS 2013:353-361. [DOI: 10.1002/9781118637272.ch24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
20
|
Hepatitis C virus and hepatocellular carcinoma. BIOLOGY 2013; 2:304-16. [PMID: 24832662 PMCID: PMC4009856 DOI: 10.3390/biology2010304] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2013] [Revised: 01/18/2013] [Accepted: 01/23/2013] [Indexed: 12/28/2022]
Abstract
Hepatitis C virus (HCV), a hepatotropic virus, is a single stranded-positive RNA virus of ~9,600 nt. length belonging to the Flaviviridae family. HCV infection causes acute hepatitis, chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC). It has been reported that HCV-coding proteins interact with host-cell factors that are involved in cell cycle regulation, transcriptional regulation, cell proliferation and apoptosis. Severe inflammation and advanced liver fibrosis in the liver background are also associated with the incidence of HCV-related HCC. In this review, we discuss the mechanism of hepatocarcinogenesis in HCV-related liver diseases.
Collapse
|
|
21
|
Selimovic D, El-Khattouti A, Ghozlan H, Haikel Y, Abdelkader O, Hassan M. Hepatitis C virus-related hepatocellular carcinoma: An insight into molecular mechanisms and therapeutic strategies. World J Hepatol 2012; 4:342-55. [PMID: 23355912 PMCID: PMC3554798 DOI: 10.4254/wjh.v4.i12.342] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2012] [Revised: 11/17/2012] [Accepted: 11/24/2012] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infects more than 170 million people worldwide, and thereby becomes a series global health challenge. Chronic infection with HCV is considered one of the major causes of end-stage liver disease including cirrhosis and hepatocellular carcinoma. Although the multiple functions of the HCV proteins and their impacts on the modulation of the intracellular signaling transduction processes, the drive of carcinogenesis during the infection with HCV, is thought to result from the interactions of viral proteins with host cell proteins. Thus, the induction of mutator phenotype, in liver, by the expression of HCV proteins provides a key mechanism for the development of HCV-associated hepatocellular carcinoma (HCC). HCC is considered one of the most common malignancies worldwide with increasing incidence during the past decades. In many countries, the trend of HCC is attributed to several liver diseases including HCV infection. However, the development of HCC is very complicated and results mainly from the imbalance between tumor suppressor genes and oncogenes, as well as from the alteration of cellular factors leading to a genomic instability. Besides the poor prognosis of HCC patients, this type of tumor is quite resistance to the available therapies. Thus, understanding the molecular mechanisms, which are implicated in the development of HCC during the course of HCV infection, may help to design a general therapeutic protocol for the treatment and/or the prevention of this malignancy. This review summarizes the current knowledge of the molecular mechanisms, which are involved in the development of HCV-associated HCC and the possible therapeutic strategies.
Collapse
Affiliation(s)
- Denis Selimovic
- Denis Selimovic, Youssef Haikel, Mohamed Hassan, Institut National de la Santé et de la Recherche Médicale, U 977, 67000 Strasbourg, France
| | | | | | | | | | | |
Collapse
|
|
22
|
Jeong SW, Jang JY, Chung RT. Hepatitis C virus and hepatocarcinogenesis. Clin Mol Hepatol 2012; 18:347-56. [PMID: 23323249 PMCID: PMC3540370 DOI: 10.3350/cmh.2012.18.4.347] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2012] [Revised: 11/19/2012] [Accepted: 11/30/2012] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus (HCV) is an RNA virus that is unable to integrate into the host genome. However, its proteins interact with various host proteins and induce host responses. The oncogenic process of HCV infection is slow and insidious and probably requires multiple steps of genetic and epigenetic alterations, the activation of cellular oncogenes, the inactivation of tumor suppressor genes, and dysregulation of multiple signal transduction pathways. Stellate cells may transdifferentiate into progenitor cells and possibly be linked to the development of hepatocellular carcinoma (HCC). Viral proteins also have been implicated in several cellular signal transduction pathways that affect cell survival, proliferation, migration and transformation. Current advances in gene expression profile and selective messenger RNA analysis have improved approach to the pathogenesis of HCC. The heterogeneity of genetic events observed in HCV-related HCCs has suggested that complex mechanisms underlie malignant transformation induced by HCV infection. Considering the complexity and heterogeneity of HCCs of both etiological and genetic aspects, further molecular classification is required and an understanding of these molecular complexities may provide the opportunity for effective chemoprevention and personalized therapy for HCV-related HCC patients in the future. In this review, we summarize the current knowledge of the mechanisms of hepatocarcinogenesis induced by HCV infection.
Collapse
Affiliation(s)
- Soung Won Jeong
- Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, Korea
| | | | | |
Collapse
|
|
23
|
Taura M, Suico MA, Koyama K, Komatsu K, Miyakita R, Matsumoto C, Kudo E, Kariya R, Goto H, Kitajima S, Takahashi C, Shuto T, Nakao M, Okada S, Kai H. Rb/E2F1 regulates the innate immune receptor Toll-like receptor 3 in epithelial cells. Mol Cell Biol 2012; 32:1581-1590. [PMID: 22310660 PMCID: PMC3318576 DOI: 10.1128/mcb.06454-11] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2011] [Accepted: 01/25/2012] [Indexed: 12/16/2022] Open
Abstract
Tumor suppressor genes regulate the antiviral host defense through molecular mechanisms that are not yet well explored. Here, we show that the tumor suppressor retinoblastoma (Rb) protein positively regulates Toll-like receptor 3 (TLR3) expression, the sensing receptor for viral double-stranded RNA and poly(I · C). TLR3 expression was lower in Rb knockout (Rb(-/-)) mouse embryonic fibroblasts (MEF) and in mammalian epithelial cells transfected with Rb small-interfering RNA (siRNA) than in control cells. Consequently, induction of cytokines interleukin-8 and beta interferon after poly(I · C) stimulation was impaired in Rb(-/-) MEF and Rb siRNA-transfected cells compared to controls. TLR3 promoter analysis showed that Rb modulates the transcription factor E2F1, which directly binds to the proximal promoter of TLR3. Exogenous addition of E2F1 decreased TLR3 promoter activity, while Rb dose dependently curbed the effect of E2F1. Interestingly, poly(I · C) increased the Rb expression, and the poly(I · C)-induced TLR3 expression was impaired in Rb-depleted cells, suggesting the importance of Rb in TLR3 induction by poly(I · C). Together, these data indicated that E2F1 suppresses TLR3 transcription, but during immune stimulation, Rb is upregulated to block the inhibitory effect of E2F1 on TLR3, highlighting a role of Rb-E2F1 axis in the innate immune response in epithelial cells.
Collapse
Affiliation(s)
- Manabu Taura
- Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto, Japan
| | - Mary Ann Suico
- Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Global COE Cell Fate Regulation Research and Education Unit, Kumamoto University, Kumamoto, Japan
| | - Kosuke Koyama
- Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Global COE Cell Fate Regulation Research and Education Unit, Kumamoto University, Kumamoto, Japan
| | - Kensei Komatsu
- Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Global COE Cell Fate Regulation Research and Education Unit, Kumamoto University, Kumamoto, Japan
| | - Rui Miyakita
- Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Global COE Cell Fate Regulation Research and Education Unit, Kumamoto University, Kumamoto, Japan
| | - Chizuru Matsumoto
- Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Global COE Cell Fate Regulation Research and Education Unit, Kumamoto University, Kumamoto, Japan
| | - Eriko Kudo
- Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto, Japan
| | - Ryusho Kariya
- Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto, Japan
| | - Hiroki Goto
- Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto, Japan
| | - Shunsuke Kitajima
- Division of Oncology and Molecular Biology, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Chiaki Takahashi
- Division of Oncology and Molecular Biology, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Tsuyoshi Shuto
- Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Global COE Cell Fate Regulation Research and Education Unit, Kumamoto University, Kumamoto, Japan
| | - Mitsuyoshi Nakao
- Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
| | - Seiji Okada
- Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto, Japan
| | - Hirofumi Kai
- Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Global COE Cell Fate Regulation Research and Education Unit, Kumamoto University, Kumamoto, Japan
| |
Collapse
|
|
24
|
Marra M, Sordelli IM, Lombardi A, Lamberti M, Tarantino L, Giudice A, Stiuso P, Abbruzzese A, Sperlongano R, Accardo M, Agresti M, Caraglia M, Sperlongano P. Molecular targets and oxidative stress biomarkers in hepatocellular carcinoma: an overview. J Transl Med 2011; 9:171. [PMID: 21985599 PMCID: PMC3213217 DOI: 10.1186/1479-5876-9-171] [Citation(s) in RCA: 170] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2011] [Accepted: 10/10/2011] [Indexed: 12/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with multiple genetic aberrations. Several molecular pathways involved in the regulation of proliferation and cell death are implicated in the hepatocarcinogenesis. The major etiological factors for HCC are both hepatitis B virus (HBV) and hepatitis C virus infection (HCV). Continuous oxidative stress, which results from the generation of reactive oxygen species (ROS) by environmental factors or cellular mitochondrial dysfunction, has recently been associated with hepatocarcinogenesis. On the other hand, a distinctive pathological hallmark of HCC is a dramatic down-regulation of oxido-reductive enzymes that constitute the most important free radical scavenger systems represented by catalase, superoxide dismutase and glutathione peroxidase. The multikinase inhibitor sorafenib represents the most promising target agent that has undergone extensive investigation up to phase III clinical trials in patients with advanced HCC. The combination with other target-based agents could potentiate the clinical benefits obtained by sorafenib alone. In fact, a phase II multicenter study has demonstrated that the combination between sorafenib and octreotide LAR (So.LAR protocol) was active and well tolerated in advanced HCC patients. The detection of molecular factors predictive of response to anti-cancer agents such as sorafenib and the identification of mechanisms of resistance to anti-cancer agents may probably represent the direction to improve the treatment of HCC.
Collapse
Affiliation(s)
- Monica Marra
- Department of Biochemistry and Biophysics, Second University of Naples, Naples, Italy
| | - Ignazio M Sordelli
- Department of Anaesthesiology and Special Surgery, Second University of Naples, Naples, Italy
| | - Angela Lombardi
- Department of Biochemistry and Biophysics, Second University of Naples, Naples, Italy
| | - Monica Lamberti
- Departement of Experimental Medicine, Sezione di Medicina del lavoro, Igiene e Tossicologia Industriale, Second University of Naples, Naples, Italy
| | - Luciano Tarantino
- Interventional US Unit, Department of Medicine, S. Giovanni di Dio Hospital, 80059 Torre del Greco (Naples), Italy
| | - Aldo Giudice
- Animal Facility Unit, National Institute of Tumours "Fondazione G. Pascale" of Naples, Naples, Italy
| | - Paola Stiuso
- Department of Biochemistry and Biophysics, Second University of Naples, Naples, Italy
| | - Alberto Abbruzzese
- Department of Biochemistry and Biophysics, Second University of Naples, Naples, Italy
| | - Rossella Sperlongano
- Department of Anaesthesiology and Special Surgery, Second University of Naples, Naples, Italy
| | - Marina Accardo
- Department of Morphopathology, II University Naples, Napoli, Italy
| | - Massimo Agresti
- Department of Anaesthesiology and Special Surgery, Second University of Naples, Naples, Italy
| | - Michele Caraglia
- Department of Biochemistry and Biophysics, Second University of Naples, Naples, Italy
| | - Pasquale Sperlongano
- Department of Anaesthesiology and Special Surgery, Second University of Naples, Naples, Italy
| |
Collapse
|
|
25
|
Bouchard MJ, Navas-Martin S. Hepatitis B and C virus hepatocarcinogenesis: lessons learned and future challenges. Cancer Lett 2011; 305:123-43. [PMID: 21168955 PMCID: PMC3071446 DOI: 10.1016/j.canlet.2010.11.014] [Citation(s) in RCA: 120] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2010] [Revised: 11/15/2010] [Accepted: 11/25/2010] [Indexed: 12/15/2022]
Abstract
Worldwide, hepatocellular carcinoma (HCC) is one of the most common cancers. It is thought that 80% of hepatocellular carcinomas are linked to chronic infections with the hepatitis B (HBV) or hepatitis C (HCV) viruses. Chronic HBV and HCV infections can alter hepatocyte physiology in similar ways and may utilize similar mechanisms to influence the development of HCC. There has been significant progress towards understanding the molecular biology of HBV and HCV and identifying the cellular signal transduction pathways that are altered by HBV and HCV infections. Although the precise molecular mechanisms that link HBV and HCV infections to the development of HCC are not entirely understood, there is considerable evidence that both inflammatory responses to infections with these viruses, and associated destruction and regeneration of hepatocytes, as well as activities of HBV- or HCV-encoded proteins, contribute to hepatocyte transformation. In this review, we summarize progress in defining mechanisms that may link HBV and HCV infections to the development of HCC, discuss the challenges of directly defining the processes that underlie HBV- and HCV-associated HCC, and describe areas that remain to be explored.
Collapse
Affiliation(s)
- Michael J Bouchard
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, 245 N. 15th Street, Philadelphia, PA 19102, USA.
| | | |
Collapse
|
|
26
|
Liu J, Wang Z, Tang J, Tang R, Shan X, Zhang W, Chen Q, Zhou F, Chen K, Huang A, Tang N. Hepatitis C virus core protein activates Wnt/β-catenin signaling through multiple regulation of upstream molecules in the SMMC-7721 cell line. Arch Virol 2011; 156:1013-23. [PMID: 21340743 DOI: 10.1007/s00705-011-0943-x] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2010] [Accepted: 02/01/2011] [Indexed: 01/04/2023]
Abstract
The core protein of hepatitis C virus (HCV) has been implicated in HCV-induced liver pathogenesis. Previous data have shown that the HCV core protein has pleiotropic functions, including transcriptional regulation of a number of cellular genes, although the mechanism of gene regulation remains unclear. Wnt/β-catenin signaling is also involved in hepatocellular carcinoma (HCC) tumorigenesis. To elucidate the molecular mechanism of HCV pathogenesis, we examined whether HCV core protein activates Wnt/β-catenin signaling in the hepatoma cell line SMMC-7721. The effects of core protein on Wnt/β-catenin signaling cascades were investigated by luciferase reporter gene assay, immunofluorescence, western blot and RT-PCR analysis. Here, we demonstrate that HCV core protein plays an essential role in activating β-catenin/Tcf-4-dependent transcriptional activity and increases active β-catenin expression and nuclear accumulation in SMMC-7721 cells. An RT-PCR assay indicated that core protein upregulates gene expression of canonical Wnt ligands, such as Wnt2, Wnt3, Wnt3a, Wnt8b, Wnt10a, Wnt10b, frizzled receptors Fzd1, 2, 5, 6, 7, 9, and LRP5/6 co-receptors. However, Wnt antagonists SFRP3, 5 and Dkk1 were moderately repressed. Furthermore, ectopic expression of core protein markedly promoted cell proliferation. The soluble Fzd molecule FrzB or the β-catenin inhibitor siBC efficiently blocked cell growth stimulation by the core gene. Our present findings demonstrate that the HCV core protein activates canonical Wnt signaling through tight regulation of several important molecules upstream of β-catenin and presumably results in promotion of cell proliferation in the SMMC-7721 cell line. Taken together, these data suggested that the core protein may be directly involved in Wnt/β-catenin-mediated liver pathogenesis.
Collapse
Affiliation(s)
- Jiao Liu
- The Second Affiliated Hospital, Chongqing Medical University, Lin Jiang Road, No.74, Chongqing, 400010 Chongqing, China
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
27
|
Saha A, Kaul R, Murakami M, Robertson ES. Tumor viruses and cancer biology: Modulating signaling pathways for therapeutic intervention. Cancer Biol Ther 2010; 10:961-78. [PMID: 21084867 DOI: 10.4161/cbt.10.10.13923] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Tumor viruses have provided relatively simple genetic systems, which can be manipulated for understanding the molecular mechanisms of the cellular transformation process. A growing body of information in the tumor virology field provides several prospects for rationally targeted therapies. However, further research is needed to better understand the multiple mechanisms utilized by these viruses in cancer progression in order to develop therapeutic strategies. Initially viruses were believed to be associated with cancers as causative agents only in animals. It was almost half a century before the first human tumor virus, Epstein-Barr virus (EBV), was identified in 1964. Subsequently, several human tumor viruses have been identified including Kaposi sarcoma associated herpesvirus (KSHV), human Papillomaviruses (HPV), Hepatitis B virus (HBV), Hepatitis C virus (HCV), Human T lymphotropic virus (HTLV-1) and recently identified Merkel cell Polyomavirus (MCPyV). Tumor viruses are sub-categorized as either DNA viruses, which include EBV, KSHV, HPV, HBV, and MCPyV, or RNA viruses such as HCV and HTLV-1. Tumor-viruses induce oncogenesis through manipulating an array of different cellular pathways. These viruses initiate a series of cellular events, which lead to immortalization and proliferation of the infected cells by disrupting the mitotic checkpoint upon infection of the host cell. This is often accomplished by functional inhibition or proteasomal degradation of many tumor suppressor proteins by virally encoded gene products. The virally infected cells can either be eliminated via cell-mediated apoptosis or persist in a state of chronic infection. Importantly, the chronic persistence of infection by tumor viruses can lead to oncogenesis. This review discusses the major human tumor associated viruses and their ability to modulate numerous cell signaling pathways, which can be targeted for potential therapeutic approaches.
Collapse
Affiliation(s)
- Abhik Saha
- Department of Microbiology and Tumor Virology, University of Pennsylvania School of Medicine, Philadelphia, USA
| | | | | | | |
Collapse
|
|
28
|
Banerjee A, Ray RB, Ray R. Oncogenic potential of hepatitis C virus proteins. Viruses 2010; 2:2108-2133. [PMID: 21994721 PMCID: PMC3185750 DOI: 10.3390/v2092108] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2010] [Revised: 09/23/2010] [Accepted: 09/24/2010] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection is a major risk factor for liver disease progression, and may lead to cirrhosis and hepatocellular carcinoma (HCC). The HCV genome contains a single-stranded positive sense RNA with a cytoplasmic lifecycle. HCV proteins interact with many host-cell factors and are involved in a wide range of activities, including cell cycle regulation, transcriptional regulation, cell proliferation, apoptosis, lipid metabolism, and cell growth promotion. Increasing experimental evidences suggest that HCV contributes to HCC by modulating pathways that may promote malignant transformation of hepatocytes. At least four of the 10 HCV gene products, namely core, NS3, NS5A and NS5B play roles in several potentially oncogenic pathways. Induction of both endoplasmic reticulum (ER) stress and oxidative stress by HCV proteins may also contribute to hepatocyte growth promotion. The current review identifies important functions of the viral proteins connecting HCV infections and potential for development of HCC. However, most of the putative transforming potentials of the HCV proteins have been defined in artificial cellular systems, and need to be established relevant to infection and disease models. The new insight into the mechanisms for HCV mediated disease progression may offer novel therapeutic targets for one of the most devastating human malignancies in the world today.
Collapse
Affiliation(s)
- Arup Banerjee
- Department of Internal Medicine, Edward A. Doisy Research Center, 1100 S. Grand Blvd., 8th Floor, St. Louis, MO 63104, USA; E-Mail:
| | - Ratna B. Ray
- Department of Pathology, Edward A. Doisy Research Center, 1100 S. Grand Blvd., 2nd Floor, St. Louis, MO 63104, USA; E-Mail:
| | - Ranjit Ray
- Department of Internal Medicine, Edward A. Doisy Research Center, 1100 S. Grand Blvd., 8th Floor, St. Louis, MO 63104, USA; E-Mail:
- Molecular Microbiology & Immunology, Edward A. Doisy Research Center, 1100 S. Grand Blvd., 8th Floor, St. Louis, MO 63104, USA
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: 1-314- 977-9034; Fax: 1-314-771-3816
| |
Collapse
|
|
29
|
Tsai WL, Chung RT. Viral hepatocarcinogenesis. Oncogene 2010; 29:2309-24. [PMID: 20228847 PMCID: PMC3148694 DOI: 10.1038/onc.2010.36] [Citation(s) in RCA: 192] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2009] [Revised: 12/29/2009] [Accepted: 01/06/2010] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death worldwide. Despite recent advances in the diagnosis and treatment of HCC, its prognosis remains dismal. Infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) are the major risk factors for HCC. Although both are hepatotropic viral infections, there are important differences between the oncogenic mechanisms of these two viruses. In addition to the oncogenic potential of its viral proteins, HBV, as a DNA virus, can integrate into host DNA and directly transform hepatocytes. In contrast, HCV, an RNA virus, is unable to integrate into the host genome, and viral protein expression has a more critical function in hepatocarcinogenesis. Both HBV and HCV proteins have been implicated in disrupting cellular signal transduction pathways that lead to unchecked cell growth. Most HCC develops in the cirrhotic liver, but the linkage between cirrhosis and HCC is likely multifactorial. In this review, we summarize current knowledge regarding the pathogenetic mechanisms of viral HCC.
Collapse
Affiliation(s)
- W-L Tsai
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - RT Chung
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
30
|
Abstract
Although there is strong evidence that hepatitis C virus (HCV) is one of the leading causes of hepatocellular carcinoma (HCC), there is still much to understand regarding the mechanism of HCV-induced transformation. While liver fibrosis resulting from long-lasting chronic inflammation and liver regeneration resulting from immune-mediated cell death are likely factors that contribute to the development of HCC, the direct role of HCV proteins remains to be determined. In vitro studies have shown that HCV expression may interfere with cellular functions that are important for cell differentiation and cell growth. However, most studies were performed in artificial models which can only give clues for potential mechanisms that need to be confirmed in more relevant models. Furthermore, the difficulty to identify HCV proteins and infected liver cells in patients, contributes to the complexity of our current understanding. For these reasons, there is currently very little experimental evidence for a direct oncogenic role of HCV. Further studies are warranted to clarify these issues.
Collapse
Affiliation(s)
- Birke Bartosch
- INSERM, U871, 151 Cours Albert Thomas, 69003 Lyon, France
| | | | | | | |
Collapse
|
|
31
|
Hepatitis C virus causes uncoupling of mitotic checkpoint and chromosomal polyploidy through the Rb pathway. J Virol 2009; 83:12590-600. [PMID: 19793824 DOI: 10.1128/jvi.02643-08] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Hepatitis C virus (HCV) infection is associated with the development of hepatocellular carcinoma and probably also non-Hodgkin's B-cell lymphoma. The molecular mechanisms of HCV-associated carcinogenesis are unknown. Here we demonstrated that peripheral blood mononuclear cells obtained from hepatitis C patients and hepatocytes infected with HCV in vitro showed frequent chromosomal polyploidy. HCV infection or the expression of viral core protein alone in hepatocyte culture or transgenic mice inhibited mitotic spindle checkpoint function because of reduced Rb transcription and enhanced E2F-1 and Mad2 expression. The silencing of E2F-1 by RNA interference technology restored the function of mitotic checkpoint in core-expressing cells. Taken together, these data suggest that HCV infection may inhibit the mitotic checkpoint to induce polyploidy, which likely contributes to neoplastic transformation.
Collapse
|
|
32
|
Abstract
HCV (hepatitis C virus) infects nearly 3% of the population worldwide and has emerged as a major causative agent of liver disease, resulting in acute and chronic infections that can lead to fibrosis, cirrhosis and hepatocellular carcinoma. Hepatitis C represents the leading cause of liver transplantation in the United States and Europe. A positive-strand RNA virus of the Flaviviridae family, HCV contains a single-stranded RNA genome of approx. 9600 nucleotides. The genome RNA serves as both mRNA for translation of viral proteins and the template for RNA replication. Cis-acting RNA elements within the genome regulate RNA replication by forming secondary structures that interact with each other and trans-acting factors. Although structural proteins are clearly dispensable for RNA replication, recent evidence points to an important role of several non-structural proteins in particle assembly and release, turning their designation on its head. HCV enters host cells through receptor-mediated endocytosis, and the process requires the co-ordination of multiple cellular receptors and co-receptors. RNA replication takes place at specialized intracellular membrane structures called 'membranous webs' or 'membrane-associated foci', whereas viral assembly probably occurs on lipid droplets and endoplasmic reticulum. Liver inflammation plays a central role in the liver damage seen in hepatitis C, but many HCV proteins also directly contribute to HCV pathogenesis. In the present review, the molecular and cellular aspects of the HCV life cycle and the role of viral proteins in pathological liver conditions caused by HCV infection are described.
Collapse
|
|
33
|
McGivern DR, Lemon SM. Tumor suppressors, chromosomal instability, and hepatitis C virus-associated liver cancer. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2009; 4:399-415. [PMID: 18928409 DOI: 10.1146/annurev.pathol.4.110807.092202] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatitis C virus (HCV) is the only known RNA virus with an exclusively cytoplasmic life cycle that is associated with cancer. The mechanisms by which it causes cancer are unclear, but chronic immune-mediated inflammation and associated oxidative chromosomal DNA damage probably play a role. Compelling data suggest that the path to hepatocellular carcinoma in chronic hepatitis C shares some important features with the mechanisms of transformation employed by DNA tumor viruses. Interactions of viral proteins with key regulators of the cell cycle, the retinoblastoma-susceptibility protein, p53, and possibly DDX5 and DDX3 lead to enhanced cellular proliferation and may also compromise multiple cell-cycle checkpoints that maintain genomic integrity, thus setting the stage for carcinogenesis. Dysfunctional DNA damage and mitotic spindle checkpoints resulting from these interactions may promote chromosomal instability and leave the hepatocyte unable to control DNA damage caused by oxidative stress mediated by HCV proteins, alcohol, and immune-mediated inflammation.
Collapse
Affiliation(s)
- David R McGivern
- The Center for Hepatitis Research, Institute for Human Infections and Immunity, Sealy Center for Cancer Cell Biology, Galveston, TX 77555, USA
| | | |
Collapse
|
|
34
|
Sheahan S, Bellamy CO, Harland SN, Harrison DJ, Prost S. TGFbeta induces apoptosis and EMT in primary mouse hepatocytes independently of p53, p21Cip1 or Rb status. BMC Cancer 2008; 8:191. [PMID: 18611248 PMCID: PMC2467431 DOI: 10.1186/1471-2407-8-191] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2008] [Accepted: 07/08/2008] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND TGFbeta has pleiotropic effects that range from regulation of proliferation and apoptosis to morphological changes and epithelial-mesenchymal transition (EMT). Some evidence suggests that these effects may be interconnected. We have recently reported that P53, P21Cip1 and pRB, three critical regulators of the G1/S transition are variably involved in TGFbeta-induced cell cycle arrest in hepatocytes. As these proteins are also involved in the regulation of apoptosis in many circumstances, we investigated their contribution to other relevant TGFbeta-induced effects, namely apoptosis and EMT, and examined how the various processes were interrelated. METHODS Primary mouse hepatocytes deficient in p53, p21 and/or Rb, singly or in combination were treated with TGFbeta for 24 to 96 hours. Apoptosis was quantified according to morphology and by immunostaining for cleaved-capsase 3. Epithelial and mesenchymal marker expression was studied using immunocytochemistry and real time PCR. RESULTS We found that TGFbeta similarly induced morphological changes regardless of genotype and independently of proliferation index or sensitivity to inhibition of proliferation by TGFbeta. Morphological changes were accompanied by decrease in E-cadherin and increased Snail expression but the mesenchymal markers (N-cadherin, SMAalpha and Vimentin) studied remained unchanged. TGFbeta induced high levels of apoptosis in p53-/-, Rb-/-, p21cip1-/- and control hepatocytes although with slight differences in kinetics. This was unrelated to proliferation or changes in morphology and loss of cell-cell adhesion. However, hepatocytes deficient in both p53 and p21cip1were less sensitive to TGFbeta-induced apoptosis. CONCLUSION Although p53, p21Cip1 and pRb are well known regulators of both proliferation and apoptosis in response to a multitude of stresses, we conclude that they are critical for TGFbeta-driven inhibition of hepatocytes proliferation, but only slightly modulate TGFbeta-induced apoptosis. This effect may depend on other parameters such as proliferation and the presence of other regulatory proteins as suggested by the consequences of p53, p21Cip1 double deficiency. Similarly, p53, p21Cip1 and pRB deficiency had no effect on the morphological changes and loss of cell adhesion which is thought to be critical for metastasis. This indicates that possible association of these genes with metastasis potential would be unlikely to involve TGFbeta-induced EMT.
Collapse
Affiliation(s)
- Sharon Sheahan
- Division of Pathology, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, EH16 4TJ, Edinburgh, UK
- Biotransfer Unit, BioSciences Institute, University College, Cork, Ireland
| | - Christopher O Bellamy
- Division of Pathology, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, EH16 4TJ, Edinburgh, UK
| | - Stephen N Harland
- MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Little France Crescent, Edinburgh, UK
| | - David J Harrison
- Division of Pathology, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, EH16 4TJ, Edinburgh, UK
- Division of Pathology, Edinburgh Cancer Research Centre, Crewe Road South, EH4 2XR, Edinburgh, UK
| | - Sandrine Prost
- Division of Pathology, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, EH16 4TJ, Edinburgh, UK
- Division of Pathology, Edinburgh Cancer Research Centre, Crewe Road South, EH4 2XR, Edinburgh, UK
| |
Collapse
|
|
35
|
Yan XB, Mei L, Feng X, Wan MR, Chen Z, Pavio N, Brechot C. Hepatitis C virus core proteins derived from different quasispecies of genotype 1b inhibit the growth of Chang liver cells. World J Gastroenterol 2008; 14:2877-81. [PMID: 18473414 PMCID: PMC2710731 DOI: 10.3748/wjg.14.2877] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [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
AIM: To investigate the influence of different quasispecies of hepatitis C virus (HCV) genotype 1b core protein on growth of Chang liver cells.
METHODS: Three eukaryotic expression plasmids (pEGFP-N1/core) that contained different quasispecies truncated core proteins of HCV genotype 1b were constructed. These were derived from tumor (T) and non-tumor (NT) tissues of a patient infected with HCV and C191 (HCV-J6). The core protein expression plasmids were transiently transfected into Chang liver cells. At different times, the cell cycle and apoptosis was assayed by flow cytometry, and cell proliferation was assayed by methyl thiazolyl tetrazolium (MTT) assay.
RESULTS: The proportion of S-phase Chang liver cells transfected with pEGFP-N1/core was significantly lower than that of cells transfected with blank plasmid at three different times after transfection (all P < 0.05). The proliferation ratio of cells transfected with pEGFP-N1/core was significantly lower than that of cells transfected with blank plasmid. Among three different quasispecies, T, NT and C191 core expression cells, there was no significant difference in the proportion of S- and G0/G1-phase cells. The percentage of apoptotic cells was highest for T (T > NT > C191), and apoptosis was increased in cells transfected with pEGFP-N1/core as the transfection time increased (72 h > 48 h > 24 h).
CONCLUSION: These results suggest that HCV genotype 1b core protein induces apoptosis, and inhibits cell-cycle progression and proliferation of Chang liver cells. Different quasispecies core proteins of HCV genotype 1b might have some differences in the pathogenesis of HCV persistent infection and hepatocellular carcinoma.
Collapse
|
|
36
|
Abstract
In recent years, the effects of hepatitis C virus (HCV) proteins on hepatocarcinogenesis have undergone intense investigations. The potentially oncogenic proteins include at least three HCV proteins: core (C) protein, NS3, and NS5A. Several authors indicated relationships between subcellular localization, concentration, a specific molecular form of the proteins (full length, truncated, phosphorylated), the presence of specific domains (the nuclear localization signal homologous to e.g. Bcl-2) and their effects on the mechanisms linked to oncogenesis. The involvement of all the proteins has been described as being in control of the cell cycle, through interactions with key proteins of the process (p53, p21, cyclins, proliferating cell nuclear antigen), transcription factors, proto-oncogenes, growth factors/cytokines and their receptors, and proteins linked to the apoptotic process. Untilnow, the involvement of the core protein of HCV in liver carcinogenesis is the most recognized. One of the most common proteins affected by HCV proteins is the p53 tumor-suppressor protein. The p21/WAF1 gene is a major target of p53, and the effect of HCV proteins on the gene is frequently considered in parallel. The results of studies on the effects of HCV proteins on the apoptotic process are controversial. This work summarizes the information collected thus far in the field of HCV molecular virology and principal intracellular signaling pathways in which HCV oncogenic proteins are involved.
Collapse
Affiliation(s)
- Aldona Kasprzak
- Department of Histology and Embryology, Medical University, Poznań, Poland
| | | |
Collapse
|
|
37
|
Sheahan S, Bellamy CO, Dunbar DR, Harrison DJ, Prost S. Deficiency of G1 regulators P53, P21Cip1 and/or pRb decreases hepatocyte sensitivity to TGFbeta cell cycle arrest. BMC Cancer 2007; 7:215. [PMID: 18021445 PMCID: PMC2206047 DOI: 10.1186/1471-2407-7-215] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2007] [Accepted: 11/19/2007] [Indexed: 12/31/2022] Open
Abstract
Background TGFβ is critical to control hepatocyte proliferation by inducing G1-growth arrest through multiple pathways leading to inhibition of E2F transcription activity. The retinoblastoma protein pRb is a key controller of E2F activity and G1/S transition which can be inhibited in viral hepatitis. It is not known whether the impairment of pRb would alter the growth inhibitory potential of TGFβ in disease. We asked how Rb-deficiency would affect responses to TGFβ-induced cell cycle arrest. Results Primary hepatocytes isolated from Rb-floxed mice were infected with an adenovirus expressing CRE-recombinase to delete the Rb gene. In control cells treatment with TGFβ prevented cells to enter S phase via decreased cMYC activity, activation of P16INK4A and P21Cip and reduction of E2F activity. In Rb-null hepatocytes, cMYC activity decreased slightly but P16INK4A was not activated and the great majority of cells continued cycling. Rb is therefore central to TGFβ-induced cell cycle arrest in hepatocytes. However some Rb-null hepatocytes remained sensitive to TGFβ-induced cell cycle arrest. As these hepatocytes expressed very high levels of P21Cip1 and P53 we investigated whether these proteins regulate pRb-independent signaling to cell cycle arrest by evaluating the consequences of disruption of p53 and p21Cip1. Hepatocytes deficient in p53 or p21Cip1 showed diminished growth inhibition by TGFβ. Double deficiency had a similar impact showing that in cells containing functional pRb; P21Cip and P53 work through the same pathway to regulate G1/S in response to TGFβ. In Rb-deficient cells however, p53 but not p21Cip deficiency had an additive effect highlighting a pRb-independent-P53-dependent effector pathway of inhibition of E2F activity. Conclusion The present results show that otherwise genetically normal hepatocytes with disabled p53, p21Cip1 or Rb genes respond less well to the antiproliferative effects of TGFβ. As the function of these critical cellular proteins can be impaired by common causes of chronic liver disease and HCC, including viral hepatitis B and C proteins, we suggest that disruption of pRb function, and to a lesser extend P21Cip1 and P53 in hepatocytes may represent an additional new mechanism of escape from TGFβ-growth-inhibition in the inflammatory milieu of chronic liver disease and contribute to cancer development.
Collapse
Affiliation(s)
- Sharon Sheahan
- Division of Pathology, Queen's Medical Research Institute, Edinburgh, UK.
| | | | | | | | | |
Collapse
|
|
38
|
Affiliation(s)
- Clara Balsano
- Dipartimento di Medicina Interna e Sanità Pubblica (MISP), University of L'Aquila, L'Aquila, Italy.
| | | |
Collapse
|
|
39
|
Abstract
Chronic infection with the hepatitis C virus (HCV) is a major risk factor for the development of hepatocellular carcinoma (HCC) worldwide. The pathogenesis of HCC in HCV infection has extensively been analysed. Hepatitis C virus-induced chronic inflammation and the effects of cytokines in the development of fibrosis and liver cell proliferation are considered as one of the major pathogenic mechanisms. Increasing experimental evidence suggests that HCV contributes to HCC by directly modulating pathways that promote the malignant transformation of hepatocytes. Hepatitis C virus is an RNA virus that does not integrate into the host genome but HCV proteins interact with many host-cell factors well beyond their roles in the viral life cycle and are involved in a wide range of activities, including cell signaling, transcription, cell proliferation, apoptosis, membrane rearrangements, vesicular trafficking and translational regulation. At least four of the HCV gene products, namely HCV core, NS3, NS4B and NS5A, have been shown to exhibit transformation potential in tissue culture and several potentially oncogenic pathways have been shown to be altered by the expression of HCV proteins. Both HCV core and NS5A induce the accumulation of wild-type beta-catenin and the Wnt-beta-catenin pathway emerges as a common target for HCV (and HBV) in human HCCs, also independently from axin/beta-catenin gene mutations. Induction of both endoplasmic reticulum stress and oxidative stress by HCV proteins might also contribute to HCV transformation. Most of the putative transforming functions of the HCV proteins have been defined in artificial cellular systems, which may not be applicable to HCV infection in vivo, and still need to be established in relevant infection and disease models.
Collapse
Affiliation(s)
- M Levrero
- Department of Internal Medicine, University of Rome La Sapienza, Rome, Italy.
| |
Collapse
|
|
40
|
Hassan M, Ghozlan H, Abdel-Kader O. Activation of RB/E2F signaling pathway is required for the modulation of hepatitis C virus core protein-induced cell growth in liver and non-liver cells. Cell Signal 2005; 16:1375-85. [PMID: 15381253 DOI: 10.1016/j.cellsig.2004.04.005] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2004] [Revised: 04/20/2004] [Accepted: 04/20/2004] [Indexed: 12/16/2022]
Abstract
Hepatitis C virus (HCV) core protein is a multifunctional protein that affects transcription and cell growth in vitro and in vivo. Here, we confirm the proliferative activities of core protein in liver and non-liver cells and delineate part of the mechanism whereby core protein promotes cell growth. We show that core protein suppresses the expression of tumor suppressor protein p53 and cyclin-dependent kinase (CDK) inhibitor p21 and enhances the activation of cyclin-dependent kinase 2 (CDK2), the phosphorylation of retinoblastoma (Rb), the activation of the transcription factor E2F-1, and the expression of E2F-1 and S phase kinase-interacting protein 2 (SKP2) genes. Pretreatment of core protein-expressing cells with the inhibitor of CDK2, Butyrolactone I, abolished the phosphorylation of Rb, the activation of E2F-1, and inhibited the expression of E2F-1 gene and cell growth induced. Consistent with these findings, we define a new signaling pathway whereby the HCV core protein mediates cell growth in infected cells.
Collapse
Affiliation(s)
- Mohamed Hassan
- Faculty of Medicine, Institute of Pathology, University of Düsseldorf, Mooren Str. 5, 40225 Düsseldorf, Germany.
| | | | | |
Collapse
|
|
41
|
Gómez-Gonzalo M, Benedicto I, Carretero M, Lara-Pezzi E, Maldonado-Rodríguez A, Moreno-Otero R, Lai MMC, López-Cabrera M. Hepatitis C virus core protein regulates p300/CBP co-activation function. Possible role in the regulation of NF-AT1 transcriptional activity. Virology 2004; 328:120-30. [PMID: 15380363 DOI: 10.1016/j.virol.2004.06.044] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2004] [Revised: 03/25/2004] [Accepted: 06/30/2004] [Indexed: 01/28/2023]
Abstract
Hepatitis C virus (HCV) core is a viral structural protein; it also participates in some cellular processes, including transcriptional regulation. However, the mechanisms of core-mediated transcriptional regulation remain poorly understood. Oncogenic virus proteins often target p300/CBP, a known co-activator of a wide variety of transcription factors, to regulate the expression of cellular and viral genes. Here we demonstrate, for the first time, that HCV core protein interacts with p300/CBP and enhances both its acetyl-transferase and transcriptional activities. In addition, we demonstrate that nuclear core protein activates the NH2-terminal transcription activation domain (TAD) of NF-AT1 in a p300/CBP-dependent manner. We propose a model in which core protein regulates the co-activation function of p300/CBP and activates NF-AT1, and probably other p300/CBP-regulated transcription factors, by a novel mechanism involving the regulation of the acetylation state of histones and/or components of the transcriptional machinery.
Collapse
Affiliation(s)
- Marta Gómez-Gonzalo
- Unidad de Biología Molecular, Hospital Universitario de la Princesa, 28006 Madrid, Spain
| | | | | | | | | | | | | | | |
Collapse
|
|
42
|
van Pelt JF, Severi T, Crabbé T, Eetveldt AV, Verslype C, Roskams T, Fevery J. Expression of hepatitis C virus core protein impairs DNA repair in human hepatoma cells. Cancer Lett 2004; 209:197-205. [PMID: 15159022 DOI: 10.1016/j.canlet.2003.11.035] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2003] [Revised: 11/26/2003] [Accepted: 11/28/2003] [Indexed: 02/07/2023]
Abstract
Several studies have documented the important association between hepatitis C virus (HCV) infection and hepatocellular carcinoma. The mechanisms involved are still unknown and could involve viral proteins. We investigated the effect of HCV-core protein on DNA repair after UV-induced DNA damage. Therefore, we developed and characterized stably transfected HepG2 cell lines that express HCV-core protein as demonstrated by immunohistochemistry. These cells were significantly less capable to repair the DNA damage than control cells. This suppression of DNA repair by HCV-core protein renders the cells more sensitive to acquire mutations that in combination with enhanced in vivo cell turnover in the infected liver might increase the likelihood of malignant transformation of HCV-infected cells by other viral factors or upon exposure to environmental factors (food, drugs, smoking, alcohol, etc.). Interestingly, expression of the full-length HCV core did increase the cell doubling time in one of the cell lines we had developed that could not be attributed to an increase in apoptosis or change in telomerase activity in these cells.
Collapse
Affiliation(s)
- Jos F van Pelt
- Department of Liver and Pancreatic Diseases, University Hospital Gasthuisberg, Herestraat 49, Leuven B 3000, Belgium.
| | | | | | | | | | | | | |
Collapse
|
|
43
|
Nguyen H, Mudryj M, Guadalupe M, Dandekar S. Hepatitis C virus core protein expression leads to biphasic regulation of the p21 cdk inhibitor and modulation of hepatocyte cell cycle. Virology 2003; 312:245-53. [PMID: 12890637 DOI: 10.1016/s0042-6822(03)00209-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Hepatitis C virus (HCV) Core protein is implicated in viral pathogenesis by the modulation of hepatocyte gene expression and function. To determine the effect of Core protein on the cell-cycle control of hepatocytes, a HepG2 cell line containing a Flag-tagged Core under the control of an inducible promoter was generated. Initial Core protein expression included the presence of unprocessed (191 aa) and processed (173 aa) forms of the Core proteins with the processed form becoming dominant later. Expression of the 191 aa form of Core protein corresponded to an increase in the expression of the p21, a decrease in cdk2-dependent kinase activity, and a decrease in the percentage of cells in S-phase along with an accumulation of cells in the G(0)/G(1) phase of the cell cycle. As the processed form accumulated, the p21 levels started to decline, suggesting that Core protein regulates p21 expression in a biphasic manner. These findings implicate Core protein in potentially modulating hepatocyte cell cycle differentially in the early stages of infection through biphasic regulation of p21 cdk kinase inhibitor.
Collapse
Affiliation(s)
- Hau Nguyen
- Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, CA 95616, USA
| | | | | | | |
Collapse
|
|
44
|
N/A. N/A. Shijie Huaren Xiaohua Zazhi 2003; 11:1011-1014. [DOI: 10.11569/wcjd.v11.i7.1011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
|
|
45
|
Giannini C, Bréchot C. Hepatitis C virus biology. Cell Death Differ 2003; 10 Suppl 1:S27-38. [PMID: 12655344 DOI: 10.1038/sj.cdd.4401121] [Citation(s) in RCA: 142] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2002] [Revised: 06/11/2002] [Accepted: 06/13/2002] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus infection represents a major problem of public health with around 350 millions of chronically infected individuals worldwide. The frequent evolution towards severe liver disease and cancer are the main features of HCV chronic infection. Antiviral therapies, mainly based on the combination of IFN and ribavirin can only assure a long term eradication of the virus in less than half of treated patients. The mechanisms underlying HCV pathogenesis and persistence in the host are still largely unknown and the efforts made by researchers in the understanding the viral biology have been hampered by the absence of a reliable in vitro and in vivo system reproducing HCV infection. The present review will mainly focus on viral pathogenetic mechanisms based on the interaction of HCV proteins (especially core, NS3 and NS5A) with host cellular signaling transduction pathways regulating cell growth and viability and on the strategies developed by the virus to persist in the host and escape to antiviral therapy. Past and recent data obtained in this field with different experimental approaches will be discussed.
Collapse
Affiliation(s)
- C Giannini
- Liver Cancer and Molecular Virology, Pasteur-INSERM Unit 370, 156, Rue de Vaugirard 75015 Paris, France
| | | |
Collapse
|
|
46
|
Lee MN, Jung EY, Kwun HJ, Jun HK, Yu DY, Choi YH, Jang KL. Hepatitis C virus core protein represses the p21 promoter through inhibition of a TGF-beta pathway. J Gen Virol 2002; 83:2145-2151. [PMID: 12185267 DOI: 10.1099/0022-1317-83-9-2145] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
The increased proliferation rate of hepatocytes is one of the major risk factors for the development of hepatocellular carcinoma. In this study, we investigated the mechanism by which hepatitis C virus (HCV) core protein represses transcription of the universal cyclin-dependent kinase inhibitor p21 gene in murine fibroblast NIH 3T3 cells. From the transient reporter assays of p21 promoter, we found that the TGF-beta-responsive element (TbetaRE) located between -83 and -74 of the p21 promoter is responsible for the effect. The TGF-beta-induced p21 promoter activity was specifically decreased by HCV core protein and in the presence of the inhibitory Smad7 the repression effect was almost completely abolished. Furthermore, HCV core protein stimulated the growth rate of NIH 3T3 cells and could overcome growth arrest by TGF-beta but not by butyrate, suggesting that HCV core protein stimulates cell cycle progression by repressing p21 transcription through a TGF-beta pathway.
Collapse
Affiliation(s)
- Mi Nam Lee
- Department of Microbiology, College of Natural Sciences, Pusan National University, Pusan 609-735, Korea1
| | - Eun Young Jung
- Department of Microbiology, College of Natural Sciences, Pusan National University, Pusan 609-735, Korea1
| | - Hyun Jin Kwun
- Department of Microbiology, College of Natural Sciences, Pusan National University, Pusan 609-735, Korea1
| | - Hong Ki Jun
- Department of Microbiology, College of Natural Sciences, Pusan National University, Pusan 609-735, Korea1
| | - Dae-Yeul Yu
- Korea Research Institute of Bioscience and Biotechnology, Taejon 305-333, Korea2
| | - Yung Hyun Choi
- Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Pusan 614-052, Korea3
| | - Kyung Lib Jang
- Department of Microbiology, College of Natural Sciences, Pusan National University, Pusan 609-735, Korea1
| |
Collapse
|
|
47
|
Abstract
Since the discovery of the hepatitis C virus (HCV) as the causative agent of non-A, non-B hepatitis, significant effort has been devoted to understanding this important pathogen. Despite the difficulty in culturing this virus efficiently, much is known about the organization of the viral genome and the functions of many of the viral proteins. Through the use of surrogate expression systems combined with cellular fractionation, pull-down experiments and yeast two-hybrid screens, numerous interactions between hepatitis C virus proteins and cellular components have been identified. The relevance of many of these interactions to hepatitis C biology remains to be demonstrated. This review discusses recent developments in this area of HCV research.
Collapse
Affiliation(s)
- Timothy L Tellinghuisen
- Center for the Study of Hepatitis C, The Rockefeller University, 1230 York Avenue, Box 64, New York, NY 10021, USA.
| | | |
Collapse
|
|
48
|
Pascale RM, Simile MM, De Miglio MR, Muroni MR, Calvisi DF, Asara G, Casabona D, Frau M, Seddaiu MA, Feo F. Cell cycle deregulation in liver lesions of rats with and without genetic predisposition to hepatocarcinogenesis. Hepatology 2002; 35:1341-50. [PMID: 12029619 DOI: 10.1053/jhep.2002.33682] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Preneoplastic and neoplastic hepatocytes undergo c-Myc up-regulation and overgrowth in rats genetically susceptible to hepatocarcinogenesis, but not in resistant rats. Because c-Myc regulates the pRb-E2F pathway, we evaluated cell cycle gene expression in neoplastic nodules and hepatocellular carcinomas (HCCs), induced by initiation/selection (IS) protocols 40 and 70 weeks after diethylnitrosamine treatment, in susceptible Fisher 344 (F344) rats, and resistant Wistar and Brown Norway (BN) rats. No interstrain differences in gene expression occurred in normal liver. Overexpression of c-myc, Cyclins D1, E, and A, and E2F1 genes, at messenger RNA (mRNA) and protein levels, rise in Cyclin D1-CDK4, Cyclin E-CDK2, and E2F1-DP1 complexes, and pRb hyperphosphorylation occurred in nodules and HCCs of F344 rats. Expression of Cdk4, Cdk2, p16(INK4A), and p27(KIP1) did not change. In nodules and/or HCCs of Wistar and BN rats, low or no increases in c-myc, Cyclins D1, E, and A, and E2F1 expression, and Cyclin-CDKs complex formation were associated with p16(INK4A) overexpression and pRb hypophosphorylation. In conclusion, these results suggest deregulation of G1 and S phases in liver lesions of susceptible rats and block of G1-S transition in lesions of resistant strains, which explains their low progression capacity.
Collapse
MESH Headings
- Animals
- Carcinoma, Hepatocellular/chemically induced
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Cell Cycle Proteins/metabolism
- Cyclin A/genetics
- Cyclin D1/genetics
- Cyclin E/genetics
- Cyclin-Dependent Kinase Inhibitor p16/genetics
- DNA-Binding Proteins
- Disease Models, Animal
- E2F Transcription Factors
- E2F1 Transcription Factor
- G1 Phase/genetics
- Gene Expression Regulation, Neoplastic
- Genetic Predisposition to Disease
- Liver/pathology
- Liver Neoplasms, Experimental/chemically induced
- Liver Neoplasms, Experimental/genetics
- Liver Neoplasms, Experimental/pathology
- Male
- Phosphorylation
- Proto-Oncogene Proteins c-myc/genetics
- Rats
- Rats, Inbred BN
- Rats, Inbred F344
- Rats, Wistar
- Retinoblastoma Protein/metabolism
- S Phase/genetics
- Transcription Factor DP1
- Transcription Factors/genetics
- Transcription Factors/metabolism
Collapse
Affiliation(s)
- Rosa M Pascale
- Department of Biomedical Sciences, Division of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy
| | | | | | | | | | | | | | | | | | | |
Collapse
|