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Ganesan IP, Kiyokawa H. A Perspective on Therapeutic Targeting Against Ubiquitin Ligases to Stabilize Tumor Suppressor Proteins. Cancers (Basel) 2025; 17:626. [PMID: 40002221 PMCID: PMC11853300 DOI: 10.3390/cancers17040626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 01/26/2025] [Accepted: 02/04/2025] [Indexed: 02/27/2025] Open
Abstract
The loss of functions of tumor suppressor (TS) genes plays a key role in not only tumor initiation but also tumor progression leading to poor prognosis. While therapeutic inhibition of oncogene-encoded kinases has shown clinical success, restoring TS functions remains challenging due to conceptual and technical limitations. E3 ubiquitin ligases that ubiquitinate TS proteins for accelerated degradation in cancers emerge as promising therapeutic targets. Unlike proteasomal inhibitors with a broad spectrum, inhibitors of an E3 ligase would offer superior selectivity and efficacy in enhancing expression of its substrate TS proteins as far as the TS proteins retain wild-type structures. Recent advances in developing E3 inhibitors, including MDM2 inhibitors, highlight their potential and ultimately guide the framework to establish E3 inhibition as effective strategies to treat specific types of cancers. This review explores E3 ligases that negatively regulate bona fide TS proteins, the developmental status of E3 inhibitors, and their promise and pitfalls as therapeutic agents for anti-cancer precision medicine.
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Affiliation(s)
| | - Hiroaki Kiyokawa
- Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
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2
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López-Ansio M, Ramos-García P, González-Moles MÁ. Predictive Value of the Loss of pRb Expression in the Malignant Transformation Risk of Oral Potentially Malignant Disorders: A Systematic Review and Meta-Analysis. Cancers (Basel) 2025; 17:329. [PMID: 39858110 PMCID: PMC11764026 DOI: 10.3390/cancers17020329] [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: 12/16/2024] [Revised: 01/10/2025] [Accepted: 01/17/2025] [Indexed: 01/27/2025] Open
Abstract
OBJECTIVE The aim of this systematic review and meta-analysis was to qualitatively and quantitatively evaluate the current evidence on the significance of the loss of early stages of oral carcinogenesis in lesions diagnosed according to clinical and/or histopathological criteria and their evolution to oral cancer. MATERIALS AND METHODS We searched MEDLINE (through PubMed), Embase, Scopus and Web of Science for primary-level studies published before November 2024, designed as prospective or retrospective longitudinal cohorts, and not restricted by language or publication date. The risk of bias was critically assessed using the QUIPS tool. Meta-analyses, heterogeneity exploration, sensitivity and small-study effect analyses were conducted. RESULTS The inclusion criteria were met by six primary-level studies, which recruited 330 patients with OPMDs with follow-up data. The loss of pRb expression, assessed through immunohistochemistry, was significantly associated with a higher malignant transformation risk of OPMDs (RR = 1.92, 95%CI = 1.25-2.94, p = 0.003). The leukoplakia subgroup retained this significant association (p = 0.006), being the OPMD where the loss of pRb expression showed the best predictive value for malignant transformation (RR = 2.00, 95%CI = 1.22-3.29). Regarding the immunohistochemical technique and scoring methods, better performance and results were achieved by applying a cutoff point > 10% pRb-positive cells with nuclear staining (RR = 2.10, 95%CI = 1.30-3.38, 95%CI = 0.002). CONCLUSSION The present systematic review and meta-analysis supports that the loss of expression of the tumor suppressor pRb, assessed through immunohistochemistry, is a predictor of the malignant transformation risk of oral leukoplakias. Future studies are needed in other OPMDs following the recommendations provided based on current evidence gaps.
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Affiliation(s)
| | - Pablo Ramos-García
- Biohealth Research Institute, IBS, School of Dentistry, University of Granada, 18071 Granada, Spain;
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3
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Weng W, Zhang B, Deng D. P16 INK4A drives RB1 degradation by UTP14A-catalyzed K810 ubiquitination. iScience 2024; 27:110882. [PMID: 39351198 PMCID: PMC11440251 DOI: 10.1016/j.isci.2024.110882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 07/31/2024] [Accepted: 09/02/2024] [Indexed: 10/04/2024] Open
Abstract
P16INK4A expression is inversely associated with RB1 expression in cancer cells, and P16INK4A inhibits CDK4-catalyzed RB1 phosphorylation. How P16INK4A and RB1 coordinately express and regulate the cell cycle remains to be studied. In the present study, we found that P16INK4A upregulated the E3 ligase UTP14A, which led to the ubiquitination of RB1 at K810 and RB1 degradation. P16INK4A loss consistently disrupted the UTP14A-mediated degradation of RB1 and caused RB1 accumulation. Functionally, P16INK4A loss inhibited RB1 ubiquitination in a cell cycle progression-independent fashion and inhibited proteome-scale ubiquitination in a cell cycle progression-dependent manner. Our findings indicate that there is a negative feedback loop between P16INK4A and RB1 expression and that disruption of this loop may partially rescue the biological outcomes of P16INK4A loss. We also revealed a hitherto unknown function for P16 INK4A in regulating proteome-scale ubiquitination by inhibiting cell proliferation, which may be useful for the development of anticancer drugs.
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Affiliation(s)
- Wenjie Weng
- Key Laboratory of Carcinogenesis and Translational Research (MOE/Beijing) Division of Etiology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Baozhen Zhang
- Key Laboratory of Carcinogenesis and Translational Research (MOE/Beijing) Division of Etiology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Dajun Deng
- Key Laboratory of Carcinogenesis and Translational Research (MOE/Beijing) Division of Etiology, Peking University Cancer Hospital and Institute, Beijing 100142, China
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4
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Contreras A, Sánchez SA, Rodríguez-Medina C, Botero JE. The role and impact of viruses on cancer development. Periodontol 2000 2024; 96:170-184. [PMID: 38641954 DOI: 10.1111/prd.12566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Revised: 02/13/2024] [Accepted: 03/16/2024] [Indexed: 04/21/2024]
Abstract
This review focuses on three major aspects of oncoviruses' role in cancer development. To begin, we discuss their geographic distribution, revealing that seven oncoviruses cause 20% of all human cancers worldwide. Second, we investigate the primary carcinogenic mechanisms, looking at how these oncogenic viruses can induce cellular transformation, angiogenesis, and local and systemic inflammation. Finally, we investigate the possibility of SARS-CoV-2 infection reactivating latent oncoviruses, which could increase the risk of further disease. The development of oncovirus vaccines holds great promise for reducing cancer burden. Many unanswered questions about the host and environmental cofactors that contribute to cancer development and prevention remain, which ongoing research is attempting to address.
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Affiliation(s)
| | - Sandra Amaya Sánchez
- Advanced Periodontology Program, Escuela de Odontología, Universidad del Valle, Cali, Colombia
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5
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Liu B, Liu L, Liu Y. Targeting cell death mechanisms: the potential of autophagy and ferroptosis in hepatocellular carcinoma therapy. Front Immunol 2024; 15:1450487. [PMID: 39315094 PMCID: PMC11416969 DOI: 10.3389/fimmu.2024.1450487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 08/21/2024] [Indexed: 09/25/2024] Open
Abstract
Ferroptosis is a type of cell death that plays a remarkable role in the growth and advancement of malignancies including hepatocellular carcinoma (HCC). Non-coding RNAs (ncRNAs) have a considerable impact on HCC by functioning as either oncogenes or suppressors. Recent research has demonstrated that non-coding RNAs (ncRNAs) have the ability to control ferroptosis in HCC cells, hence impacting the advancement of tumors and the resistance of these cells to drugs. Autophagy is a mechanism that is conserved throughout evolution and plays a role in maintaining balance in the body under normal settings. Nevertheless, the occurrence of dysregulation of autophagy is evident in the progression of various human disorders, specifically cancer. Autophagy plays dual roles in cancer, potentially influencing both cell survival and cell death. HCC is a prevalent kind of liver cancer, and genetic mutations and changes in molecular pathways might worsen its advancement. The role of autophagy in HCC is a subject of debate, as it has the capacity to both repress and promote tumor growth. Autophagy activation can impact apoptosis, control proliferation and glucose metabolism, and facilitate tumor spread through EMT. Inhibiting autophagy can hinder the growth and spread of HCC and enhance the ability of tumor cells to respond to treatment. Autophagy in HCC is regulated by several signaling pathways, such as STAT3, Wnt, miRNAs, lncRNAs, and circRNAs. Utilizing anticancer drugs to target autophagy may have advantageous implications for the efficacy of cancer treatment.
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Affiliation(s)
- Beibei Liu
- Department of Radiology and Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ling Liu
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yang Liu
- Day Surgery Center, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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6
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Rasouli S, Dakic A, Wang QE, Mitchell D, Blakaj DM, Putluri N, Li J, Liu X. Noncanonical functions of telomerase and telomeres in viruses-associated cancer. J Med Virol 2024; 96:e29665. [PMID: 38738582 DOI: 10.1002/jmv.29665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 04/26/2024] [Accepted: 04/30/2024] [Indexed: 05/14/2024]
Abstract
The cause of cancer is attributed to the uncontrolled growth and proliferation of cells resulting from genetic changes and alterations in cell behavior, a phenomenon known as epigenetics. Telomeres, protective caps on the ends of chromosomes, regulate both cellular aging and cancer formation. In most cancers, telomerase is upregulated, with the telomerase reverse transcriptase (TERT) enzyme and telomerase RNA component (TERC) RNA element contributing to the maintenance of telomere length. Additionally, it is noteworthy that two viruses, human papillomavirus (HPV) and Epstein-Barr virus (EBV), utilize telomerase for their replication or persistence in infected cells. Also, TERT and TERC may play major roles in cancer not related to telomere biology. They are involved in the regulation of gene expression, signal transduction pathways, cellular metabolism, or even immune response modulation. Furthermore, the crosstalk between TERT, TERC, RNA-binding proteins, and microRNAs contributes to a greater extent to cancer biology. To understand the multifaceted roles played by TERT and TERC in cancer and viral life cycles, and then to develop effective therapeutic strategies against these diseases, are fundamental for this goal. By investigating deeply, the complicated mechanisms and relationships between TERT and TERC, scientists will open the doors to new therapies. In its analysis, the review emphasizes the significance of gaining insight into the multifaceted roles that TERT and TERC play in cancer pathogenesis, as well as their involvement in the viral life cycle for designing effective anticancer therapy approaches.
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Affiliation(s)
- Sara Rasouli
- Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA
| | - Aleksandra Dakic
- Division of Neuroscience, National Institute of Aging, Bethesda, Maryland, USA
| | - Qi-En Wang
- Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA
- Department of Radiation Oncology, Wexner Medical Center, Ohio State University, Columbus, Ohio, USA
| | - Darrion Mitchell
- Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA
- Department of Radiation Oncology, Wexner Medical Center, Ohio State University, Columbus, Ohio, USA
| | - Dukagjin M Blakaj
- Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA
- Department of Radiation Oncology, Wexner Medical Center, Ohio State University, Columbus, Ohio, USA
| | - Nagireddy Putluri
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Jenny Li
- Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA
| | - Xuefeng Liu
- Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA
- Department of Radiation Oncology, Wexner Medical Center, Ohio State University, Columbus, Ohio, USA
- Department of Pathology, Wexner Medical Center, Ohio State University, Columbus, Ohio, USA
- Department of Urology, Wexner Medical Center, Ohio State University, Columbus, Ohio, USA
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Milosevic I, Todorovic N, Filipovic A, Simic J, Markovic M, Stevanovic O, Malinic J, Katanic N, Mitrovic N, Nikolic N. HCV and HCC Tango-Deciphering the Intricate Dance of Disease: A Review Article. Int J Mol Sci 2023; 24:16048. [PMID: 38003240 PMCID: PMC10671156 DOI: 10.3390/ijms242216048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 10/12/2023] [Accepted: 10/25/2023] [Indexed: 11/26/2023] Open
Abstract
Hepatitis C virus (HCV) is a major cause of hepatocellular carcinoma (HCC) accounting for around one-third of all HCC cases. Prolonged inflammation in chronic hepatitis C (CHC), maintained through a variety of pro- and anti-inflammatory mediators, is one of the aspects of carcinogenesis, followed by mitochondrial dysfunction and oxidative stress. Immune response dysfunction including the innate and adaptive immunity also plays a role in the development, as well as in the recurrence of HCC after treatment. Some of the tumor suppressor genes inhibited by the HCV proteins are p53, p73, and retinoblastoma 1. Mutations in the telomerase reverse transcriptase promoter and the oncogene catenin beta 1 are two more important carcinogenic signaling pathways in HCC associated with HCV. Furthermore, in HCV-related HCC, numerous tumor suppressor and seven oncogenic genes are dysregulated by epigenetic changes. Epigenetic regulation of gene expression is considered as a lasting "epigenetic memory", suggesting that HCV-induced changes persist and are associated with liver carcinogenesis even after cure. Epigenetic changes and immune response dysfunction are recognized targets for potential therapy of HCC.
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Affiliation(s)
- Ivana Milosevic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Nevena Todorovic
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Ana Filipovic
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Jelena Simic
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Marko Markovic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Olja Stevanovic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Jovan Malinic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Natasa Katanic
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
- Faculty of Medicine, University of Pristina Situated in Kosovska Mitrovica, 28000 Kosovska Mitrovica, Serbia
| | - Nikola Mitrovic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Natasa Nikolic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
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8
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Chaudhary P, Proulx J, Park IW. Ubiquitin-protein ligase E3A (UBE3A) mediation of viral infection and human diseases. Virus Res 2023; 335:199191. [PMID: 37541588 PMCID: PMC10430597 DOI: 10.1016/j.virusres.2023.199191] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/01/2023] [Accepted: 08/02/2023] [Indexed: 08/06/2023]
Abstract
The Ubiquitin-protein ligase E3A, UBE3A, also known as E6-associated protein (E6-AP), is known to play an essential role in regulating the degradation of various proteins by transferring Ub from E2 Ub conjugating enzymes to the substrate proteins. Several studies indicate that UBE3A regulates the stabilities of key viral proteins in the virus-infected cells and, thereby, the infected virus-mediated diseases, even if it were reported that UBE3A participates in non-viral-related human diseases. Furthermore, mutations such as deletions and duplications in the maternally inherited gene in the brain cause human neurodevelopmental disorders such as Angelman syndrome (AS) and autism. It is also known that UBE3A functions as a transcriptional coactivator for the expression of steroid hormone receptors. These reports establish that UBE3A is distinguished by its multitudinous functions that are paramount to viral pathology and human diseases. This review is focused on molecular mechanisms for such intensive participation of UBE3A in disease formation and virus regulation.
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Affiliation(s)
- Pankaj Chaudhary
- Department of Microbiology, Immunology and Genetics, School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, United States.
| | - Jessica Proulx
- Department of Microbiology, Immunology and Genetics, School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, United States
| | - In-Woo Park
- Department of Microbiology, Immunology and Genetics, School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, United States.
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López-Ansio M, Ramos-García P, González-Moles MÁ. Prognostic and Clinicopathological Significance of the Loss of Expression of Retinoblastoma Protein (pRb) in Oral Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis. Cancers (Basel) 2023; 15:3132. [PMID: 37370742 DOI: 10.3390/cancers15123132] [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: 05/10/2023] [Revised: 06/02/2023] [Accepted: 06/08/2023] [Indexed: 06/29/2023] Open
Abstract
This systematic review and meta-analysis aims to evaluate the scientific evidence on the implications of retinoblastoma protein (pRb) alterations in oral cancer, in order to determine its prognostic and clinicopathological significance. PubMed, Embase, Web of Science, and Scopus were searched for studies published before February 2022, with no restrictions by publication date or language. The quality of the studies using the Quality in Prognosis Studies tool (QUIPS tool). Meta-analysis was conducted to achieve the proposed objectives, as well as heterogeneity, subgroup, meta-regression, and small study-effects analyses. Twenty studies that met the inclusion criteria (2451 patients) were systematically reviewed and meta-analyzed. Our results were significant for the association between the loss of pRb expression and a better overall survival (HR = 0.79, 95%CI = 0.64-0.98, p = 0.03), whereas no significant results were found for disease-free survival or clinico-pathological parameters (T/N status, clinical stage, histological grade). In conclusion, our evidence-based results demonstrate that loss of pRb function is a factor associated with improved survival in patients with OSCC. Research lines that should be developed in the future are highlighted.
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Affiliation(s)
- María López-Ansio
- School of Dentistry, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
| | - Pablo Ramos-García
- School of Dentistry, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
| | - Miguel Ángel González-Moles
- School of Dentistry, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
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10
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Kouroumalis E, Tsomidis I, Voumvouraki A. Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy. Biomedicines 2023; 11:1166. [PMID: 37189787 PMCID: PMC10135776 DOI: 10.3390/biomedicines11041166] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 04/09/2023] [Accepted: 04/12/2023] [Indexed: 05/17/2023] Open
Abstract
The pathogenesis of hepatocellular carcinoma (HCC) is a multifactorial process that has not yet been fully investigated. Autophagy and apoptosis are two important cellular pathways that are critical for cell survival or death. The balance between apoptosis and autophagy regulates liver cell turnover and maintains intracellular homeostasis. However, the balance is often dysregulated in many cancers, including HCC. Autophagy and apoptosis pathways may be either independent or parallel or one may influence the other. Autophagy may either inhibit or promote apoptosis, thus regulating the fate of the liver cancer cells. In this review, a concise overview of the pathogenesis of HCC is presented, with emphasis on new developments, including the role of endoplasmic reticulum stress, the implication of microRNAs and the role of gut microbiota. The characteristics of HCC associated with a specific liver disease are also described and a brief description of autophagy and apoptosis is provided. The role of autophagy and apoptosis in the initiation, progress and metastatic potential is reviewed and the experimental evidence indicating an interplay between the two is extensively analyzed. The role of ferroptosis, a recently described specific pathway of regulated cell death, is presented. Finally, the potential therapeutic implications of autophagy and apoptosis in drug resistance are examined.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, PAGNI University Hospital, University of Crete School of Medicine, 71500 Heraklion, Crete, Greece
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
| | - Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Central Macedonia, Greece
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Central Macedonia, Greece
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Kitab B, Tsukiyama-Kohara K. Regulatory Role of Ribonucleotide Reductase Subunit M2 in Hepatocyte Growth and Pathogenesis of Hepatitis C Virus. Int J Mol Sci 2023; 24:ijms24032619. [PMID: 36768940 PMCID: PMC9916403 DOI: 10.3390/ijms24032619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/27/2023] [Accepted: 01/27/2023] [Indexed: 01/31/2023] Open
Abstract
Hepatitis C virus (HCV) frequently causes chronic infection in the human liver, which may progress to advanced hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. HCV primarily infects highly differentiated quiescent hepatocytes and can modulate cell cycle-regulatory genes and proliferation pathways, which ultimately contribute to persistent infection and pathogenesis. On the other hand, several studies have shown differential regulation of HCV RNA and viral protein expression levels, depending on the proliferation state of hepatocytes and the phase of the cell cycle. HCV typically requires factors provided by host cells for efficient and persistent viral replication. Previously, we found that HCV infection upregulates the expression of ribonucleotide reductase subunit M2 (RRM2) in quiescent hepatocytes. RRM2 is a rate-limiting protein that catalyzes de novo synthesis of deoxyribonucleotide triphosphates, and its expression is highly regulated during various phases of the cell cycle. RRM2 functions as a pro-viral factor essential for HCV RNA synthesis, but its functional role in HCV-induced liver diseases remains unknown. Here, we present a comprehensive review of the role of the hepatocyte cell cycle, in correlation with RRM2 expression, in the regulation of HCV replication. We also discuss the potential relevance of this protein in the pathogenesis of HCV, particularly in the development of hepatocellular carcinoma.
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Heredia-Torres TG, Rincón-Sánchez AR, Lozano-Sepúlveda SA, Galan-Huerta K, Arellanos-Soto D, García-Hernández M, Garza-Juarez ADJ, Rivas-Estilla AM. Unraveling the Molecular Mechanisms Involved in HCV-Induced Carcinogenesis. Viruses 2022; 14:2762. [PMID: 36560766 PMCID: PMC9786602 DOI: 10.3390/v14122762] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/01/2022] [Accepted: 12/06/2022] [Indexed: 12/14/2022] Open
Abstract
Cancer induced by a viral infection is among the leading causes of cancer. Hepatitis C Virus (HCV) is a hepatotropic oncogenic positive-sense RNA virus that leads to chronic infection, exposing the liver to a continuous process of damage and regeneration and promoting hepatocarcinogenesis. The virus promotes the development of carcinogenesis through indirect and direct molecular mechanisms such as chronic inflammation, oxidative stress, steatosis, genetic alterations, epithelial-mesenchymal transition, proliferation, and apoptosis, among others. Recently, direct-acting antivirals (DAAs) showed sustained virologic response in 95% of cases. Nevertheless, patients treated with DAAs have reported an unexpected increase in the early incidence of Hepatocellular carcinoma (HCC). Studies suggest that HCV induces epigenetic regulation through non-coding RNAs, DNA methylation, and chromatin remodeling, which modify gene expressions and induce genomic instability related to HCC development that persists with the infection's clearance. The need for a better understanding of the molecular mechanisms associated with the development of carcinogenesis is evident. The aim of this review was to unravel the molecular pathways involved in the development of carcinogenesis before, during, and after the viral infection's resolution, and how these pathways were regulated by the virus, to find control points that can be used as potential therapeutic targets.
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Affiliation(s)
- Tania Guadalupe Heredia-Torres
- Department of Biochemistry and Molecular Medicine, CIIViM, School of Medicine, Universidad Autónoma de Nuevo León (UANL), Monterrey 64460, Mexico
| | - Ana Rosa Rincón-Sánchez
- IBMMTG, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44100, Mexico
| | - Sonia Amelia Lozano-Sepúlveda
- Department of Biochemistry and Molecular Medicine, CIIViM, School of Medicine, Universidad Autónoma de Nuevo León (UANL), Monterrey 64460, Mexico
| | - Kame Galan-Huerta
- Department of Biochemistry and Molecular Medicine, CIIViM, School of Medicine, Universidad Autónoma de Nuevo León (UANL), Monterrey 64460, Mexico
| | - Daniel Arellanos-Soto
- Department of Biochemistry and Molecular Medicine, CIIViM, School of Medicine, Universidad Autónoma de Nuevo León (UANL), Monterrey 64460, Mexico
| | - Marisela García-Hernández
- Department of Biochemistry and Molecular Medicine, CIIViM, School of Medicine, Universidad Autónoma de Nuevo León (UANL), Monterrey 64460, Mexico
| | - Aurora de Jesús Garza-Juarez
- Department of Biochemistry and Molecular Medicine, CIIViM, School of Medicine, Universidad Autónoma de Nuevo León (UANL), Monterrey 64460, Mexico
| | - Ana María Rivas-Estilla
- Department of Biochemistry and Molecular Medicine, CIIViM, School of Medicine, Universidad Autónoma de Nuevo León (UANL), Monterrey 64460, Mexico
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13
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González-Moles MÁ, Warnakulasuriya S, López-Ansio M, Ramos-García P. Hallmarks of Cancer Applied to Oral and Oropharyngeal Carcinogenesis: A Scoping Review of the Evidence Gaps Found in Published Systematic Reviews. Cancers (Basel) 2022; 14:3834. [PMID: 35954497 PMCID: PMC9367256 DOI: 10.3390/cancers14153834] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 08/04/2022] [Accepted: 08/04/2022] [Indexed: 02/07/2023] Open
Abstract
In 2000 and 2011, Hanahan and Weinberg published two papers in which they defined the characteristics that cells must fulfil in order to be considered neoplastic cells in all types of tumours that affect humans, which the authors called "hallmarks of cancer". These papers have represented a milestone in our understanding of the biology of many types of cancers and have made it possible to reach high levels of scientific evidence in relation to the prognostic impact that these hallmarks have on different tumour types. However, to date, there is no study that globally analyses evidence-based knowledge on the importance of these hallmarks in oral and oropharyngeal squamous cell carcinomas. For this reason, we set out to conduct this scoping review of systematic reviews with the aim of detecting evidence gaps in relation to the relevance of the cancer hallmarks proposed by Hanahan and Weinberg in oral and oropharyngeal cancer, and oral potentially malignant disorders, and to point out future lines of research in this field.
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Affiliation(s)
- Miguel Ángel González-Moles
- School of Dentistry, University of Granada, 18011 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
| | - Saman Warnakulasuriya
- Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London SE1 9RT, UK
- WHO Collaborating for Oral Cancer, King’s College London, London SE1 9RT, UK
| | - María López-Ansio
- School of Dentistry, University of Granada, 18011 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
| | - Pablo Ramos-García
- School of Dentistry, University of Granada, 18011 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
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14
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Song J, Lin Z, Liu Q, Huang S, Han L, Fang Y, Zhong P, Dou R, Xiang Z, Zheng J, Zhang X, Wang S, Xiong B. MiR-192-5p/RB1/NF-κBp65 signaling axis promotes IL-10 secretion during gastric cancer EMT to induce Treg cell differentiation in the tumour microenvironment. Clin Transl Med 2022; 12:e992. [PMID: 35969010 PMCID: PMC9377151 DOI: 10.1002/ctm2.992] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 07/04/2022] [Accepted: 07/08/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Regulatory T (Treg) cells are important components of the tumour microenvironment (TME) that play roles in gastric cancer (GC) metastasis. Although tumour cells that undergo epithelial-mesenchymal transition (EMT) regulate Treg cell function, their regulatory mechanism in GC remains unclear. METHODS The miR-192-5p was identified by examining three Gene Expression Omnibus GC miRNA expression datasets. RNA immunoprecipitation (RIP) and dual-luciferase reporter assays were conducted to identify interactions between miR-192-5p and RB1. The role of miR-192-5p/RB1 in GC progression was evaluated based on EdU incorporation, wound healing and Transwell assays. An in vitro co-culture assay was performed to measure the effect of miR-192-5p/RB1 on Treg cell differentiation. In vivo experiments were conducted to explore the role of miR-192-5p in GC progression and Treg cell differentiation. RESULTS MiR-192-5p was overexpressed in tumour and was associated with poor prognosis in GC. MiR-192-5p bound to the RB1 3'-untranslated region, resulting in GC EMT, proliferation, migration and invasion. MiR-192-5p/RB1 mediated interleukin-10 (IL-10) secretion by regulating nuclear factor-kappaBp65 (NF-κBp65), affecting Treg cell differentiation. NF-κBp65, in turn, promoted miR-192-5p expression and formed a positive feedback loop. Furthermore, in vivo experiments confirmed that miR-192-5p/RB1 promotes GC growth and Treg cell differentiation. CONCLUSION Collectively, our studies indicate that miR-192-5p/RB1 promotes EMT of tumour cells, and the miR-192-5p/RB1/NF-κBp65 signaling axis induces Treg cell differentiation by regulating IL-10 secretion in GC. Our results suggest that targeting miR-192-5p/RB1/NF-κBp65 /IL-10 may pave the way for the development of new immune treatments for GC.
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Affiliation(s)
- Jialin Song
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Zaihuan Lin
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Qing Liu
- Department of Respiratory and Critical Care MedicineZhongnan Hospital of Wuhan UniversityWuhanChina
- Wuhan Research Center for Infectious Diseases and CancerChinese Academy of Medical SciencesWuhanChina
| | - Sihao Huang
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Lei Han
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Yan Fang
- Department of obstetrics and gynecologyGuangzhou Women and Children's Medical CenterGuangzhouChina
| | - Panyi Zhong
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Rongzhang Dou
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Zhenxian Xiang
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Jinsen Zheng
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Xinyao Zhang
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Shuyi Wang
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Bin Xiong
- Department of Gastrointestinal SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumour Biological BehavioursWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
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15
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Zhou Z, Zhang J, Zhou E, Ren C, Wang J, Wang Y. Small molecule NS5B RdRp non-nucleoside inhibitors for the treatment of HCV infection: A medicinal chemistry perspective. Eur J Med Chem 2022; 240:114595. [PMID: 35868125 DOI: 10.1016/j.ejmech.2022.114595] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 07/01/2022] [Accepted: 07/05/2022] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) infection has become a global health problem with enormous risks. Nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase (RdRp) is a component of HCV, which can promote the formation of the viral RNA replication complex and is also an essential part of the replication complex itself. It plays a vital role in the synthesis of the positive and negative strands of HCV RNA. Therefore, the development of small-molecule inhibitors targeting NS5B RdRp is of great value for treating HCV infection-related diseases. Compared with NS5B RdRp nucleoside inhibitors, non-nucleoside inhibitors have more flexible structures, simpler mechanisms of action, and more predictable efficacy and safety of drugs in humans. Technological advances over the past decade have led to remarkable achievements in developing NS5B RdRp inhibitors. This review will summarize the non-nucleoside inhibitors targeting NS5B RdRp developed in the past decade and describe their structure optimization process and structure-activity relationship.
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Affiliation(s)
- Zhilan Zhou
- Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Jifa Zhang
- Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Tianfu Jincheng Laboratory, Chengdu, 610041, Sichuan, China
| | - Enda Zhou
- Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Changyu Ren
- Department of Pharmacy, Chengdu Fifth People's Hospital, Chengdu, Sichuan, 611130, China
| | - Jiaxing Wang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, 38163, Tennessee, United States
| | - Yuxi Wang
- Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Tianfu Jincheng Laboratory, Chengdu, 610041, Sichuan, China.
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16
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Pan F, Lin X, Hao L, Wang T, Song H, Wang R. The Critical Role of Ferroptosis in Hepatocellular Carcinoma. Front Cell Dev Biol 2022; 10:882571. [PMID: 35800895 PMCID: PMC9255949 DOI: 10.3389/fcell.2022.882571] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 06/03/2022] [Indexed: 12/14/2022] Open
Abstract
Liver cancer is the sixth most frequently diagnosed cancer and the third dominant cause of cancer death worldwide. Ferroptosis is characterized as an iron-dependent form of regulated cell death, with accumulation of lipid peroxides to lethal amounts. Evidences have showed that ferroptosis is closely associated with HCC, but the mechanisms are still poorly understood. In this review, we mainly summarize the roles of several typical molecules as well as radiotherapy in regulating the ferroptosis process in HCC. Chances are that this review may help address specific issues in the treatment of HCC.
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17
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Zhou L, Ng DSC, Yam JC, Chen LJ, Tham CC, Pang CP, Chu WK. Post-translational modifications on the retinoblastoma protein. J Biomed Sci 2022; 29:33. [PMID: 35650644 PMCID: PMC9161509 DOI: 10.1186/s12929-022-00818-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 05/26/2022] [Indexed: 11/21/2022] Open
Abstract
The retinoblastoma protein (pRb) functions as a cell cycle regulator controlling G1 to S phase transition and plays critical roles in tumour suppression. It is frequently inactivated in various tumours. The functions of pRb are tightly regulated, where post-translational modifications (PTMs) play crucial roles, including phosphorylation, ubiquitination, SUMOylation, acetylation and methylation. Most PTMs on pRb are reversible and can be detected in non-cancerous cells, playing an important role in cell cycle regulation, cell survival and differentiation. Conversely, altered PTMs on pRb can give rise to anomalies in cell proliferation and tumourigenesis. In this review, we first summarize recent findings pertinent to how individual PTMs impinge on pRb functions. As many of these PTMs on pRb were published as individual articles, we also provide insights on the coordination, either collaborations and/or competitions, of the same or different types of PTMs on pRb. Having a better understanding of how pRb is post-translationally modulated should pave the way for developing novel and specific therapeutic strategies to treat various human diseases.
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Affiliation(s)
- Linbin Zhou
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Danny Siu-Chun Ng
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Jason C Yam
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China
- Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong, China
| | - Li Jia Chen
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China
- Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong, China
| | - Clement C Tham
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China
- Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong, China
| | - Chi Pui Pang
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China
- Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong, China
| | - Wai Kit Chu
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China.
- Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong, China.
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong Eye Hospital, 147K Argyle Street, Kowloon, Hong Kong, China.
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18
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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.
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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.
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19
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Sheng J, Kohno S, Okada N, Okahashi N, Teranishi K, Matsuda F, Shimizu H, Linn P, Nagatani N, Yamamura M, Harada K, Horike SI, Inoue H, Yano S, Kumar S, Kitajima S, Ajioka I, Takahashi C. Treatment of Retinoblastoma 1-Intact Hepatocellular Carcinoma With Cyclin-Dependent Kinase 4/6 Inhibitor Combination Therapy. Hepatology 2021; 74:1971-1993. [PMID: 33931882 DOI: 10.1002/hep.31872] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 04/02/2021] [Accepted: 04/19/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Synthetic cyclin-dependent kinase (CDK) 4/6 inhibitors exert antitumor effects by forcing RB1 in unphosphorylated status, causing not only cell cycle arrest but also cellular senescence, apoptosis, and increased immunogenicity. These agents currently have an indication in advanced breast cancers and are in clinical trials for many other solid tumors. HCC is one of promising targets of CDK4/6 inhibitors. RB family dysfunction is often associated with the initiation of HCC; however, this is revivable, as RB family members are not frequently mutated or deleted in this malignancy. APPROACH AND RESULTS Loss of all Rb family members in transformation related protein 53 (Trp53)-/- mouse liver resulted in liver tumor reminiscent of human HCC, and re-expression of RB1 sensitized these tumors to a CDK4/6 inhibitor, palbociclib. Introduction of an unphosphorylatable form of RB1 (RB7LP) into multiple liver tumor cell lines induced effects similar to palbociclib. By screening for compounds that enhance the efficacy of RB7LP, we identified an I kappa B kinase (IKK)β inhibitor Bay 11-7082. Consistently, RB7LP expression and treatment with palbociclib enhanced IKKα/β phosphorylation and NF-κB activation. Combination therapy using palbociclib with Bay 11-7082 was significantly more effective in hepatoblastoma and HCC treatment than single administration. Moreover, blockade of IKK-NF-κB or AKT pathway enhanced effects of palbociclib on RB1-intact KRAS Kirsten rat sarcoma viral oncogene homolog mutated lung and colon cancers. CONCLUSIONS In conclusion, CDK4/6 inhibitors have a potential to treat a wide variety of RB1-intact cancers including HCC when combined with an appropriate kinase inhibitor.
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Affiliation(s)
- Jindan Sheng
- Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Susumu Kohno
- Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Nobuhiro Okada
- Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, Japan
| | - Nobuyuki Okahashi
- Graduate School of Information Science and Technology, Osaka University, Suita, Japan
| | - Kana Teranishi
- Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Fumio Matsuda
- Graduate School of Information Science and Technology, Osaka University, Suita, Japan
| | - Hiroshi Shimizu
- Graduate School of Information Science and Technology, Osaka University, Suita, Japan
| | - Paing Linn
- Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Naoko Nagatani
- Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Minako Yamamura
- Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Kenichi Harada
- Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Shin-Ichi Horike
- Advanced Science Research Center, Kanazawa University, Kanazawa, Japan
| | - Hiroshi Inoue
- Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, Japan
| | - Seiji Yano
- Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Sharad Kumar
- Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia
| | - Shunsuke Kitajima
- Cancer Research Institute, Kanazawa University, Kanazawa, Japan.,Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.,Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | - Itsuki Ajioka
- Center for Brain Integration Research, Tokyo Medical Dental University, Tokyo, Japan.,Kanagawa Institute of Industrial Science and Technology, Kanagawa, Japan
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20
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Mahoney KE, Shabanowitz J, Hunt DF. MHC Phosphopeptides: Promising Targets for Immunotherapy of Cancer and Other Chronic Diseases. Mol Cell Proteomics 2021; 20:100112. [PMID: 34129940 PMCID: PMC8724925 DOI: 10.1016/j.mcpro.2021.100112] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 05/11/2021] [Accepted: 06/02/2021] [Indexed: 12/27/2022] Open
Abstract
Major histocompatibility complex-associated peptides have been considered as potential immunotherapeutic targets for many years. MHC class I phosphopeptides result from dysregulated cell signaling pathways that are common across cancers and both viral and bacterial infections. These antigens are recognized by central memory T cells from healthy donors, indicating that they are considered antigenic by the immune system and that they are presented across different individuals and diseases. Based on these responses and the similar dysregulation, phosphorylated antigens are promising candidates for prevention or treatment of different cancers as well as a number of other chronic diseases.
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Affiliation(s)
- Keira E Mahoney
- Department of Chemistry, University of Virginia, Charlottesville, Virginia, USA
| | - Jeffrey Shabanowitz
- Department of Chemistry, University of Virginia, Charlottesville, Virginia, USA.
| | - Donald F Hunt
- Department of Chemistry, University of Virginia, Charlottesville, Virginia, USA; Department of Pathology, University of Virginia, Charlottesville, Virginia, USA.
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21
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Wen X, Ge X, Zhou L, Zhang Y, Guo X, Yang H. PRRSV Promotes MARC-145 Cells Entry Into S Phase of the Cell Cycle to Facilitate Viral Replication via Degradation of p21 by nsp11. Front Vet Sci 2021; 8:642095. [PMID: 33869322 PMCID: PMC8044838 DOI: 10.3389/fvets.2021.642095] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 03/03/2021] [Indexed: 12/21/2022] Open
Abstract
Porcine reproductive and respiratory syndrome virus (PRRSV) remains one of the most economically significant pathogens that seriously affect the global swine industry. Despite sustained efforts, the factors that affect PRRSV replication in host cells are far from being fully elucidated and thus warrants further investigation. In this study, we first demonstrated that PRRSV infection can cause downregulation of endogenous p21 protein in MARC-145 cells in a virus dose-dependent manner. Next, we analyzed the effect of p21 knockdown by RNA interference on cell cycle progression using flow cytometric analysis, and found that knockdown of p21 promotes MARC-145 cells entry into S phase of the cell cycle. Interestingly, we further discovered PRRSV infection is also able to promote MARC-145 cells entry into the S phase. Subsequently, we synchronized MARC-145 cells into G0/G1, S and G2/M phases, respectively, and then determined PRRSV replication in these cells. Results here show that the MARC-145 cells synchronized into the S phase exhibited the highest viral titer among the cells synchronized to different phases. Additionally, to reliably analyze the potential role of endogenous p21 protein in PRRSV replication, we constructed a p21 gene-knockout MARC-145 cell line (p21-/-) using CRISPR/Cas9 technology and evaluated its capability to support PRRSV replication. Our results indicate that knockout of p21 is conducive to PRRSV replication in MARC-145 cells. Furthermore, through construction of a series of eukaryotic plasmids expressing each of individual PRRSV proteins combined with cell transfection, we demonstrated that the nonstructural protein 11 (nsp11) of PRRSV mediates p21 degradation, which was further confirmed by generating a stable MARC-145 cell line constitutively expressing nsp11 using a lentivirus system. Notably, we further demonstrated that the endoribonuclease activity rather than the deubiquitinating activity of nsp11 is essential for p21 degradation via mutagenic analysis. Finally, we demonstrated that nsp11 mediates p21 degradation via a ubiquitin-independent proteasomal degradation manner. Altogether, our study not only uncovers a new pathogenesis of PRRSV, but also provides new insights into development of novel antiviral strategies.
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Affiliation(s)
- Xuexia Wen
- Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China.,Key Laboratory of Livestock Infectious Diseases in Northeast China, Ministry of Education, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, China
| | - Xinna Ge
- Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Lei Zhou
- Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Yongning Zhang
- Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Xin Guo
- Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Hanchun Yang
- Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
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22
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Akt Interacts with Usutu Virus Polymerase, and Its Activity Modulates Viral Replication. Pathogens 2021; 10:pathogens10020244. [PMID: 33672588 PMCID: PMC7924047 DOI: 10.3390/pathogens10020244] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/09/2021] [Accepted: 02/18/2021] [Indexed: 12/17/2022] Open
Abstract
Usutu virus (USUV) is a flavivirus that mainly infects wild birds through the bite of Culex mosquitoes. Recent outbreaks have been associated with an increased number of cases in humans. Despite being a growing source of public health concerns, there is yet insufficient data on the virus or host cell targets for infection control. In this work we have investigated whether the cellular kinase Akt and USUV polymerase NS5 interact and co-localize in a cell. To this aim, we performed co-immunoprecipitation (Co-IP) assays, followed by confocal microscopy analyses. We further tested whether NS5 is a phosphorylation substrate of Akt in vitro. Finally, to examine its role in viral replication, we chemically silenced Akt with three inhibitors (MK-2206, honokiol and ipatasertib). We found that both proteins are localized (confocal) and pulled down (Co-IP) together when expressed in different cell lines, supporting the fact that they are interacting partners. This possibility was further sustained by data showing that NS5 is phosphorylated by Akt. Treatment of USUV-infected cells with Akt-specific inhibitors led to decreases in virus titers (>10-fold). Our results suggest an important role for Akt in virus replication and stimulate further investigations to examine the PI3K/Akt/mTOR pathway as an antiviral target.
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23
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Singh S, Ng J, Sivaraman J. Exploring the "Other" subfamily of HECT E3-ligases for therapeutic intervention. Pharmacol Ther 2021; 224:107809. [PMID: 33607149 DOI: 10.1016/j.pharmthera.2021.107809] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 12/13/2020] [Accepted: 01/26/2021] [Indexed: 12/14/2022]
Abstract
The HECT E3 ligase family regulates key cellular signaling pathways, with its 28 members divided into three subfamilies: NEDD4 subfamily (9 members), HERC subfamily (6 members) and "Other" subfamily (13 members). Here, we focus on the less-explored "Other" subfamily and discuss the recent findings pertaining to their biological roles. The N-terminal regions preceding the conserved HECT domains are significantly diverse in length and sequence composition, and are mostly unstructured, except for short regions that incorporate known substrate-binding domains. In some of the better-characterized "Other" members (e.g., HUWE1, AREL1 and UBE3C), structure analysis shows that the extended region (~ aa 50) adjacent to the HECT domain affects the stability and activity of the protein. The enzymatic activity is also influenced by interactions with different adaptor proteins and inter/intramolecular interactions. Primarily, the "Other" subfamily members assemble atypical ubiquitin linkages, with some cooperating with E3 ligases from the other subfamilies to form branched ubiquitin chains on substrates. Viruses and pathogenic bacteria target and hijack the activities of "Other" subfamily members to evade host immune responses and cause diseases. As such, these HECT E3 ligases have emerged as potential candidates for therapeutic drug development.
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Affiliation(s)
- Sunil Singh
- Department of Biological Sciences, 14 Science Drive 4, National University of Singapore, 117543, Singapore
| | - Joel Ng
- Department of Biological Sciences, 14 Science Drive 4, National University of Singapore, 117543, Singapore
| | - J Sivaraman
- Department of Biological Sciences, 14 Science Drive 4, National University of Singapore, 117543, Singapore.
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24
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Salimi-Jeda A, Badrzadeh F, Esghaei M, Abdoli A. The role of telomerase and viruses interaction in cancer development, and telomerase-dependent therapeutic approaches. Cancer Treat Res Commun 2021; 27:100323. [PMID: 33530025 DOI: 10.1016/j.ctarc.2021.100323] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 01/19/2021] [Accepted: 01/21/2021] [Indexed: 12/21/2022]
Abstract
Human telomerase reverse transcriptase (hTERT) is an enzyme that is critically involved in elongating and maintaining telomeres length to control cell life span and replicative potential. Telomerase activity is continuously expressed in human germ-line cells and most cancer cells, whereas it is suppressed in most somatic cells. In normal cells, by reducing telomerase activity and progressively shortening the telomeres, the cells progress to the senescence or apoptosis process. However, in cancer cells, telomere lengths remain constant due to telomerase's reactivation, and cells continue to proliferate and inhibit apoptosis, and ultimately lead to cancer development and human death due to metastasis. Studies demonstrated that several DNA and RNA oncoviruses could interact with telomerase by integrating their genome sequence within the host cell telomeres specifically. Through the activation of the hTERT promoter and lengthening the telomere, these cells contributes to cancer development. Since oncoviruses can activate telomerase and increase hTERT expression, there are several therapeutic strategies based on targeting the telomerase of cancer cells like telomerase-targeted peptide vaccines, hTERT-targeting dendritic cells (DCs), hTERT-targeting gene therapy, and hTERT-targeting CRISPR/Cas9 system that can overcome tumor-mediated toleration mechanisms and specifically apoptosis in cancer cells. This study reviews available data on the molecular structure of telomerase and the role of oncoviruses and telomerase interaction in cancer development and telomerase-dependent therapeutic approaches to conquest the cancer cells.
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Affiliation(s)
- Ali Salimi-Jeda
- Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Fariba Badrzadeh
- Faculti of Medicine, Golestan University of Medical sciences, Golestan, Iran.
| | - Maryam Esghaei
- Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Asghar Abdoli
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran.
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25
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Ali A, Farooqui SR, Rai J, Singh J, Kumar V, Mishra R, Banerjea AC. HIV-1 Nef promotes ubiquitination and proteasomal degradation of p53 tumor suppressor protein by using E6AP. Biochem Biophys Res Commun 2020; 529:1038-1044. [PMID: 32819562 DOI: 10.1016/j.bbrc.2020.05.188] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 05/25/2020] [Indexed: 01/19/2023]
Abstract
Human Immunodeficiency Virus-1 (HIV-1) Nef promotes p53 protein degradation to protect HIV-1 infected cells from p53 induced apoptosis. We found that Nef mediated p53 degradation is accomplished through ubiquitin proteasome pathway in an Mdm2-independent manner. By GST pulldown and immunoprecipitation assays, we have shown that Nef interacts with E3 ubiquitin ligase E6AP in both Nef transfected HEK-293T cells and HIV-1 infected MOLT3 cells. The p53 ubiquitination and degradation was found to be enhanced by Nef with E6AP but not by Nef with E6AP-C843A, a dominant negative E6AP mutant. We show that Nef binds with E6AP and promotes E6AP dependent p53 ubiquitination. Further, Nef inhibits apoptosis of p53 null H1299 cells after exogenous expression of p53 protein. The p53 dependent apoptosis of H1299 cells was further reduced after the expression of Nef with E6AP. However, Nef mediated reduction in p53 induced apoptosis of H1299 cells was restored when Nef was co-expressed with E6AP-C843A. Thus, Nef and E6AP co-operate to promote p53 ubiquitination and degradation in order to suppress p53 dependent apoptosis. CHME3 cells, which are a natural host of HIV-1, also show p53 ubiquitination and degradation by Nef and E6AP. These results establish that Nef induces p53 degradation via cellular E3 ligase E6AP to inhibit apoptosis during HIV-1 infection.
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Affiliation(s)
- Amjad Ali
- Virology Lab, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, 110067, India; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA 01605.
| | - Sabihur Rahman Farooqui
- Virology Lab, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, 110067, India.
| | - Jagdish Rai
- IFSC, Panjab University, Chandigarh, 160014, India.
| | - Jyotsna Singh
- Virology Lab, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, 110067, India.
| | - Vivek Kumar
- Virology Lab, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, 110067, India.
| | - Ritu Mishra
- Virology Lab, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, 110067, India.
| | - Akhil C Banerjea
- Virology Lab, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, 110067, India.
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The HECT E3 Ligase E6AP/UBE3A as a Therapeutic Target in Cancer and Neurological Disorders. Cancers (Basel) 2020; 12:cancers12082108. [PMID: 32751183 PMCID: PMC7464832 DOI: 10.3390/cancers12082108] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/24/2020] [Accepted: 07/27/2020] [Indexed: 11/23/2022] Open
Abstract
The HECT (Homologous to the E6-AP Carboxyl Terminus)-family protein E6AP (E6-associated protein), encoded by the UBE3A gene, is a multifaceted ubiquitin ligase that controls diverse signaling pathways involved in cancer and neurological disorders. The oncogenic role of E6AP in papillomavirus-induced cancers is well known, with its action to trigger p53 degradation in complex with the E6 viral oncoprotein. However, the roles of E6AP in non-viral cancers remain poorly defined. It is well established that loss-of-function alterations of the UBE3A gene cause Angelman syndrome, a severe neurodevelopmental disorder with autosomal dominant inheritance modified by genomic imprinting on chromosome 15q. Moreover, excess dosage of the UBE3A gene markedly increases the penetrance of autism spectrum disorders, suggesting that the expression level of UBE3A must be regulated tightly within a physiologically tolerated range during brain development. In this review, current the knowledge about the substrates of E6AP-mediated ubiquitination and their functions in cancer and neurological disorders is discussed, alongside with the ongoing efforts to pharmacologically modulate this ubiquitin ligase as a promising therapeutic target.
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27
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Cancer Patients Have a Higher Risk Regarding COVID-19 - and Vice Versa? Pharmaceuticals (Basel) 2020; 13:ph13070143. [PMID: 32640723 PMCID: PMC7408191 DOI: 10.3390/ph13070143] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 06/24/2020] [Accepted: 07/03/2020] [Indexed: 02/06/2023] Open
Abstract
The world is currently suffering from a pandemic which has claimed the lives of over 230,000 people to date. The responsible virus is called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and causes the coronavirus disease 2019 (COVID-19), which is mainly characterized by fever, cough and shortness of breath. In severe cases, the disease can lead to respiratory distress syndrome and septic shock, which are mostly fatal for the patient. The severity of disease progression was hypothesized to be related to an overshooting immune response and was correlated with age and comorbidities, including cancer. A lot of research has lately been focused on the pathogenesis and acute consequences of COVID-19. However, the possibility of long-term consequences caused by viral infections which has been shown for other viruses are not to be neglected. In this regard, this opinion discusses the interplay of SARS-CoV-2 infection and cancer with special focus on the inflammatory immune response and tissue damage caused by infection. We summarize the available literature on COVID-19 suggesting an increased risk for severe disease progression in cancer patients, and we discuss the possibility that SARS-CoV-2 could contribute to cancer development. We offer lines of thought to provide ideas for urgently needed studies on the potential long-term effects of SARS-CoV-2 infection.
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28
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Borsetto D, Fussey J, Fabris L, Bandolin L, Gaudioso P, Phillips V, Polesel J, Boscolo-Rizzo P. HCV infection and the risk of head and neck cancer: A meta-analysis. Oral Oncol 2020; 109:104869. [PMID: 32599500 DOI: 10.1016/j.oraloncology.2020.104869] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 06/09/2020] [Accepted: 06/17/2020] [Indexed: 12/29/2022]
Abstract
Recent evidence has consistently suggested a role for HCV in the etiology of head and neck squamous cell carcinoma (HNSCC), but the conclusions of these studies have often been limited by small sample size. Therefore, a meta-analysis was performed to summarize present evidence on the association between HCV infection and HNSCC. After screening citations from literature search, eight observational studies investigating the association between HCV and cancer(s) of either oral cavity, oropharynx, hypopharynx or larynx were included. For each cancer site, risk ratios from individual studies were displayed in forest plots; pooled risk ratios (RR) and corresponding confidence intervals (CI) were calculated. A significant association was found between HCV infection and cancers of the oral cavity (RR = 2.13; 95%: 1.61-2.83), oropharynx (RR = 1.81; 95% CI: 1.21-2.72), and larynx (RR = 2.57; 95% CI: 1.11-5.94). A similar picture emerged for hypopharyngeal cancer, though this result did not fully reach statistical significance because of the small number of available studies (RR = 2.15; 95% CI: 0.73-6.31). These findings remained similar after exclusion of patients with HIV co-infection. Our results highlighted the importance of surveillance of the upper aerodigestive tract in patients with known chronic HCV infections in order to enable HNSCC early diagnosis. In addition, they could be a reminder of the possibility of undiagnosed HCV infection to the clinicians treating HNSCC.
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Affiliation(s)
- Daniele Borsetto
- Department of Otolaryngology, Guy's and St. Thomas' Hospital NHS Foundation Trust, London, United Kingdom
| | - Jonathan Fussey
- Department of Otolaryngology, Royal Devon and Exeter Hospital, Exeter, United Kingdom
| | - Luca Fabris
- Department of Molecular Medicine, University of Padova, Padova, Italy; Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Luigia Bandolin
- Department of Neurosciences, Section of Otolaryngology, University of Padova, Treviso, Italy
| | - Piergiorgio Gaudioso
- Department of Neurosciences, Section of Otolaryngology, University of Padova, Treviso, Italy
| | | | - Jerry Polesel
- Unit of Cancer Epidemiology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.
| | - Paolo Boscolo-Rizzo
- Department of Neurosciences, Section of Otolaryngology, University of Padova, Treviso, Italy.
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29
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Dash S, Aydin Y, Wu T. Integrated stress response in hepatitis C promotes Nrf2-related chaperone-mediated autophagy: A novel mechanism for host-microbe survival and HCC development in liver cirrhosis. Semin Cell Dev Biol 2020; 101:20-35. [PMID: 31386899 PMCID: PMC7007355 DOI: 10.1016/j.semcdb.2019.07.015] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 06/26/2019] [Accepted: 07/30/2019] [Indexed: 02/06/2023]
Abstract
The molecular mechanism(s) how liver damage during the chronic hepatitis C virus (HCV) infection evolve into cirrhosis and hepatocellular carcinoma (HCC) is unclear. HCV infects hepatocyte, the major cell types in the liver. During infection, large amounts of viral proteins and RNA replication intermediates accumulate in the endoplasmic reticulum (ER) of the infected hepatocyte, which creates a substantial amount of stress response. Infected hepatocyte activates a different type of stress adaptive mechanisms such as unfolded protein response (UPR), antioxidant response (AR), and the integrated stress response (ISR) to promote virus-host cell survival. The hepatic stress is also amplified by another layer of innate and inflammatory response associated with cellular sensing of virus infection through the production of interferon (IFN) and inflammatory cytokines. The interplay between various types of cellular stress signal leads to different forms of cell death such as apoptosis, necrosis, and autophagy depending on the intensity of the stress and nature of the adaptive cellular response. How do the adaptive cellular responses decode such death programs that promote host-microbe survival leading to the establishment of chronic liver disease? In this review, we discuss how the adaptive cellular response through the Nrf2 pathway that promotes virus and cell survival. Furthermore, we provide a glimpse of novel stress-induced Nrf2 mediated compensatory autophagy mechanisms in virus-cell survival that degrade tumor suppressor gene and activation of oncogenic signaling during HCV infection. Based on these facts, we hypothesize that the balance between hepatic stress, inflammation and different types of cell death determines liver disease progression outcomes. We propose that a more nuanced understanding of virus-host interactions under excessive cellular stress may provide an answer to the fundamental questions why some individuals with chronic HCV infection remain at risk of developing cirrhosis, cancer and some do not.
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Affiliation(s)
- Srikanta Dash
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, 70112, USA.
| | - Yucel Aydin
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, 70112, USA
| | - Tong Wu
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, 70112, USA
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30
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Dash S, Aydin Y, Widmer KE, Nayak L. Hepatocellular Carcinoma Mechanisms Associated with Chronic HCV Infection and the Impact of Direct-Acting Antiviral Treatment. J Hepatocell Carcinoma 2020; 7:45-76. [PMID: 32346535 PMCID: PMC7167284 DOI: 10.2147/jhc.s221187] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 03/06/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus (HCV) infection is the major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). The mechanisms of HCC initiation, growth, and metastasis appear to be highly complex due to the decade-long interactions between the virus, immune system, and overlapping bystander effects of host metabolic liver disease. The lack of a readily accessible animal model system for HCV is a significant obstacle to understand the mechanisms of viral carcinogenesis. Traditionally, the primary prevention strategy of HCC has been to eliminate infection by antiviral therapy. The success of virus elimination by antiviral treatment is determined by the SVR when the HCV is no longer detectable in serum. Interferon-alpha (IFN-α) and its analogs, pegylated IFN-α (PEG-IFN-α) alone with ribavirin (RBV), have been the primary antiviral treatment of HCV for many years with a low cure rate. The cloning and sequencing of HCV have allowed the development of cell culture models, which accelerated antiviral drug discovery. It resulted in the selection of highly effective direct-acting antiviral (DAA)-based combination therapy that now offers incredible success in curing HCV infection in more than 95% of all patients, including those with cirrhosis. However, several emerging recent publications claim that patients who have liver cirrhosis at the time of DAAs treatment face the risk of HCC occurrence and recurrence after viral cure. This remains a substantial challenge while addressing the long-term benefit of antiviral medicine. The host-related mechanisms that drive the risk of HCC in the absence of the virus are unknown. This review describes the multifaceted mechanisms that create a tumorigenic environment during chronic HCV infection. In addition to the potential oncogenic programming that drives HCC after viral clearance by DAAs, the current status of a biomarker development for early prediction of cirrhosis regression and HCC detection post viral treatment is discussed. Since DAAs treatment does not provide full protection against reinfection or viral transmission to other individuals, the recent studies for a vaccine development are also reviewed.
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Affiliation(s)
- Srikanta Dash
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA70112, USA
- Southeast Louisiana Veterans Health Care System, New Orleans, LA70119, USA
- Department of Medicine, Division of Gastroenterology, Tulane University Health Sciences Center, New Orleans, LA70112, USA
| | - Yucel Aydin
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA70112, USA
| | - Kyle E Widmer
- Southeast Louisiana Veterans Health Care System, New Orleans, LA70119, USA
| | - Leela Nayak
- Southeast Louisiana Veterans Health Care System, New Orleans, LA70119, USA
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31
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Kim JY, Kim KM, Yang JH, Cho SS, Kim SJ, Park SJ, Ahn SG, Lee GH, Yang JW, Lim SC, Kang KW, Ki SH. Induction of E6AP by microRNA-302c dysregulation inhibits TGF-β-dependent fibrogenesis in hepatic stellate cells. Sci Rep 2020. [PMID: 31949242 DOI: 10.1038/s41598-019-57322-w.] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Hepatic stellate cells (HSCs) are essential for liver fibrosis. E6 associated protein (E6AP) is one of the E3-ubiquitin-protein ligase and has been studied in proliferation and cellular stress. Currently, no information is available on the role of E6AP on transforming growth factor-β (TGF-β) signaling and hepatic fibrogenesis. This study examined whether E6AP is overexpressed in activated HSCs, and if so, its effect on hepatic fibrogenesis and the molecular mechanism. E6AP was expressed higher in HSCs than hepatocytes, and was up-regulated in activated HSCs, HSCs from the livers of carbon tetrachloride-injected mice, or TGF-β-treated LX-2 cells. The TGF-β-mediated E6AP up-regulation was not due to altered mRNA level nor protein stability. Thus, we performed microRNA (miRNA, miR) analysis and found that miR-302c was dysregulated in TGF-β-treated LX-2 cells or activated primary HSCs. We revealed that miR-302c was a modulator of E6AP. E6AP overexpression inhibited TGF-β-induced expression of plasminogen activator inhibitor-1 in LX-2 cells, albeit it was independent of Smad pathway. Additionally, E6AP inhibited TGF-β-mediated phosphorylation of mitogen-activated protein kinases. To conclude, E6AP overexpression due to decreased miR-302c in HSCs attenuated hepatic fibrogenesis through inhibition of the TGF-β-induced mitogen-activated protein kinase signaling pathway, implying that E6AP and other molecules may contribute to protection against liver fibrosis.
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Affiliation(s)
- Ji Young Kim
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Kyu Min Kim
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Ji Hye Yang
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea.,College of Korean Medicine, Dongshin University, Naju, Jeollanam-do, 58245, Republic of Korea
| | - Sam Seok Cho
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Seung Jung Kim
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Su Jung Park
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Sang-Gun Ahn
- Department of Pathology, College of Dentistry, Chosun University, Gwangju, 61452, Republic of Korea
| | - Gum Hwa Lee
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Jin Won Yang
- College of Pharmacy, Woosuk University, Wanju, Jeonbuk, 55338, Republic of Korea
| | - Sung Chul Lim
- College of Medicine, Chosun University, Gwangju, 61452, Republic of Korea
| | - Keon Wook Kang
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Sung Hwan Ki
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea.
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Induction of E6AP by microRNA-302c dysregulation inhibits TGF-β-dependent fibrogenesis in hepatic stellate cells. Sci Rep 2020; 10:444. [PMID: 31949242 PMCID: PMC6965100 DOI: 10.1038/s41598-019-57322-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 12/27/2019] [Indexed: 12/13/2022] Open
Abstract
Hepatic stellate cells (HSCs) are essential for liver fibrosis. E6 associated protein (E6AP) is one of the E3-ubiquitin-protein ligase and has been studied in proliferation and cellular stress. Currently, no information is available on the role of E6AP on transforming growth factor-β (TGF-β) signaling and hepatic fibrogenesis. This study examined whether E6AP is overexpressed in activated HSCs, and if so, its effect on hepatic fibrogenesis and the molecular mechanism. E6AP was expressed higher in HSCs than hepatocytes, and was up-regulated in activated HSCs, HSCs from the livers of carbon tetrachloride-injected mice, or TGF-β-treated LX-2 cells. The TGF-β-mediated E6AP up-regulation was not due to altered mRNA level nor protein stability. Thus, we performed microRNA (miRNA, miR) analysis and found that miR-302c was dysregulated in TGF-β-treated LX-2 cells or activated primary HSCs. We revealed that miR-302c was a modulator of E6AP. E6AP overexpression inhibited TGF-β-induced expression of plasminogen activator inhibitor-1 in LX-2 cells, albeit it was independent of Smad pathway. Additionally, E6AP inhibited TGF-β-mediated phosphorylation of mitogen-activated protein kinases. To conclude, E6AP overexpression due to decreased miR-302c in HSCs attenuated hepatic fibrogenesis through inhibition of the TGF-β-induced mitogen-activated protein kinase signaling pathway, implying that E6AP and other molecules may contribute to protection against liver fibrosis.
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33
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Dash S, Aydin Y, Moroz K. Chaperone-Mediated Autophagy in the Liver: Good or Bad? Cells 2019; 8:E1308. [PMID: 31652893 PMCID: PMC6912708 DOI: 10.3390/cells8111308] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 10/17/2019] [Accepted: 10/22/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection triggers autophagy processes, which help clear out the dysfunctional viral and cellular components that would otherwise inhibit the virus replication. Increased cellular autophagy may kill the infected cell and terminate the infection without proper regulation. The mechanism of autophagy regulation during liver disease progression in HCV infection is unclear. The autophagy research has gained a lot of attention recently since autophagy impairment is associated with the development of hepatocellular carcinoma (HCC). Macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA) are three autophagy processes involved in the lysosomal degradation and extracellular release of cytosolic cargoes under excessive stress. Autophagy processes compensate for each other during extreme endoplasmic reticulum (ER) stress to promote host and microbe survival as well as HCC development in the highly stressed microenvironment of the cirrhotic liver. This review describes the molecular details of how excessive cellular stress generated during HCV infection activates CMA to improve cell survival. The pathological implications of stress-related CMA activation resulting in the loss of hepatic innate immunity and tumor suppressors, which are most often observed among cirrhotic patients with HCC, are discussed. The oncogenic cell programming through autophagy regulation initiated by a cytoplasmic virus may facilitate our understanding of HCC mechanisms related to non-viral etiologies and metabolic conditions such as uncontrolled type II diabetes. We propose that a better understanding of how excessive cellular stress leads to cancer through autophagy modulation may allow therapeutic development and early detection of HCC.
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Affiliation(s)
- Srikanta Dash
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
- Southeast Louisiana Veterans Health Care System, 2400 Canal Street, New Orleans, LA 70119, USA.
| | - Yucel Aydin
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
| | - Krzysztof Moroz
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
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34
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Bandilovska I, Keam SP, Gamell C, Machicado C, Haupt S, Haupt Y. E6AP goes viral: the role of E6AP in viral- and non-viral-related cancers. Carcinogenesis 2019; 40:707-714. [DOI: 10.1093/carcin/bgz072] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 03/12/2019] [Accepted: 04/08/2019] [Indexed: 02/07/2023] Open
Abstract
Abstract
Since its discovery, the E3 ubiquitin ligase E6-associated protein (E6AP) has been studied extensively in two pathological contexts: infection by the human papillomavirus (HPV), and the neurodevelopmental disorder, Angelman syndrome. Vital biological links between E6AP and other viruses, namely hepatitis C virus and encephalomyocarditis virus, have been recently uncovered. Critically, oncogenic E6AP activities have been demonstrated to contribute to cancers of both viral and non-viral origins. HPV-associated cancers serve as the primary example of E6AP involvement in cancers driven by viruses. Studies over the past few years have exposed a role for E6AP in non-viral-related cancers. This has been demonstrated in B-cell lymphoma and prostate cancers, where oncogenic E6AP functions drive these cancers by acting on key tumour suppressors. In this review we discuss the role of E6AP in viral infection, viral propagation and viral-related cancer. We discuss processes affected by oncogenic E6AP, which promote cancers of viral and non-viral aetiology. Overall, recent findings support the role of oncogenic E6AP in disrupting key cellular processes, including tumour suppression and the immune response. E6AP is consequently emerging as an attractive therapeutic target for a number of specific cancers.
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Affiliation(s)
- Ivona Bandilovska
- Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
| | - Simon P Keam
- Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Cristina Gamell
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
| | - Claudia Machicado
- Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima, Peru
- Institute for Biocomputation and Physics of Complex Systems, University of Zaragoza, Zaragoza, Spain
| | - Sue Haupt
- Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
| | - Ygal Haupt
- Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia
- Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia
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Virzì A, Roca Suarez AA, Baumert TF, Lupberger J. Oncogenic Signaling Induced by HCV Infection. Viruses 2018; 10:v10100538. [PMID: 30279347 PMCID: PMC6212953 DOI: 10.3390/v10100538] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 09/29/2018] [Accepted: 09/30/2018] [Indexed: 02/07/2023] Open
Abstract
The liver is frequently exposed to toxins, metabolites, and oxidative stress, which can challenge organ function and genomic stability. Liver regeneration is therefore a highly regulated process involving several sequential signaling events. It is thus not surprising that individual oncogenic mutations in hepatocytes do not necessarily lead to cancer and that the genetic profiles of hepatocellular carcinomas (HCCs) are highly heterogeneous. Long-term infection with hepatitis C virus (HCV) creates an oncogenic environment by a combination of viral protein expression, persistent liver inflammation, oxidative stress, and chronically deregulated signaling events that cumulate as a tipping point for genetic stability. Although novel direct-acting antivirals (DAA)-based treatments efficiently eradicate HCV, the associated HCC risk cannot be fully eliminated by viral cure in patients with advanced liver disease. This suggests that HCV may persistently deregulate signaling pathways beyond viral cure and thereby continue to perturb cancer-relevant gene function. In this review, we summarize the current knowledge about oncogenic signaling pathways derailed by chronic HCV infection. This will not only help to understand the mechanisms of hepatocarcinogenesis but will also highlight potential chemopreventive strategies to help patients with a high-risk profile of developing HCC.
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Affiliation(s)
- Alessia Virzì
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.
- Université de Strasbourg, 67000 Strasbourg, France.
| | - Armando Andres Roca Suarez
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.
- Université de Strasbourg, 67000 Strasbourg, France.
| | - Thomas F Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.
- Université de Strasbourg, 67000 Strasbourg, France.
- Pôle Hépato-digestif, Institut Hospitalo-universitaire, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France.
| | - Joachim Lupberger
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.
- Université de Strasbourg, 67000 Strasbourg, France.
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Molecular Mechanisms of Hepatocarcinogenesis Following Sustained Virological Response in Patients with Chronic Hepatitis C Virus Infection. Viruses 2018; 10:v10100531. [PMID: 30274202 PMCID: PMC6212901 DOI: 10.3390/v10100531] [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: 08/28/2018] [Revised: 09/25/2018] [Accepted: 09/27/2018] [Indexed: 02/07/2023] Open
Abstract
Despite the success of direct-acting antiviral (DAA) agents in treating chronic hepatitis C virus (HCV) infection, the number of cases of HCV-related hepatocellular carcinoma (HCC) is expected to increase over the next five years. HCC develops over the span of decades and is closely associated with fibrosis stage. HCV both directly and indirectly establishes a pro-inflammatory environment favorable for viral replication. Repeated cycles of cell death and regeneration lead to genomic instability and loss of cell cycle control. DAA therapy offers >90% sustained virological response (SVR) rates with fewer side effects and restrictions than interferon. While elimination of HCV helps to restore liver function and reverse mild fibrosis, post-SVR patients remain at elevated risk of HCC. A series of studies reporting higher than expected rates of HCC development among DAA-treated patients ignited debate over whether use of DAAs elevates HCC risk compared to interferon. However, recent prospective and retrospective studies based on larger patient cohorts have found no significant difference in risk between DAA and interferon therapy once other factors are taken into account. Although many mechanisms and pathways involved in hepatocarcinogenesis have been elucidated, our understanding of drivers specific to post-SVR hepatocarcinogenesis is still limited, and lack of suitable in vivo and in vitro experimental systems has hampered efforts to examine etiology-specific mechanisms that might serve to answer this question more thoroughly. Further research is needed to identify risk factors and biomarkers for post-SVR HCC and to develop targeted therapies based on more complete understanding of the molecules and pathways implicated in hepatocarcinogenesis.
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Ubiquitination at the interface of tumor viruses and DNA damage responses. Curr Opin Virol 2018; 32:40-47. [PMID: 30261451 DOI: 10.1016/j.coviro.2018.08.017] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 08/31/2018] [Indexed: 01/09/2023]
Abstract
Viruses exploit cellular ubiquitination machinery to shape the host proteome and promote productive infection. Among the cellular processes influenced by viral manipulation of ubiquitination is the DNA damage response (DDR), a network of cellular signaling pathways that sense and respond to genomic damage. This host-pathogen interaction is particularly important during virus replication and transformation by DNA tumor viruses. Manipulating DDR pathways can promote virus replication but also impacts host genomic instability, potentially leading to cellular transformation and tumor formation. We review ways in which viruses are known to hijack the cellular ubiquitin system to reshape host DDR pathways.
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Golemis EA, Scheet P, Beck TN, Scolnick EM, Hunter DJ, Hawk E, Hopkins N. Molecular mechanisms of the preventable causes of cancer in the United States. Genes Dev 2018; 32:868-902. [PMID: 29945886 PMCID: PMC6075032 DOI: 10.1101/gad.314849.118] [Citation(s) in RCA: 97] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Annually, there are 1.6 million new cases of cancer and nearly 600,000 cancer deaths in the United States alone. The public health burden associated with these numbers has motivated enormous research efforts into understanding the root causes of cancer. These efforts have led to the recognition that between 40% and 45% of cancers are associated with preventable risk factors and, importantly, have identified specific molecular mechanisms by which these exposures modify human physiology to induce or promote cancer. The increasingly refined knowledge of these mechanisms, which we summarize here, emphasizes the need for greater efforts toward primary cancer prevention through mitigation of modifiable risk factors. It also suggests exploitable avenues for improved secondary prevention (which includes the development of therapeutics designed for cancer interception and enhanced techniques for noninvasive screening and early detection) based on detailed knowledge of early neoplastic pathobiology. Such efforts would complement the current emphasis on the development of therapeutic approaches to treat established cancers and are likely to result in far greater gains in reducing morbidity and mortality.
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Affiliation(s)
- Erica A Golemis
- Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
| | - Paul Scheet
- Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
| | - Tim N Beck
- Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
- Molecular and Cell Biology and Genetics Program, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129, USA
| | - Eward M Scolnick
- Eli and Edythe L. Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA
| | - David J Hunter
- Nuffield Department of Population Health, University of Oxford, Medical Sciences Division, Oxford OX3 7LF, United Kingdom
| | - Ernest Hawk
- Division of Cancer Prevention and Population Sciences, University of Texas M.D. Anderson Cancer Center, Houston Texas 77030, USA
| | - Nancy Hopkins
- Koch Institute for Integrative Cancer Research, Biology Department, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
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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.
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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.
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Hepatitis C Virus core+1/ARF Protein Modulates the Cyclin D1/pRb Pathway and Promotes Carcinogenesis. J Virol 2018; 92:JVI.02036-17. [PMID: 29444947 DOI: 10.1128/jvi.02036-17] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 02/06/2018] [Indexed: 02/06/2023] Open
Abstract
Viruses often encompass overlapping reading frames and unconventional translation mechanisms in order to maximize the output from a minimum genome and to orchestrate their timely gene expression. Hepatitis C virus (HCV) possesses such an unconventional open reading frame (ORF) within the core-coding region, encoding an additional protein, initially designated ARFP, F, or core+1. Two predominant isoforms of core+1/ARFP have been reported, core+1/L, initiating from codon 26, and core+1/S, initiating from codons 85/87 of the polyprotein coding region. The biological significance of core+1/ARFP expression remains elusive. The aim of the present study was to gain insight into the functional and pathological properties of core+1/ARFP through its interaction with the host cell, combining in vitro and in vivo approaches. Our data provide strong evidence that the core+1/ARFP of HCV-1a stimulates cell proliferation in Huh7-based cell lines expressing either core+1/S or core+1/L isoforms and in transgenic liver disease mouse models expressing core+1/S protein in a liver-specific manner. Both isoforms of core+1/ARFP increase the levels of cyclin D1 and phosphorylated Rb, thus promoting the cell cycle. In addition, core+1/S was found to enhance liver regeneration and oncogenesis in transgenic mice. The induction of the cell cycle together with increased mRNA levels of cell proliferation-related oncogenes in cells expressing the core+1/ARFP proteins argue for an oncogenic potential of these proteins and an important role in HCV-associated pathogenesis.IMPORTANCE This study sheds light on the biological importance of a unique HCV protein. We show here that core+1/ARFP of HCV-1a interacts with the host machinery, leading to acceleration of the cell cycle and enhancement of liver carcinogenesis. This pathological mechanism(s) may complement the action of other viral proteins with oncogenic properties, leading to the development of hepatocellular carcinoma. In addition, given that immunological responses to core+1/ARFP have been correlated with liver disease severity in chronic HCV patients, we expect that the present work will assist in clarifying the pathophysiological relevance of this protein as a biomarker of disease progression.
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Abstract
Most hepatitis C virus (HCV) infection results in persistent infection. Significant portion of chronic HCV-infected patients develop hepatocellular carcinoma (HCC). Chronic hepatitis C is also associated with extrahepatic manifestations, including cryoglobulinemia, lymphoma, insulin resistance, type 2 diabetes, and neurological disorders. The molecular mechanisms of how HCV infection causes liver cancer are largely unknown. HCV replication or viral proteins may perturb cellular hemostasis and induce the generation of reactive oxygen species (ROS); viral components or viral replication products act as agonist to trigger innate immune response and cause chronic inflammation. Within the liver, non-hepatocytes such as hepatic stellate cell (HSC) are activated upon HCV infection to provide the major source of extracellular proteins and play important roles in fibrogenesis. With the great achievements of HCV treatment, especially the direct-acting antivirals (DAAs) against HCV, HCV eradication is possible. However, until now there are only very limited data on the effect of DAA-based anti-HCV treatment on HCC patients.
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Ringelhan M, McKeating JA, Protzer U. Viral hepatitis and liver cancer. Philos Trans R Soc Lond B Biol Sci 2018; 372:rstb.2016.0274. [PMID: 28893941 PMCID: PMC5597741 DOI: 10.1098/rstb.2016.0274] [Citation(s) in RCA: 227] [Impact Index Per Article: 32.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/09/2017] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B and C viruses are a global health problem causing acute and chronic infections that can lead to liver cirrhosis and hepatocellular carcinoma (HCC). These infections are the leading cause for HCC worldwide and are associated with significant mortality, accounting for more than 1.3 million deaths per year. Owing to its high incidence and resistance to treatment, liver cancer is the second leading cause of cancer-related death worldwide, with HCC representing approximately 90% of all primary liver cancer cases. The majority of viral-associated HCC cases develop in subjects with liver cirrhosis; however, hepatitis B virus infection can promote HCC development without prior end-stage liver disease. Thus, understanding the role of hepatitis B and C viral infections in HCC development is essential for the future design of treatments and therapies for this cancer. In this review, we summarize the current knowledge on hepatitis B and C virus hepatocarcinogenesis and highlight direct and indirect risk factors. This article is part of the themed issue ‘Human oncogenic viruses’.
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Affiliation(s)
- Marc Ringelhan
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Trogerstrasse 30, 81675 Muenchen, Germany.,Department of Internal Medicine II, University Hopsital rechts der Isar, Technical University of Munich, Ismaninger Strasse 22, 81675 Muenchen, Germany.,German Center for Infection Research (DZIF), partner site Munich
| | - Jane A McKeating
- Institute for Advanced Science, Technical University of Munich, Muenchen, Germany .,Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Ulrike Protzer
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Trogerstrasse 30, 81675 Muenchen, Germany .,German Center for Infection Research (DZIF), partner site Munich.,Institute for Advanced Science, Technical University of Munich, Muenchen, Germany
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Irshad M, Gupta P, Irshad K. Molecular basis of hepatocellular carcinoma induced by hepatitis C virus infection. World J Hepatol 2017; 9:1305-1314. [PMID: 29359013 PMCID: PMC5756719 DOI: 10.4254/wjh.v9.i36.1305] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 11/08/2017] [Accepted: 12/05/2017] [Indexed: 02/06/2023] Open
Abstract
Present study outlines a comprehensive view of published information about the underlying mechanisms operational for progression of chronic hepatitis C virus (HCV) infection to development of hepatocellular carcinoma (HCC). These reports are based on the results of animal experiments and human based studies. Although, the exact delineated mechanism is not yet established, there are evidences available to emphasize the involvement of HCV induced chronic inflammation, oxidative stress, insulin resistance, endoplasmic reticulum stress, hepato steatosis and liver fibrosis in the progression of HCV chronic disease to HCC. Persistent infection with replicating HCV not only initiates several liver alterations but also creates an environment for development of liver cancer. Various studies have reported that HCV acts both directly as well as indirectly in promoting this process. Whereas HCV related proteins, like HCV core, E1, E2, NS3 and NS5A, modulate signal pathways dysregulating cell cycle and cell metabolism, the chronic infection produces similar changes in an indirect way. HCV is an RNA virus and does not integrate with host genome and therefore, HCV induced hepatocarcinogenesis pursues a totally different mechanism causing imbalance between suppressors and proto-oncogenes and genomic integrity. However, the exact mechanism of HCC inducement still needs a full understanding of various steps involved in this process.
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Affiliation(s)
- Mohammad Irshad
- Clinical Biochemistry Division, Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi 110029, India.
| | - Priyanka Gupta
- Clinical Biochemistry Division, Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Khushboo Irshad
- Clinical Biochemistry Division, Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi 110029, India
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Ronchi VP, Kim ED, Summa CM, Klein JM, Haas AL. In silico modeling of the cryptic E2∼ubiquitin-binding site of E6-associated protein (E6AP)/UBE3A reveals the mechanism of polyubiquitin chain assembly. J Biol Chem 2017; 292:18006-18023. [PMID: 28924046 DOI: 10.1074/jbc.m117.813477] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Indexed: 12/13/2022] Open
Abstract
To understand the mechanism for assembly of Lys48-linked polyubiquitin degradation signals, we previously demonstrated that the E6AP/UBE3A ligase harbors two functionally distinct E2∼ubiquitin-binding sites: a high-affinity Site 1 required for E6AP Cys820∼ubiquitin thioester formation and a canonical Site 2 responsible for subsequent chain elongation. Ordered binding to Sites 1 and 2 is here revealed by observation of UbcH7∼ubiquitin-dependent substrate inhibition of chain formation at micromolar concentrations. To understand substrate inhibition, we exploited the PatchDock algorithm to model in silico UbcH7∼ubiquitin bound to Site 1, validated by chain assembly kinetics of selected point mutants. The predicted structure buries an extensive solvent-excluded surface bringing the UbcH7∼ubiquitin thioester bond within 6 Å of the Cys820 nucleophile. Modeling onto the active E6AP trimer suggests that substrate inhibition arises from steric hindrance between Sites 1 and 2 of adjacent subunits. Confirmation that Sites 1 and 2 function in trans was demonstrated by examining the effect of E6APC820A on wild-type activity and single-turnover pulse-chase kinetics. A cyclic proximal indexation model proposes that Sites 1 and 2 function in tandem to assemble thioester-linked polyubiquitin chains from the proximal end attached to Cys820 before stochastic en bloc transfer to the target protein. Non-reducing SDS-PAGE confirms assembly of the predicted Cys820-linked 125I-polyubiquitin thioester intermediate. Other studies suggest that Glu550 serves as a general base to generate the Cys820 thiolate within the low dielectric binding interface and Arg506 functions to orient Glu550 and to stabilize the incipient anionic transition state during thioester exchange.
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Affiliation(s)
| | - Elizabeth D Kim
- From the Department of Biochemistry and Molecular Biology and
| | - Christopher M Summa
- the Department of Computer Science, University of New Orleans, New Orleans, Louisiana 70148
| | | | - Arthur L Haas
- From the Department of Biochemistry and Molecular Biology and .,the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112 and
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Aydin Y, Chedid M, Chava S, Danielle Williams D, Liu S, Hagedorn CH, Sumitran-Holgersson S, Reiss K, Moroz K, Lu H, Balart LA, Dash S. Activation of PERK-Nrf2 oncogenic signaling promotes Mdm2-mediated Rb degradation in persistently infected HCV culture. Sci Rep 2017; 7:9223. [PMID: 28835697 PMCID: PMC5569052 DOI: 10.1038/s41598-017-10087-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Accepted: 07/26/2017] [Indexed: 02/06/2023] Open
Abstract
The mechanism of how chronic hepatitis C virus (HCV) infection leads to such a high rate of hepatocellular carcinoma (HCC) is unknown. We found that the PERK axis of endoplasmic reticulum (ER) stress elicited prominent nuclear translocation of Nrf2 in 100% of HCV infected hepatocytes. The sustained nuclear translocation of Nrf2 in chronically infected culture induces Mdm2-mediated retinoblastoma protein (Rb) degradation. Silencing PERK and Nrf2 restored Mdm2-mediated Rb degradation, suggesting that sustained activation of PERK/Nrf2 axis creates oncogenic stress in chronically infected HCV culture model. The activation of Nrf2 and its nuclear translocation were prevented by ER-stress and PERK inhibitors, suggesting that PERK axis is involved in the sustained activation of Nrf2 signaling during chronic HCV infection. Furthermore, we show that HCV clearance induced by interferon-α based antiviral normalized the ER-stress response and prevented nuclear translocation of Nrf2, whereas HCV clearance by DAAs combination does neither. In conclusion, we report here a novel mechanism for how sustained activation of PERK axis of ER-stress during chronic HCV infection activates oncogenic Nrf2 signaling that promotes hepatocyte survival and oncogenesis by inducing Mdm2-mediated Rb degradation.
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Affiliation(s)
- Yucel Aydin
- Department of Medicine, Division of Gastroenterology and Hepatology, New Orleans, Louisiana, USA
| | - Milad Chedid
- Department of Pathology and Laboratory Medicine, New Orleans, Louisiana, USA
| | - Srinivas Chava
- Department of Pathology and Laboratory Medicine, New Orleans, Louisiana, USA
| | | | - Shuanghu Liu
- Department of Medicinal Chemistry, College of Pharmacy, University of Utah, Salt Lake City, UT, USA
| | - Curt H Hagedorn
- Department of Medicine and Genetics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | | | - Krzysztof Reiss
- School of Medicine, LSU Health Sciences Center, New Orleans, Louisiana, USA
| | - Krzysztof Moroz
- Department of Pathology and Laboratory Medicine, New Orleans, Louisiana, USA
| | - Hua Lu
- Department of Biochemistry, Tulane University Health Sciences Center, New Orleans, Louisiana, USA
| | - Luis A Balart
- Department of Medicine, Division of Gastroenterology and Hepatology, New Orleans, Louisiana, USA
| | - Srikanta Dash
- Department of Pathology and Laboratory Medicine, New Orleans, Louisiana, USA. .,Department of Medicine, Division of Gastroenterology and Hepatology, New Orleans, Louisiana, USA.
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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.
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Affiliation(s)
- Lingyao Du
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China. E-mail.
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miR-215 promotes cell migration and invasion of gastric cancer by targeting Retinoblastoma tumor suppressor gene 1. Pathol Res Pract 2017; 213:889-894. [PMID: 28689850 DOI: 10.1016/j.prp.2017.06.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Revised: 05/27/2017] [Accepted: 06/04/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND Gastric cancer (GC) is one of the most common malignant tumor and has high mortality worldwide. microRNAs (miRNAs) play critical roles in carcinogenesis. Previous studied showed that miR-215 was involved in tumorigenesis and progression. This study was designed to clarify the biological function of miR-215 in GC. METHODS qRT-PCR was used to detect the miR-215 expression in GC tissues and 6 human GC cell lines (AGS, SGC-7901, NCI-N87, GES-1, MKN-45 and BGC-823) as well. Transwell assay was used to investigate the biological function of miR-215 in GC. Luciferase reporter assay was used to confirm its effect on the regulation of the target gene Retinoblastoma tumor suppressor gene 1 (RB1). RESULTS miR-215 was frequently up-regulated in GC tissues compared to adjacent non-tumor tissues and GC cell lines. miR-215 expression level was correlated with the progression of tumor invasion and tumor-node-metastasis (TNM) stage. Over-expression miR-215 in GC cell lines promoted cell migration and invasion. Besides, miR-215 could down-regulate the expression of RB1 in vitro via directly binding to its 3'-untranslated region (UTR), while the expression of RB1 would suppress the miR-215-indueced GC cell migration and invasion. CONCLUSIONS miR-215 promoted cell migration and invasion of gastric cancer by directly targeting RB1.
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Arora P, Basu A, Schmidt ML, Clark GJ, Donninger H, Nichols DB, Calvisi DF, Kaushik-Basu N. Nonstructural protein 5B promotes degradation of the NORE1A tumor suppressor to facilitate hepatitis C virus replication. Hepatology 2017; 65:1462-1477. [PMID: 28090674 PMCID: PMC5397368 DOI: 10.1002/hep.29049] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 01/06/2017] [Accepted: 01/09/2017] [Indexed: 12/16/2022]
Abstract
UNLABELLED Hepatitis C virus (HCV) infection is a common risk factor for the development of liver cancer. The molecular mechanisms underlying this effect are only partially understood. Here, we show that the HCV protein, nonstructural protein (NS) 5B, directly binds to the tumor suppressor, NORE1A (RASSF5), and promotes its proteosomal degradation. In addition, we show that NORE1A colocalizes to sites of HCV viral replication and suppresses the replication process. Thus, NORE1A has antiviral activity, which is specifically antagonized by NS5B. Moreover, the suppression of NORE1A protein levels correlated almost perfectly with elevation of Ras activity in primary human samples. Therefore, NORE1A inactivation by NS5B may be essential for maximal HCV replication and may make a major contribution to HCV-induced liver cancer by shifting Ras signaling away from prosenescent/proapoptotic signaling pathways. CONCLUSION HCV uses NS5B to specifically suppress NORE1A, facilitating viral replication and elevated Ras signaling. (Hepatology 2017;65:1462-1477).
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Affiliation(s)
- Payal Arora
- Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103, USA
| | - Amartya Basu
- Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103, USA
| | - M. Lee Schmidt
- Dept. Pharmacology and Toxicology, University of Louisville, Rm 417, CTRB 505, S. Hancock St., Louisville, KY 40202, USA
| | - Geoffrey J. Clark
- Dept. Pharmacology and Toxicology, University of Louisville, Rm 417, CTRB 505, S. Hancock St., Louisville, KY 40202, USA,To whom correspondence should be addressed: ,
| | - Howard Donninger
- Dept. Pharmacology and Toxicology, University of Louisville, Rm 417, CTRB 505, S. Hancock St., Louisville, KY 40202, USA
| | - Daniel B. Nichols
- Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103, USA,Department of Biological Sciences, Seton Hall University, South Orange, NJ 07079, USA
| | - Diego F. Calvisi
- Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy
| | - Neerja Kaushik-Basu
- Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103, USA,To whom correspondence should be addressed: ,
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Hepatitis C Virus Indirectly Disrupts DNA Damage-Induced p53 Responses by Activating Protein Kinase R. mBio 2017; 8:mBio.00121-17. [PMID: 28442604 PMCID: PMC5405228 DOI: 10.1128/mbio.00121-17] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Many DNA tumor viruses promote cellular transformation by inactivating the critically important tumor suppressor protein p53. In contrast, it is not known whether p53 function is disrupted by hepatitis C virus (HCV), a unique, oncogenic RNA virus that is the leading infectious cause of liver cancer in many regions of the world. Here we show that HCV-permissive, liver-derived HepG2 cells engineered to constitutively express microRNA-122 (HepG2/miR-122 cells) have normal p53-mediated responses to DNA damage and that HCV replication in these cells potently suppresses p53 responses to etoposide, an inducer of DNA damage, or nutlin-3, an inhibitor of p53 degradation pathways. Upregulation of p53-dependent targets is consequently repressed within HCV-infected cells, with potential consequences for cell survival. Despite this, p53 function is not disrupted by overexpression of the complete HCV polyprotein, suggesting that altered p53 function may result from the host response to viral RNA replication intermediates. Clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-mediated ablation of double-stranded RNA (dsRNA)-activated protein kinase R (PKR) restored p53 responses while boosting HCV replication, showing that p53 inhibition results directly from viral activation of PKR. The hepatocellular abundance of phosphorylated PKR is elevated in HCV-infected chimpanzees, suggesting that PKR activation and consequent p53 inhibition accompany HCV infection in vivo. These findings reveal a feature of the host response to HCV infection that may contribute to hepatocellular carcinogenesis. Chronic infection with hepatitis C virus (HCV) is the leading cause of liver cancer in most developed nations. However, the mechanisms whereby HCV infection promotes carcinogenesis remain unclear. Here, we demonstrate that HCV infection inhibits the activation of p53 following DNA damage. Contrary to previous reports, HCV protein expression is insufficient to inhibit p53. Rather, p53 inhibition is mediated by cellular protein kinase R (PKR), which is activated by HCV RNA replication and subsequently suppresses global protein synthesis. These results redefine our understanding of how HCV infection influences p53 function. We speculate that persistent disruption of p53-mediated DNA damage responses may contribute to hepatocellular carcinogenesis in chronically infected individuals.
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Zhou Y, Zhao Y, Gao Y, Hu W, Qu Y, Lou N, Zhu Y, Zhang X, Yang H. Hepatitis C virus NS3 protein enhances hepatocellular carcinoma cell invasion by promoting PPM1A ubiquitination and degradation. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2017; 36:42. [PMID: 28283039 PMCID: PMC5345236 DOI: 10.1186/s13046-017-0510-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 02/23/2017] [Indexed: 01/03/2023]
Abstract
Background Growing evidence suggests that hepatitis C virus (HCV) contributes to hepatocellular carcinoma (HCC) by directly modulating oncogenic signaling pathways. Protein phosphatase magnesium-dependent 1A (PPM1A) has recently emerged as an important tumor suppressor as it can block a range of tumor-centric signaling pathways through protein dephosphorylation. However, the role and regulatory mechanisms of PPM1A in HCV-infected cells have not been reported. Methods Total, cytoplasmic, and nuclear PPM1A protein after HCV infection or overexpression of HCV nonstructural protein 3 (NS3) were detected by western blotting. The expression of PPM1A in normal liver and HCV-related HCC tissues was quantified by immunohistochemistry. The effects of HCV infection and NS3 expression on the PPM1A protein level were systematically analyzed, and the ubiquitination level of PPM1A was determined by precipitation with anti-PPM1A and immunoblotting with either anti-ubiquitin or anti-PPM1A antibody. Finally, the roles of NS3 and PPM1A in hepatoma cell migration and invasion were assessed by wound healing and transwell assays, respectively. Results HCV infection and replication decreased PPM1A abundance, mediated by NS3, in hepatoma cells. Compared to normal liver tissues, the expression of PPM1A was significantly decreased in the HCC tumor tissues and adjacent non-tumor tissues. NS3 directly interacted with PPM1A to promote PPM1A ubiquitination and degradation, which was dependent on its protease domain. Blockade of PPM1A through small interfering RNA significantly promoted HCC cell migration, invasion, and epithelial mesenchymal transition (EMT), which were further intensified by TGF-β1 stimulation, in vitro. Furthermore, restoration of PPM1A abrogated the NS3-mediated promotion of HCC migration and invasion to a great extent, which was dependent on its protein phosphatase function. Conclusions Our findings demonstrate that the HCV protein NS3 can downregulate PPM1A by promoting its ubiquitination and proteasomal degradation, which might contribute to the migration and invasion of hepatoma cells and may represent a new strategy of HCV in carcinogenesis. Electronic supplementary material The online version of this article (doi:10.1186/s13046-017-0510-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yali Zhou
- Department of Pathogenic Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Yan Zhao
- Department of Pathogenic Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Yaoying Gao
- Department of Pathogenic Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Wenjun Hu
- Department of Pathogenic Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Yan Qu
- Department of Pathogenic Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Ning Lou
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei Province, China
| | - Ying Zhu
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430072, Hubei Province, China
| | - Xiaoping Zhang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei Province, China.
| | - Hongmei Yang
- Department of Pathogenic Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.
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