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Mimura S, Morishita A, Oura K, Takuma K, Nakahara M, Tadokoro T, Fujita K, Tani J, Kobara H. Galectins and Liver Diseases. Int J Mol Sci 2025; 26:790. [PMID: 39859504 PMCID: PMC11766161 DOI: 10.3390/ijms26020790] [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: 12/18/2024] [Revised: 01/13/2025] [Accepted: 01/15/2025] [Indexed: 01/27/2025] Open
Abstract
Galectins are widely distributed throughout the animal kingdom, from marine sponges to mammals. Galectins are a family of soluble lectins that specifically recognize β-galactoside-containing glycans and are categorized into three subgroups based on the number and function of their carbohydrate recognition domains (CRDs). The interaction of galectins with specific ligands mediates a wide range of biological activities, depending on the cell type, tissue context, expression levels of individual galectin, and receptor involvement. Galectins affect various immune cell processes through both intracellular and extracellular mechanisms and play roles in processes, such as apoptosis, angiogenesis, and fibrosis. Their importance has increased in recent years because they are recognized as biomarkers, therapeutic agents, and drug targets, with many other applications in conditions such as cardiovascular diseases and cancer. However, little is known about the involvement of galectins in liver diseases. Here, we review the functions of various galectins and evaluate their roles in liver diseases.
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Affiliation(s)
- Shima Mimura
- Departments of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita-gun, Takamatsu 761-0793, Kagawa Prefecture, Japan
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2
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Jasim SA, Salahdin OD, Malathi H, Sharma N, Rab SO, Aminov Z, Pramanik A, Mohammed IH, Jawad MA, Gabel BC. Targeting Hepatic Cancer Stem Cells (CSCs) and Related Drug Resistance by Small Interfering RNA (siRNA). Cell Biochem Biophys 2024; 82:3031-3051. [PMID: 39060914 DOI: 10.1007/s12013-024-01423-5] [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] [Accepted: 07/10/2024] [Indexed: 07/28/2024]
Abstract
Tumor recurrence after curative therapy and hepatocellular carcinoma (HCC) cells' resistance to conventional therapies is the reasons for the worse clinical results of HCC patients. A tiny population of cancer cells with a strong potential for self-renewal, differentiation, and tumorigenesis has been identified as cancer stem cells (CSCs). The discovery of CSC surface markers and the separation of CSC subpopulations from HCC cells have been made possible by recent developments in the study of hepatic (liver) CSCs. Hepatic CSC surface markers include epithelial cell adhesion molecules (EpCAM), CD133, CD90, CD13, CD44, OV-6, ALDH, and K19. CSCs have a significant influence on the development of cancer, invasiveness, self-renewal, metastasis, and drug resistance in HCC, and thus provide a therapeutic chance to treat HCC and avoid its recurrence. Therefore, it is essential to develop treatment approaches that specifically and effectively target hepatic stem cells. Given this, one potential treatment approach is to use particular small interfering RNA (siRNA) to target CSC, disrupting their behavior and microenvironment as well as changing their epigenetic state. The characteristics of CSCs in HCC are outlined in this study, along with new treatment approaches based on siRNA that may be used to target hepatic CSCs and overcome HCC resistance to traditional therapies.
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Affiliation(s)
| | | | - H Malathi
- Department of Biotechnology and Genetics, School of Sciences, JAIN (Deemed to be University, Bangalore, Karnataka, India
| | - Neha Sharma
- Chandigarh Pharmacy College, Chandigarh group of Colleges, Jhanjeri, 140307, Mohali, Punjab, India
| | - Safia Obaidur Rab
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Zafar Aminov
- Department of Public Health and Healthcare management, Samarkand State Medical University, 18 Amir Temur Street, Samarkand, Uzbekistan
| | - Atreyi Pramanik
- School of Applied and Life Sciences, Division of Research and Innovation, Uttaranchal University, Dehradun, Uttarakhand, India
| | - Israa Hussein Mohammed
- College of nursing, National University of Science and Technology, Nasiriyah, Dhi Qar, Iraq
| | - Mohammed Abed Jawad
- Department of Medical Laboratories Technology, Al-Nisour University College, Baghdad, Iraq
| | - Benien C Gabel
- Medical laboratory technique college, the Islamic University, Najaf, Iraq
- Medical laboratory technique college, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Medical laboratory technique college, the Islamic University of Babylon, Babylon, Iraq
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3
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Zhang M, Liu C, Li Y, Li H, Zhang W, Liu J, Wang L, Sun C. Galectin-9 in cancer therapy: from immune checkpoint ligand to promising therapeutic target. Front Cell Dev Biol 2024; 11:1332205. [PMID: 38264357 PMCID: PMC10803597 DOI: 10.3389/fcell.2023.1332205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 12/22/2023] [Indexed: 01/25/2024] Open
Abstract
Galectin-9 (Gal-9) is a vital member of the galectin family, functioning as a multi-subtype galactose lectin with diverse biological roles. Recent research has revealed that Gal-9's interaction with tumors is an independent factor that influences tumor progression. Furthermore, Gal-9 in the immune microenvironment cross-talks with tumor-associated immune cells, informing the clarification of Gal-9's identity as an immune checkpoint. A thorough investigation into Gal-9's role in various cancer types and its interaction with the immune microenvironment could yield novel strategies for subsequent targeted immunotherapy. This review focuses on the latest advances in understanding the direct and indirect cross-talk between Gal-9 and hematologic malignancies, in addition to solid tumors. In addition, we discuss the prospects of Gal-9 in tumor immunotherapy, including its cross-talk with the ligand TIM-3 and its potential in immune-combination therapy.
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Affiliation(s)
- Minpu Zhang
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Cun Liu
- College of Traditional Chinese Medicine, Weifang Medical University, Weifang, China
| | - Ye Li
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China
| | - Huayao Li
- College of Traditional Chinese Medicine, Weifang Medical University, Weifang, China
| | - Wenfeng Zhang
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China
| | - Jingyang Liu
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China
| | - Liquan Wang
- Department of Thyroid and Breast Surgery, Weifang People’s Hospital, Weifang, China
| | - Changgang Sun
- College of Traditional Chinese Medicine, Weifang Medical University, Weifang, China
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, China
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Faghihkhorasani A, Dalvand A, Derafsh E, Tavakoli F, Younis NK, Yasamineh S, Gholizadeh O, Shokri P. The role of oncolytic virotherapy and viral oncogenes in the cancer stem cells: a review of virus in cancer stem cells. Cancer Cell Int 2023; 23:250. [PMID: 37880659 PMCID: PMC10599042 DOI: 10.1186/s12935-023-03099-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 10/13/2023] [Indexed: 10/27/2023] Open
Abstract
Cancer Stem Cells (CSCs) are the main "seeds" for the initiation, growth, metastasis, and recurrence of tumors. According to many studies, several viral infections, including the human papillomaviruses, hepatitis B virus, Epstein-Barr virus, and hepatitis C virus, promote the aggressiveness of cancer by encouraging the development of CSC features. Therefore, a better method for the targeted elimination of CSCs and knowledge of their regulatory mechanisms in human carcinogenesis may lead to the development of a future tool for the management and treatment of cancer. Oncolytic viruses (OVs), which include the herpes virus, adenovirus, vaccinia, and reovirus, are also a new class of cancer therapeutics that have favorable properties such as selective replication in tumor cells, delivery of numerous eukaryotic transgene payloads, induction of immunogenic cell death and promotion of antitumor immunity, as well as a tolerable safety profile that essentially differs from that of other cancer therapeutics. The effects of viral infection on the development of CSCs and the suppression of CSCs by OV therapy were examined in this paper. The purpose of this review is to investigate the dual role of viruses in CSCs (oncolytic virotherapy and viral oncogenes).
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Affiliation(s)
| | - Alaleh Dalvand
- Tehran Medical Branch, Islamic Azad University of Medical Sciences, Tehran, Iran
| | - Ehsan Derafsh
- Department of Basic Medical Science, Windsor University School of Medicine, Brighton's Estate, Cayton, St. Kitts And Nevis
| | - Farnaz Tavakoli
- Nephrology and Transplantation Ward, Shariati Hospital Tehran University of Medical Sciences, Tehran, Iran
| | | | - Saman Yasamineh
- Young Researchers and Elite Club, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | | | - Pooria Shokri
- Department of Medical Science, Faculty of Medical Science, Arak University of Medical Sciences, Arak, Iran.
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Ilakiyalakshmi M, Arumugam Napoleon A. Review on recent development of quinoline for anticancer activities. ARAB J CHEM 2022. [DOI: 10.1016/j.arabjc.2022.104168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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Feitelson MA, Arzumanyan A, Spector I, Medhat A. Hepatitis B x (HBx) as a Component of a Functional Cure for Chronic Hepatitis B. Biomedicines 2022; 10:biomedicines10092210. [PMID: 36140311 PMCID: PMC9496119 DOI: 10.3390/biomedicines10092210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/22/2022] [Accepted: 09/02/2022] [Indexed: 11/20/2022] Open
Abstract
Patients who are carriers of the hepatitis B virus (HBV) are at high risk of chronic liver disease (CLD) which proceeds from hepatitis, to fibrosis, cirrhosis and to hepatocellular carcinoma (HCC). The hepatitis B-encoded X antigen, HBx, promotes virus gene expression and replication, protects infected hepatocytes from immunological destruction, and promotes the development of CLD and HCC. For virus replication, HBx regulates covalently closed circular (ccc) HBV DNA transcription, while for CLD, HBx triggers cellular oxidative stress, in part, by triggering mitochondrial damage that stimulates innate immunity. Constitutive activation of NF-κB by HBx transcriptionally activates pro-inflammatory genes, resulting in hepatocellular destruction, regeneration, and increased integration of the HBx gene into the host genome. NF-κB is also hepatoprotective, which sustains the survival of infected cells. Multiple therapeutic approaches include direct-acting anti-viral compounds and immune-stimulating drugs, but functional cures were not achieved, in part, because none were yet devised to target HBx. In addition, many patients with cirrhosis or HCC have little or no virus replication, but continue to express HBx from integrated templates, suggesting that HBx contributes to the pathogenesis of CLD. Blocking HBx activity will, therefore, impact multiple aspects of the host–virus relationship that are relevant to achieving a functional cure.
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Affiliation(s)
- Mark A. Feitelson
- Room 409 Biolife Building, Department of Biology, College of Science and Technology, Temple University, 1900 N. 12th Street, Philadelphia, PA 19122, USA
- Correspondence: ; Tel.: +1-215-204-8434
| | - Alla Arzumanyan
- Room 409 Biolife Building, Department of Biology, College of Science and Technology, Temple University, 1900 N. 12th Street, Philadelphia, PA 19122, USA
| | | | - Arvin Medhat
- Department of Molecular Cell Biology, Islamic Azad University Tehran North Branch, Tehran 1975933411, Iran
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Lin H, Peng J, Zhu T, Xiong M, Zhang R, Lei L. Exosomal miR-4800-3p Aggravates the Progression of Hepatocellular Carcinoma via Regulating the Hippo Signaling Pathway by Targeting STK25. Front Oncol 2022; 12:759864. [PMID: 35756606 PMCID: PMC9214204 DOI: 10.3389/fonc.2022.759864] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 05/17/2022] [Indexed: 12/12/2022] Open
Abstract
Background Emerging evidence has shown that exosome microRNAs (miRNAs) regulate the development of hepatocellular carcinoma (HCC). Here, the influences of miR-4800-3p on the progression of HCC were explored. Materials and Methods The expression of miR-4800-3p in the exosome derived by transforming growth factor beta 1 (TGF-β1)-treated HCC cells and the serum exosome isolated from HCC patients were identified by real-time PCR. The effects of TGF-β1 and the influences of Huh7-secreted exosomes and the effects of miR-4800-3p combined with/without STK25 on cell functions were explored using the EdU assay cloning experiments, wound healing assay, and Transwell assay. The corresponding molecular mechanisms were further detected using Western blot and real-time PCR assays. The combination of miR-4800-3p and STK25 was verified by the dual-luciferase and RNA pulldown assays. The influences of miR-4800-3p on the growth and epithelial–mesenchymal transformation (EMT) of implanted tumors were tested in vivo and further confirmed by Western blot. Results The miR-4800-3p expression was highly expressed in both exosomes derived by TGF-β1-treated HCC cells and the serum exosomes of HCC patients. In the cases of treatment with both Huh7-derived exosomes, the level of miR-4800-3p expression was highest, and the treatment of TGF-β1 could greatly promote the proliferation, stemness, migration, and invasion of HCC cells via upregulating the markers of stemness and EMT, including CD44, CD133, OCT4, N-cadherin, E-cadherin, and ZO-1. Similar results could be obtained when miR-4800-3p was overexpressed in HCC cells. Furthermore, downregulation of STK25 expression, a direct target gene of miR-4800-3p, could greatly rescue the malignant biological behaviors aggravated by overexpression of miR-4800-3p. This was achieved by suppressing the expression of CD44, CD133, OCT4, N-cadherin, and PCNA and activating the Hippo pathway while increasing E-cadherin and ZO-1. Similar results were also obtained in vivo that knockdown of miR-4800-3p expression suppressed tumor growth induced by Huh7-derived exosomes by mediating the EMT markers and the Hippo signaling pathway. Conclusion Exosomal miR-4800-3p could accelerate HCC development by regulating the Hippo signal by targeting STK25, which could be used as a new therapeutic target for HCC treatment.
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Affiliation(s)
- Haoming Lin
- Department of HBP Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jicai Peng
- Department of Emergency, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Taifeng Zhu
- Department of HBP Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Meihong Xiong
- Department of HBP Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Rui Zhang
- Department of HBP Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Liming Lei
- Department of Intensive Care Unit of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Laboratory of South China Structural Heart Disease, Guangzhou, China
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Stella L, Santopaolo F, Gasbarrini A, Pompili M, Ponziani FR. Viral hepatitis and hepatocellular carcinoma: From molecular pathways to the role of clinical surveillance and antiviral treatment. World J Gastroenterol 2022; 28:2251-2281. [PMID: 35800182 PMCID: PMC9185215 DOI: 10.3748/wjg.v28.i21.2251] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 12/08/2021] [Accepted: 04/26/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a global health challenge. Due to the high prevalence in low-income countries, hepatitis B virus (HBV) and hepatitis C virus infections remain the main risk factors for HCC occurrence, despite the increasing frequencies of non-viral etiologies. In addition, hepatitis D virus coinfection increases the oncogenic risk in patients with HBV infection. The molecular processes underlying HCC development are complex and various, either independent from liver disease etiology or etiology-related. The reciprocal interlinkage among non-viral and viral risk factors, the damaged cellular microenvironment, the dysregulation of the immune system and the alteration of gut-liver-axis are known to participate in liver cancer induction and progression. Oncogenic mechanisms and pathways change throughout the natural history of viral hepatitis with the worsening of liver fibrosis. The high risk of cancer incidence in chronic viral hepatitis infected patients compared to other liver disease etiologies makes it necessary to implement a proper surveillance, both through clinical-biochemical scores and periodic ultrasound assessment. This review aims to outline viral and microenvironmental factors contributing to HCC occurrence in patients with chronic viral hepatitis and to point out the importance of surveillance programs recommended by international guidelines to promote early diagnosis of HCC.
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Affiliation(s)
- Leonardo Stella
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Maurizio Pompili
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
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Sun J, Wu G, Pastor F, Rahman N, Wang WH, Zhang Z, Merle P, Hui L, Salvetti A, Durantel D, Yang D, Andrisani O. RNA helicase DDX5 enables STAT1 mRNA translation and interferon signalling in hepatitis B virus replicating hepatocytes. Gut 2022; 71:991-1005. [PMID: 34021034 PMCID: PMC8606016 DOI: 10.1136/gutjnl-2020-323126] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Accepted: 05/09/2021] [Indexed: 12/18/2022]
Abstract
OBJECTIVE RNA helicase DDX5 is downregulated during HBV replication and poor prognosis HBV-related hepatocellular carcinoma (HCC). The objective of this study is to investigate the role of DDX5 in interferon (IFN) signalling. We provide evidence of a novel mechanism involving DDX5 that enables translation of transcription factor STAT1 mediating the IFN response. DESIGN AND RESULTS Molecular, pharmacological and biophysical assays were used together with cellular models of HBV replication, HCC cell lines and liver tumours. We demonstrate that DDX5 regulates STAT1 mRNA translation by resolving a G-quadruplex (rG4) RNA structure, proximal to the 5' end of STAT1 5'UTR. We employed luciferase reporter assays comparing wild type (WT) versus mutant rG4 sequence, rG4-stabilising compounds, CRISPR/Cas9 editing of the STAT1-rG4 sequence and circular dichroism determination of the rG4 structure. STAT1-rG4 edited cell lines were resistant to the effect of rG4-stabilising compounds in response to IFN-α, while HCC cell lines expressing low DDX5 exhibited reduced IFN response. Ribonucleoprotein and electrophoretic mobility assays demonstrated direct and selective binding of RNA helicase-active DDX5 to the WT STAT1-rG4 sequence. Immunohistochemistry of normal liver and liver tumours demonstrated that absence of DDX5 corresponded to absence of STAT1. Significantly, knockdown of DDX5 in HBV infected HepaRG cells reduced the anti-viral effect of IFN-α. CONCLUSION RNA helicase DDX5 resolves a G-quadruplex structure in 5'UTR of STAT1 mRNA, enabling STAT1 translation. We propose that DDX5 is a key regulator of the dynamic range of IFN response during innate immunity and adjuvant IFN-α therapy.
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Affiliation(s)
- Jiazeng Sun
- Basic Medical Sciences, Purdue University, West Lafayette, Indiana, USA
| | - Guanhui Wu
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana, USA
| | - Florentin Pastor
- International Center for Infectiology Research (CIRI), INSERM U1111-CNRS UMR5308, Lyon, France
| | - Naimur Rahman
- Basic Medical Sciences, Purdue University System, West Lafayette, Indiana, USA
| | - Wen-Hung Wang
- Gene Editing Core, Bindley Biosciences Center, Purdue University, West Lafayette, Indiana, USA
| | - Zhengtao Zhang
- Department of Biochemistry and Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai, China
| | - Philippe Merle
- Service d'Hépatologie, Hôpital de La Croix-Rousse Centre Livet, Lyon, Rhône-Alpes, France
| | - Lijian Hui
- Department of Biochemistry and Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai, China
| | - Anna Salvetti
- International Center for Infectiology Research (CIRI), INSERM U1111-CNRS UMR5308, Lyon, France
| | - David Durantel
- INSERM U1111-CNRS UMR5308 International Center for Infectiology Research (CIRI), Lyon, France
| | - Danzhou Yang
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana, USA
| | - Ourania Andrisani
- Basic Medical Sciences, Purdue University, West Lafayette, Indiana, USA
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Xiao Y, Cao J, Zhang Z, Zeng C, Ou G, Shi J, Liu Z, Li Y, Deng J, Xu Y, Zhang W, Li J, Li T, Zhuang H, Lu S, Xiang K. Hepatitis B Virus Pregenomic RNA Reflecting Viral Replication in Distal Non-tumor Tissues as a Determinant of the Stemness and Recurrence of Hepatocellular Carcinoma. Front Microbiol 2022; 13:830741. [PMID: 35464922 PMCID: PMC9021960 DOI: 10.3389/fmicb.2022.830741] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 02/22/2022] [Indexed: 11/24/2022] Open
Abstract
Background The existence of hepatic cancer stem cells (CSCs) contributes to chemotherapy resistance and cancer recurrence after treatment or surgery. However, very little is known about the hepatitis B virus (HBV) replication and its relationship with the stemness of hepatocellular carcinoma (HCC) in HBV-related HCC patients. Methods We collected tumor tissues (T), matched adjacent non-tumor tissues (NT), and distal non-tumor tissues (FNT) from 55 HCC patients for analysis. Results We found HBV DNA levels were higher in T samples than NT and FNT samples, but HBV pgRNA and total RNA expressed lower in T samples. HBV pgRNA and total RNA correlate to HBV DNA among the T, NT, and FNT samples. Further evidence for HBV replication in T samples was provided by HBV S, reverse transcriptase, and X genes sequencing, showing that HBV sequences and genotypes differed between T and matched NT and FNT samples. HBV pgRNA and total RNA showed more frequent significant correlations with CSC markers in NT samples in HBsAg-positive patients. The markers CD133 and OCT4 expressed higher in FNT samples, and HBV replication marker of pgRNA levels was significantly positively correlated to these two markers only in FNT samples. The detection of pgRNA and OCT4 in FNT was correlated to the recurrence of HCC in the resection of HCC patients. Analysis of HBV receptor, sodium taurocholate co-transporting polypeptide (NTCP), showed that NTCP was correlated negatively to CSC markers in T samples, except for the CD44. Conclusion HBV replication may present in HCC with a weak transcriptomic signature. Moreover, the expression level of HBV pgRNA in distal non-tumor tissues is a sensitive marker for HBV replication and prognosis, which is associated with CSC-related markers especially with OCT4 in distal non-tumor tissues and recurrence of HCC in HBV-related HCC patients.
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Affiliation(s)
- Yiwei Xiao
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Junning Cao
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA Genera Hospital, Beijing, China
| | - Ze Zhang
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA Genera Hospital, Beijing, China
| | - Chaoting Zeng
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA Genera Hospital, Beijing, China
| | - Guomin Ou
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Jihang Shi
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA Genera Hospital, Beijing, China
| | - Zhixiu Liu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.,Division of Pathology and Laboratory Medicine, Hebei Yanda Lu Daopei Hospital, Langfang, China
| | - Yi Li
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Juan Deng
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Yinzhe Xu
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA Genera Hospital, Beijing, China
| | - Wenwen Zhang
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA Genera Hospital, Beijing, China
| | - Jie Li
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Tong Li
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.,Peking University-YHLO Joint Laboratory for Molecular Diagnostic of Infectious Disease, Peking University, Beijing, China
| | - Hui Zhuang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.,Peking University-YHLO Joint Laboratory for Molecular Diagnostic of Infectious Disease, Peking University, Beijing, China
| | - Shichun Lu
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA Genera Hospital, Beijing, China
| | - Kuanhui Xiang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.,Peking University-YHLO Joint Laboratory for Molecular Diagnostic of Infectious Disease, Peking University, Beijing, China
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11
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Lan W, Wang Y, Zhou Z, Sun X, Zhang Y, Zhang F. Metabolic Regulation of Hepatitis B Virus Infection in HBV-Transgenic Mice. Metabolites 2022; 12:287. [PMID: 35448475 PMCID: PMC9031567 DOI: 10.3390/metabo12040287] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/17/2022] [Accepted: 03/23/2022] [Indexed: 11/20/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a worldwide health burden. Metabolomics analysis has revealed HBV-induced metabolism dysregulation in liver tissues and hepatocytes. However, as an infectious disease, the tissue-specific landscape of metabolic profiles of HBV infection remains unclear. To fill this gap, we applied untargeted nuclear magnetic resonance (NMR) metabolomic analysis of the heart, liver, spleen, lung, kidney, pancreas, and intestine (duodenum, jejunum, ileum) in HBV-transgenic mice and their wild-type littermates. Strikingly, we found systemic metabolic alterations induced by HBV in liver and extrahepatic organs. Significant changes in metabolites have been observed in most tissues of HBV-transgenic mice, except for ileum. The metabolic changes may provide novel therapeutic targets for the treatment of HBV infection. Moreover, tissue-specific metabolic profiles could speed up the study of HBV induced systemic metabolic reprogramming, which could help follow the progression of HBV infection and explain the underlying pathogenesis.
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Affiliation(s)
- Wenning Lan
- Key Laboratory of Gastrointestinal Cancer, Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China;
- Xiamen Key Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen Institute of Rare Earth Materials, Haixi Institute, Chinese Academy of Sciences, Xiamen 361021, China
- Ganjiang Innovation Academy, Chinese Academy of Sciences, Ganzhou 341001, China
| | - Yang Wang
- Institute of Immunotherapy, Fujian Medical University, Fuzhou 350122, China;
| | - Zixiong Zhou
- Department of Pathology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China;
| | - Xia Sun
- Fujian Science and Technology Innovation Laboratory for Optoelectronic Information of China, Fuzhou 350108, China;
| | - Yun Zhang
- Xiamen Key Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen Institute of Rare Earth Materials, Haixi Institute, Chinese Academy of Sciences, Xiamen 361021, China
- Fujian Science and Technology Innovation Laboratory for Optoelectronic Information of China, Fuzhou 350108, China;
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China
| | - Fangrong Zhang
- Key Laboratory of Gastrointestinal Cancer, Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China;
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou 350122, China
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12
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Panasiuk YV, Vlasenko NV, Churilova NS, Klushkina VV, Dubodelov DV, Kudryavtseva EN, Korabelnikova MI, Rodionova ZS, Semenenko TA, Kuzin SN, Akimkin VG. [Modern views on the role of X gene of the hepatitis B virus (Hepadnaviridae: Orthohepadnavirus: Hepatitis B virus) in the pathogenesis of the infection it causes]. Vopr Virusol 2022; 67:7-17. [PMID: 35293184 DOI: 10.36233/0507-4088-84] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 03/15/2022] [Indexed: 11/05/2022]
Abstract
The review presents information on the role of hepatitis B virus (Hepadnaviridae: Orthohepadnavirus: Hepatitis B virus) (HBV) X gene and the protein it encodes (X protein) in the pathogenesis of viral hepatitis B. The evolution of HBV from primordial to the modern version of hepadnaviruses (Hepadnaviridae), is outlined as a process that began about 407 million years ago and continues to the present. The results of scientific works of foreign researchers on the variety of the influence of X protein on the infectious process and its role in the mechanisms of carcinogenesis are summarized. The differences in the effect of the X protein on the course of the disease in patients of different ethnic groups with regard to HBV genotypes are described. The significance of determining the genetic variability of X gene as a fundamental characteristic of the virus that has significance for the assessment of risks of hepatocellular carcinoma (HCC) spread among the population of the Russian Federation is discussed.
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Affiliation(s)
- Y V Panasiuk
- FSBI «Central Research Institute for Epidemiology» of the Federal Service for Supervision of Consumer Rights Protection and Human Wellbeing (Rospotrebnadzor)
| | - N V Vlasenko
- FSBI «Central Research Institute for Epidemiology» of the Federal Service for Supervision of Consumer Rights Protection and Human Wellbeing (Rospotrebnadzor)
| | - N S Churilova
- FSBI «Central Research Institute for Epidemiology» of the Federal Service for Supervision of Consumer Rights Protection and Human Wellbeing (Rospotrebnadzor)
| | - V V Klushkina
- FSBI «Central Research Institute for Epidemiology» of the Federal Service for Supervision of Consumer Rights Protection and Human Wellbeing (Rospotrebnadzor)
| | - D V Dubodelov
- FSBI «Central Research Institute for Epidemiology» of the Federal Service for Supervision of Consumer Rights Protection and Human Wellbeing (Rospotrebnadzor)
| | - E N Kudryavtseva
- FSBI «Central Research Institute for Epidemiology» of the Federal Service for Supervision of Consumer Rights Protection and Human Wellbeing (Rospotrebnadzor)
| | - M I Korabelnikova
- FSBI «Central Research Institute for Epidemiology» of the Federal Service for Supervision of Consumer Rights Protection and Human Wellbeing (Rospotrebnadzor)
| | - Z S Rodionova
- FSBI «Central Research Institute for Epidemiology» of the Federal Service for Supervision of Consumer Rights Protection and Human Wellbeing (Rospotrebnadzor)
| | - T A Semenenko
- FSBI «National Research Centre for Epidemiology and Microbiology named after the honorary academician N.F. Gamaleya» of the Ministry of Health of Russia
| | - S N Kuzin
- FSBI «Central Research Institute for Epidemiology» of the Federal Service for Supervision of Consumer Rights Protection and Human Wellbeing (Rospotrebnadzor)
| | - V G Akimkin
- FSBI «Central Research Institute for Epidemiology» of the Federal Service for Supervision of Consumer Rights Protection and Human Wellbeing (Rospotrebnadzor)
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13
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Jiao J, Jiao D, Yang F, Zhang J, Li Y, Han D, Zhang K, Wang Y, Zhang R, Yang AG, Wang A, Wen W, Qin W. Galectin-9 expression predicts poor prognosis in hepatitis B virus-associated hepatocellular carcinoma. Aging (Albany NY) 2022; 14:1879-1890. [PMID: 35202002 PMCID: PMC8908941 DOI: 10.18632/aging.203909] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 02/14/2022] [Indexed: 12/24/2022]
Abstract
Objectives: The aim of this study was to explore the expression of Galectin-9 in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC), evaluate its clinicopathological significance, and investigate whether Galecin-9 expression has prognostic value in HBV-associated HCC. Methods: Immunohistochemistry staining was performed to examine the expression of Galectin-9 in paraffin-embedded tissues from 140 cases of HBV-associated HCC specimens. The association between Gal-9 expression, clinicopathological features and prognosis was analyzed by Kaplan-Meier method, log-rank test and Cox regression analysis. Dual immunofluorescence (IF) staining was performed to identify the cell types that have positive Gal-9 expression. Results: Among the 140 cases of HBV-associated HCC, 39 (27.9%) cases showed high Gal-9 expression (score≥6), 21 (15%) cases showed moderate Gal-9 expression (6>score≥3), 33 (23.6%) cases showed weak Gal-9 expression (3>score>0), and 47 (33.6%) cases had no detectable Gal-9 expression (score=0). Positive Gal-9 expression (score>0) was associated with lymph node metastasis (P=0.029), Ki-67 proliferation index (P=0.009) and poor prognosis. Univariate and multivariate analyses showed that Gal-9 expression could be used as an independent prognostic marker for HBV-associated HCC. Dual IF staining indicated that Gal-9 was mainly expressed in CD68+CD163+ Kupffer cells (KCs) in HBV-associated HCC. Conclusions: Gal-9 was specifically expressed in certain HBV-associated HCC. Positive Gal-9 expression was significantly associated with poor prognosis, and Gal-9 could be used as a prognostic marker in HBV-associated HCC. Specific expression of Gal-9 on KCs indicated it may have immunosuppressive function in HBV-associated HCC.
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Affiliation(s)
- Jianhua Jiao
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Dian Jiao
- Department of Urology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Fa Yang
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Jingliang Zhang
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.,Department of Health Services, Health Service Training Base, Fourth Military Medical University, Xi'an 710032, China
| | - Yu Li
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Donghui Han
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Keying Zhang
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Yingmei Wang
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Rui Zhang
- State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an 710032, China
| | - An-Gang Yang
- State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an 710032, China
| | - Anhui Wang
- Department of Epidemiology, School of Military Preventive Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Weihong Wen
- Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710072, China
| | - Weijun Qin
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
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14
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Wang BR, Chu DX, Cheng MY, Jin Y, Luo HG, Li N. Progress of HOTAIR-microRNA in hepatocellular carcinoma. Hered Cancer Clin Pract 2022; 20:4. [PMID: 35093153 PMCID: PMC8800341 DOI: 10.1186/s13053-022-00210-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 01/13/2022] [Indexed: 01/02/2023] Open
Abstract
The Hox transcript antisense intergenic RNA (HOTAIR) has been identified as a tumor gene, and its expression in HCC is significantly increased. HOTAIR is associated with the proliferation, invasion, metastasis and poor prognosis of HCC. In addition, HOTAIR can also regulate the expression and function of microRNA by recruiting the polycomb repressive complex 2 (PRC2) and competitive adsorption, thus promoting the occurrence and development of HCC. In this review, we discussed the two mechanisms of HOTAIR regulating miRNA through direct binding miRNA and indirect regulation, and emphasized the role of HOTAIR in HCC through miRNA, explained the regulatory pathway of HOTAIR-miRNA-mRNA and introduced the role of this pathway in HCC proliferation, drug resistance, invasion and metastasis.
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Affiliation(s)
- Bing-Rong Wang
- Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, Jilin, 130012, People's Republic of China
- The Basic Medical College, Jilin Medical University, Jilin, 132013, China
| | - Dong-Xia Chu
- Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, Jilin, 130012, People's Republic of China
- The Basic Medical College, Jilin Medical University, Jilin, 132013, China
| | - Mei-Yu Cheng
- Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, Jilin, 130012, People's Republic of China
- The Basic Medical College, Jilin Medical University, Jilin, 132013, China
| | - Yu Jin
- Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, Jilin, 130012, People's Republic of China
- The Basic Medical College, Jilin Medical University, Jilin, 132013, China
| | - Hao-Ge Luo
- Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, Jilin, 130012, People's Republic of China
- The Basic Medical College, Jilin Medical University, Jilin, 132013, China
| | - Na Li
- Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, Jilin, 130012, People's Republic of China.
- The Basic Medical College, Jilin Medical University, Jilin, 132013, China.
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15
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Barathan M, Riazalhosseini B, Iyadorai T, Vellasamy KM, Vadivelu J, Chang LY, Zulpa AK, Larsson M, Shankar EM, Mohamed R. Comparative expression of pro-inflammatory and apoptotic biosignatures in chronic HBV-infected patients with and without liver cirrhosis. Microb Pathog 2021; 161:105231. [PMID: 34619310 DOI: 10.1016/j.micpath.2021.105231] [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: 06/16/2021] [Revised: 09/22/2021] [Accepted: 10/01/2021] [Indexed: 11/30/2022]
Abstract
The interplay of immune mediators is paramount to optimal host anti-viral immune responses, especially against chronic hepatitis B virus (HBV) infection. Here, we investigated the dynamic changes in host immune responses in chronic HBV-infected individuals with and without liver cirrhosis by examining the signatures of apoptosis and plasma levels of pro-inflammatory cytokines, chemokines, and cytotoxic proteins. A total of 40 chronic HBV patients with and without liver cirrhosis were studied for plasma levels of immune mediators, and signatures of apoptosis in peripheral blood mononuclear cells (PBMCs). The intracellular concentrations of reactive oxygen species (ROS) in patients with chronic HBV with liver cirrhosis was relatively higher as compared to chronic HBV patients. The onset of apoptosis was sustained due to ongoing liver inflammation in concert with plasma TNF-α and IL-6 levels. Plasma VEGF was upregulated among chronic HBV patients with liver cirrhosis, whereas CCL2, CCL5 and granzyme B levels were down-regulated. High levels of ROS, IL-6 and TNF-α correlated with ongoing inflammation among chronic HBV patients with liver cirrhosis, which likely attributed to the expression of biosignatures of apoptosis and activation in immune cells.
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Affiliation(s)
- Muttiah Barathan
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, 50603, Malaysia
| | - Behnaz Riazalhosseini
- Department of Pharmacology, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, 50603, Malaysia
| | - Thevambiga Iyadorai
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, 50603, Malaysia
| | - Kumutha Malar Vellasamy
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, 50603, Malaysia
| | - Jamuna Vadivelu
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, 50603, Malaysia
| | - Li-Yen Chang
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, 50603, Malaysia
| | - Ahmad Khusairy Zulpa
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, 50603, Malaysia
| | - Marie Larsson
- Division of Molecular Medicine and Virology, Department of Biomedicine and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Esaki M Shankar
- Infection Biology, Department of Life Sciences, Central University of Tamil Nadu, Thiruvarur, 610 005, India.
| | - Rosmawati Mohamed
- Department of Medicine, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, 50603, Malaysia.
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16
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Montella L, Sarno F, Ambrosino A, Facchini S, D’Antò M, Laterza MM, Fasano M, Quarata E, Ranucci RAN, Altucci L, Berretta M, Facchini G. The Role of Immunotherapy in a Tolerogenic Environment: Current and Future Perspectives for Hepatocellular Carcinoma. Cells 2021; 10:1909. [PMID: 34440678 PMCID: PMC8393830 DOI: 10.3390/cells10081909] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 07/22/2021] [Accepted: 07/23/2021] [Indexed: 12/11/2022] Open
Abstract
In contrast to several tumors whose prognoses are radically affected by novel immunotherapeutic approaches and/or targeted therapies, the outcomes of advanced hepatocellular carcinoma (HCC) remain poor. The underlying cirrhosis that is frequently associated with it complicates medical treatment and often determines survival. The landscape of HCC treatment had included sorafenib as the only drug available for ten years, until 2018, when lenvatinib was approved for treatment. The second-line systemic treatments available for hepatocellular carcinoma include regorafenib, cabozantinib, ramucirumab, and, more recently, immune checkpoint inhibitors. However, the median survival remains below 15 months. The results obtained in clinics should be interpreted whilst considering the peculiar role of the liver as an immune organ. A healthy liver microenvironment ordinarily experiences stimulation by gut-derived antigens. This setup elucidates the response to chronic inflammation and the altered balance between tolerance and immune response in HCC development. This paper provides an overview of the mechanisms involved in HCC pathogenesis, with a special focus on the immune implications, along with current and future clinical perspectives.
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Affiliation(s)
- Liliana Montella
- ASL NA2 NORD, Oncology Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (M.M.L.); (E.Q.)
| | - Federica Sarno
- Precision Medicine Department, “Luigi Vanvitelli” University of Campania, 80138 Naples, Italy; (F.S.); (L.A.)
| | - Annamaria Ambrosino
- ASL NA2 NORD, Internal Medicine Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (A.A.); (M.D.); (R.A.N.R.)
| | - Sergio Facchini
- Department of Precision Medicine, Division of Medical Oncology, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (S.F.); (M.F.)
| | - Maria D’Antò
- ASL NA2 NORD, Internal Medicine Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (A.A.); (M.D.); (R.A.N.R.)
| | - Maria Maddalena Laterza
- ASL NA2 NORD, Oncology Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (M.M.L.); (E.Q.)
| | - Morena Fasano
- Department of Precision Medicine, Division of Medical Oncology, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (S.F.); (M.F.)
| | - Ermelinda Quarata
- ASL NA2 NORD, Oncology Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (M.M.L.); (E.Q.)
| | - Raffaele Angelo Nicola Ranucci
- ASL NA2 NORD, Internal Medicine Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (A.A.); (M.D.); (R.A.N.R.)
| | - Lucia Altucci
- Precision Medicine Department, “Luigi Vanvitelli” University of Campania, 80138 Naples, Italy; (F.S.); (L.A.)
| | - Massimiliano Berretta
- Department of Clinical and Experimental Medicine, University of Messina, 98121 Messina, Italy;
| | - Gaetano Facchini
- ASL NA2 NORD, Oncology Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (M.M.L.); (E.Q.)
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17
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Perisetti A, Goyal H, Yendala R, Thandassery RB, Giorgakis E. Non-cirrhotic hepatocellular carcinoma in chronic viral hepatitis: Current insights and advancements. World J Gastroenterol 2021; 27:3466-3482. [PMID: 34239263 PMCID: PMC8240056 DOI: 10.3748/wjg.v27.i24.3466] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/13/2021] [Accepted: 05/25/2021] [Indexed: 02/06/2023] Open
Abstract
Primary liver cancers carry significant morbidity and mortality. Hepatocellular carcinoma (HCC) develops within the hepatic parenchyma and is the most common malignancy originating from the liver. Although 80% of HCCs develop within background cirrhosis, 20% may arise in a non-cirrhotic milieu and are referred to non-cirrhotic-HCC (NCHCC). NCHCC is often diagnosed late due to lack of surveillance. In addition, the rising prevalence of non-alcoholic fatty liver disease and diabetes mellitus have increased the risk of developing HCC on non-cirrhotic patients. Viral infections such as chronic Hepatitis B and less often chronic hepatitis C with advance fibrosis are associated with NCHCC. NCHCC individuals may have Hepatitis B core antibodies and occult HBV infection, signifying the role of Hepatitis B infection in NCHCC. Given the effectiveness of current antiviral therapies, surgical techniques and locoregional treatment options, nowadays such patients have more options and potential for cure. However, these lesions need early identification with diagnostic models and multiple surveillance strategies to improve overall outcomes. Better understanding of the NCHCC risk factors, tumorigenesis, diagnostic tools and treatment options are critical to improving prognosis and overall outcomes on these patients. In this review, we aim to discuss NCHCC epidemiology, risk factors, and pathogenesis, and elaborate on NCHCC diagnosis and treatment strategies.
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Affiliation(s)
- Abhilash Perisetti
- Department of Internal Medicine, Division of Gastroenterology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States
| | - Hemant Goyal
- Department of Internal Medicine, Macon University School of Medicine, Macon, GA 31207, United States
| | - Rachana Yendala
- Department of Hematology and Oncology, Conway Regional Health System (CRHS), Conway, AR 72034, United States
| | - Ragesh B Thandassery
- Department of Gastroenterology and Hepatology, Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, United States
| | - Emmanouil Giorgakis
- Department of Transplant, University of Arkansas for Medical Sciences Little Rock, AR 72205, United States
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18
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Lin YT, Jeng LB, Chan WL, Su IJ, Teng CF. Hepatitis B Virus Pre-S Gene Deletions and Pre-S Deleted Proteins: Clinical and Molecular Implications in Hepatocellular Carcinoma. Viruses 2021; 13:v13050862. [PMID: 34066744 PMCID: PMC8151789 DOI: 10.3390/v13050862] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 04/29/2021] [Accepted: 05/07/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent and fatal human cancers worldwide and its development and prognosis are intimately associated with chronic infection with hepatitis B virus (HBV). The identification of genetic mutations and molecular mechanisms that mediate HBV-induced tumorigenesis therefore holds promise for the development of potential biomarkers and targets for HCC prevention and therapy. The presence of HBV pre-S gene deletions in the blood and the expression of pre-S deleted proteins in the liver tissues of patients with chronic hepatitis B and HBV-related HCC have emerged as valuable biomarkers for higher incidence rates of HCC development and a higher risk of HCC recurrence after curative surgical resection, respectively. Moreover, pre-S deleted proteins are regarded as important oncoproteins that activate multiple signaling pathways to induce DNA damage and promote growth and proliferation in hepatocytes, leading to HCC development. The signaling molecules dysregulated by pre-S deleted proteins have also been validated as potential targets for the prevention of HCC development. In this review, we summarize the clinical and molecular implications of HBV pre-S gene deletions and pre-S deleted proteins in HCC development and recurrence and highlight their potential applications in HCC prevention and therapy.
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Affiliation(s)
- Yueh-Te Lin
- Cancer Genome Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan;
| | - Long-Bin Jeng
- Organ Transplantation Center, China Medical University Hospital, Taichung 404, Taiwan;
| | - Wen-Ling Chan
- Department of Bioinformatics and Medical Engineering, Asia University, Taichung 413, Taiwan;
- Epigenome Research Center, China Medical University Hospital, Taichung 404, Taiwan
| | - Ih-Jen Su
- Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan 710, Taiwan;
| | - Chiao-Fang Teng
- Organ Transplantation Center, China Medical University Hospital, Taichung 404, Taiwan;
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan
- Research Center for Cancer Biology, China Medical University, Taichung 404, Taiwan
- Correspondence: ; Tel.: +886-4-2205-2121
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19
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Dowran R, Malekzadeh M, Nourollahi T, Sarkari B, Sarvari J. The Prevalence of Hepatitis B Virus Markers among Students of Shiraz University of Medical Sciences. Adv Biomed Res 2021; 10:7. [PMID: 33959564 PMCID: PMC8095257 DOI: 10.4103/abr.abr_173_20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Revised: 09/02/2020] [Accepted: 10/11/2020] [Indexed: 11/04/2022] Open
Abstract
Background Protection against hepatitis B virus (HBV) is based on the presence of antibodies against hepatitis B surface antigen (HBsAg). Vaccination of newborns is the most effective means of prevention. This study aimed to evaluate the frequency of anti-HBs antibody (anti-HBsAb), anti-HB core Ab (anti-HBcAb), HBsAg, and HBV DNA among university students in Fars province, Southern Iran. Materials and Methods In this cross-sectional study, 272 students of Shiraz University of Medical Sciences, were enrolled. Venous blood (5 mL) was collected from each participant and centrifuged; the sera were stored at -20°C until use. Anti-HBsAb, Anti-HBcAb, and HBsAg were measured using a commercial enzyme-linked immunosorbent assay kit. HBV DNA load was also measured by a real-time polymerase chain reaction. Results The mean age of the participants was 19 ± 1 years. There were 171 (62.9%) females and 101 (37.1%) males. Anti-HBsAb at a protective level (>10 mIU/mL) were detected in the sera of 104 (38.5%) of the cases. Of the anti-HBsAb seropositive participants, 82 were female and 22 were male; the difference between the gender and seropositivity to anti-HBsAb was statistically significant (P = 0.001, odds ratio: 3.3, 95% confidence interval = 1.89-5.79). Anti-HBcAb was detected in only one participant that was negative for both HBsAg and HBV DNA. Conclusion Findings of the current study show that more than half of the students do not have a protective level of anti-HBsAb and might be susceptible to HBV infection, indicating the necessity of checking the level of anti-HBsAb as well as a booster dose in high-risk groups.
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Affiliation(s)
- Razieh Dowran
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahyar Malekzadeh
- Institute for Cancer Research, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Tayyar Nourollahi
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Bahador Sarkari
- Department of Parasitology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Jamal Sarvari
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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20
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Zhang J, Song Q, Wu M, Zheng W. The Emerging Roles of Exosomes in the Chemoresistance of Hepatocellular Carcinoma. Curr Med Chem 2021; 28:93-109. [PMID: 32000636 DOI: 10.2174/0929867327666200130103206] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 10/08/2019] [Accepted: 10/23/2019] [Indexed: 11/22/2022]
Abstract
Hepatocellular carcinoma (HCC) is a common gastrointestinal malignancy with a leading incidence of cancer-related mortality worldwide. Despite the progress of treatment options, there remains low efficacy for patients with intermediate-advanced HCC, due to tumor metastasis, recurrence and chemoresistance. Increasing evidence suggests that exosomes in the tumor microenvironment (TME), along with other extracellular vesicles (EVs) and cytokines, contribute to the drug chemosensitivity of cancer cells. Exosomes, the intercellular communicators in various biological activities, have shown to play important roles in HCC progression. This review summarizes the underlying associations between exosomes and chemoresistance of HCC cells. The exosomes derived from distinct cell types mediate the drug resistance by regulating drug efflux, epithelial-mesenchymal transition (EMT), cancer stem cell (CSC) properties, autophagic phenotypes, as well as the immune response. In summary, TME-related exosomes can be a potential target to reverse chemoresistance and a candidate biomarker of drug efficacy in HCC patients.
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Affiliation(s)
- Jie Zhang
- Department of Chemotherapy, Affiliated Hospital of Nantong University, 20 Xisi Road, 226001 Nantong, Jiangsu, China
| | - Qianqian Song
- Department of Radiology, Wake Forest School of Medicine, One Medical Center Boulevard, Winston-Salem, 27157 NC, United States
| | - Mengna Wu
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, 226001 Nantong, Jiangsu, China
| | - Wenjie Zheng
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, 226001 Nantong, Jiangsu, China
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21
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Dai X, Guo Y, Hu Y, Bao X, Zhu X, Fu Q, Zhang H, Tong Z, Liu L, Zheng Y, Zhao P, Fang W. Immunotherapy for targeting cancer stem cells in hepatocellular carcinoma. Theranostics 2021; 11:3489-3501. [PMID: 33537099 PMCID: PMC7847682 DOI: 10.7150/thno.54648] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Accepted: 12/21/2020] [Indexed: 02/06/2023] Open
Abstract
The rapid development and remarkable success of checkpoint inhibitors have provided significant breakthroughs in cancer treatment, including hepatocellular carcinoma (HCC). However, only 15-20% of HCC patients can benefit from checkpoint inhibitors. Cancer stem cells (CSCs) are responsible for recurrence, metastasis, and local and systemic therapy resistance in HCC. Accumulating evidence has suggested that HCC CSCs can create an immunosuppressive microenvironment through certain intrinsic and extrinsic mechanisms, resulting in immune evasion. Intrinsic evasion mechanisms mainly include activation of immune-related CSC signaling pathways, low-level expression of antigen presenting molecules, and high-level expression of immunosuppressive molecules. External evasion mechanisms are mainly related to HBV/HCV infection, alcoholic/nonalcoholic steatohepatitis, hypoxia stimulation, abnormal angiogenesis, and crosstalk between CSCs and immune cells. A better understanding of the complex mechanisms of CSCs involved in immune evasion will contribute to therapies for HCC. Here we will outline the detailed mechanisms of immune evasion for CSCs, and provide an overview of the current immunotherapies targeting CSCs in HCC.
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MESH Headings
- Antigen Presentation/drug effects
- Antineoplastic Agents, Immunological/therapeutic use
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/therapy
- Fatty Liver/genetics
- Fatty Liver/immunology
- Fatty Liver/pathology
- Fatty Liver/therapy
- Gene Expression Regulation, Neoplastic
- Hepatitis B/genetics
- Hepatitis B/immunology
- Hepatitis B/pathology
- Hepatitis B/therapy
- Hepatitis C/genetics
- Hepatitis C/immunology
- Hepatitis C/pathology
- Hepatitis C/therapy
- Humans
- Immunologic Factors/therapeutic use
- Immunotherapy/methods
- Liver Neoplasms/genetics
- Liver Neoplasms/immunology
- Liver Neoplasms/pathology
- Liver Neoplasms/therapy
- Neoplasm Proteins/antagonists & inhibitors
- Neoplasm Proteins/genetics
- Neoplasm Proteins/immunology
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/immunology
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/therapy
- Neoplastic Stem Cells/drug effects
- Neoplastic Stem Cells/immunology
- Neoplastic Stem Cells/pathology
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/immunology
- Neovascularization, Pathologic/pathology
- Neovascularization, Pathologic/prevention & control
- Signal Transduction
- Tumor Escape/drug effects
- Tumor Microenvironment/drug effects
- Tumor Microenvironment/genetics
- Tumor Microenvironment/immunology
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Peng Zhao
- Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Weijia Fang
- Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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22
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Dorababu A. Report on Recently (2017–20) Designed Quinoline‐Based Human Cancer Cell Growth Inhibitors. ChemistrySelect 2020. [DOI: 10.1002/slct.202003888] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Atukuri Dorababu
- Department of Chemistry SRMPP Govt. First Grade College Huvinahadagali 583219 India
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23
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D'souza S, Lau KCK, Coffin CS, Patel TR. Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma. World J Gastroenterol 2020; 26:5759-5783. [PMID: 33132633 PMCID: PMC7579760 DOI: 10.3748/wjg.v26.i38.5759] [Citation(s) in RCA: 146] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/03/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic infection with viral hepatitis affects half a billion individuals worldwide and can lead to cirrhosis, cancer, and liver failure. Liver cancer is the third leading cause of cancer-associated mortality, of which hepatocellular carcinoma (HCC) represents 90% of all primary liver cancers. Solid tumors like HCC are complex and have heterogeneous tumor genomic profiles contributing to complexity in diagnosis and management. Chronic infection with hepatitis B virus (HBV), hepatitis delta virus (HDV), and hepatitis C virus (HCV) are the greatest etiological risk factors for HCC. Due to the significant role of chronic viral infection in HCC development, it is important to investigate direct (viral associated) and indirect (immune-associated) mechanisms involved in the pathogenesis of HCC. Common mechanisms used by HBV, HCV, and HDV that drive hepatocarcinogenesis include persistent liver inflammation with an impaired antiviral immune response, immune and viral protein-mediated oxidative stress, and deregulation of cellular signaling pathways by viral proteins. DNA integration to promote genome instability is a feature of HBV infection, and metabolic reprogramming leading to steatosis is driven by HCV infection. The current review aims to provide a brief overview of HBV, HCV and HDV molecular biology, and highlight specific viral-associated oncogenic mechanisms and common molecular pathways deregulated in HCC, and current as well as emerging treatments for HCC.
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Affiliation(s)
- Simmone D'souza
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
| | - Keith CK Lau
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
| | - Carla S Coffin
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
| | - Trushar R Patel
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
- Department of Chemistry and Biochemistry, Alberta RNA Research and Training Institute, University of Lethbridge, Lethbridge T1K3M4, AB, Canada
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24
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Teng CF, Wu HC, Su IJ, Jeng LB. Hepatitis B Virus Pre-S Mutants as Biomarkers and Targets for the Development and Recurrence of Hepatocellular Carcinoma. Viruses 2020; 12:v12090945. [PMID: 32859114 PMCID: PMC7552003 DOI: 10.3390/v12090945] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 08/06/2020] [Accepted: 08/25/2020] [Indexed: 12/11/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a major risk factor for the development of hepatocellular carcinoma (HCC), the leading cause of cancer-related death worldwide. Despite progress in the prevention and therapy of HCC, high incidence and recurrence rates of HCC remain big threats, resulting in poor patient survival. Effective biomarkers and targets of HCC are therefore urgently needed for better management and to improve patient outcomes. Pre-S mutants have been well demonstrated as HBV oncoproteins that play important roles in HCC development through activation of multiple oncogenic signal pathways in hepatocytes, in vitro and in vivo. The presence of pre-S mutants in patients with chronic HBV infection and HBV-related HCC has been associated with a significantly higher risk of HCC development and recurrence after curative surgical resection, respectively. In this review, we summarize the roles of pre-S mutants as biomarkers for predicting HBV-related HCC development and recurrence, and highlight the pre-S mutants-activated oncogenic signal pathways as potential targets for preventing HBV-related HCC development.
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Affiliation(s)
- Chiao-Fang Teng
- Graduate Institute of Biomedical Sciences, China Medical University, No.91, Hsueh-Shih Rd., Northern Dist., Taichung City 404, Taiwan
- Organ Transplantation Center, China Medical University Hospital, No.2, Yude Rd., North Dist., Taichung City 404, Taiwan
- Research Center for Cancer Biology, China Medical University, Taichung City 404, Taiwan
- Correspondence: (C.-F.T.); (I.-J.S.); (L.-B.J.); Tel.: +886-4-2205-2121 (C.-F.T. & L.-B.J.); +886-6-253-3131 (I.-J.S.); Fax: +886-4-2202-9083 (C.-F.T. & L.-B.J.); +886-6-242-5747 (I.-J.S.)
| | - Han-Chieh Wu
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan 350, Taiwan;
| | - Ih-Jen Su
- Department of Biotechnology, Southern Taiwan University of Science and Technology, No.1, Nantai St., Yongkang Dist., Tainan City 710, Taiwan
- Correspondence: (C.-F.T.); (I.-J.S.); (L.-B.J.); Tel.: +886-4-2205-2121 (C.-F.T. & L.-B.J.); +886-6-253-3131 (I.-J.S.); Fax: +886-4-2202-9083 (C.-F.T. & L.-B.J.); +886-6-242-5747 (I.-J.S.)
| | - Long-Bin Jeng
- Organ Transplantation Center, China Medical University Hospital, No.2, Yude Rd., North Dist., Taichung City 404, Taiwan
- Correspondence: (C.-F.T.); (I.-J.S.); (L.-B.J.); Tel.: +886-4-2205-2121 (C.-F.T. & L.-B.J.); +886-6-253-3131 (I.-J.S.); Fax: +886-4-2202-9083 (C.-F.T. & L.-B.J.); +886-6-242-5747 (I.-J.S.)
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25
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The Cancer Stem Cell in Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12030684. [PMID: 32183251 PMCID: PMC7140091 DOI: 10.3390/cancers12030684] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 03/11/2020] [Accepted: 03/12/2020] [Indexed: 12/11/2022] Open
Abstract
The recognition of intra-tumoral cellular heterogeneity has given way to the concept of the cancer stem cell (CSC). According to this concept, CSCs are able to self-renew and differentiate into all of the cancer cell lineages present within the tumor, placing the CSC at the top of a hierarchical tree. The observation that these cells—in contrast to bulk tumor cells—are able to exclusively initiate new tumors, initiate metastatic spread and resist chemotherapy implies that CSCs are solely responsible for tumor recurrence and should be therapeutically targeted. Toward this end, dissecting and understanding the biology of CSCs should translate into new clinical therapeutic approaches. In this article, we review the CSC concept in cancer, with a special focus on hepatocellular carcinoma.
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26
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Chen A, Xu C, Luo Y, Liu L, Song K, Deng G, Yang M, Cao J, Yuan L, Li X. Disruption of crosstalk between LX-2 and liver cancer stem-like cells from MHCC97H cells by DFOG via inhibiting FOXM1. Acta Biochim Biophys Sin (Shanghai) 2019; 51:1267-1275. [PMID: 31750892 DOI: 10.1093/abbs/gmz129] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Accepted: 07/29/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatic stellate cell (HSC) line LX-2 is activated by liver cancer stem-like cells (LCSLCs) and produces various cytokines that make up most of the hepatocellular carcinoma (HCC) microenvironment. The new genistein derivative, 7-difluoromethoxyl-5,4'-di-n-octylgenistein (DFOG), shows anticancer effects in multiple malignancies by controlling forkhead box M1 (FOXM1). In this study, we aimed to assess whether DFOG disrupts the crosstalk between human HSC LX-2 cells and LCSLCs. Distinct generations of MHCC97H-derived spheres were obtained with the second generation considered as LCSLCs which displayed enhanced self-renewal ability and elevated expression levels of CD133, CD44, and EpCAM proteins, as well as tumorigenicity, as revealed by colony formation assay in vitro and tumorigenicity assay in vivo. LX-2 and MHCC97H cells were co-cultured with/without DFOG (1, 5, and 10 μM, respectively) using the transwell system. FOXM1 overexpression and/or knockdown were employed for mechanistic investigations. Our results suggested that Co-CM promoted LX-2 cell transformation into liver cancer-associated HSCs. Meanwhile, FOXM1 was up-regulated and the level of hepatocyte growth factor (HGF) was increased in LX-2 cells and in the supernatant after Co-CM stimulation. Sphere and colony formation abilities in MHCC97H cells, and protein levels of CD133, CD44, and EpCAM, were also markedly elevated. DFOG dose-dependently inhibited the above effects, similar to FOXM1 knockdown in LX-2 cells. FOXM1 overexpression reversed the inhibitory effects of DFOG or FOXM1 knockdown or both on LX-2 cell activation and LCSLC feature induction in MHCC97H cells by LCSLC/LX-2 co-culture. This study demonstrated that DFOG disrupts the crosstalk between HSCs and LCSLCs to suppress LCSLC features via down-regulating FOXM1 expression and reducing HGF secretion in HSCs.
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Affiliation(s)
- A Chen
- Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha 410013, China
- Department of Pharmaceutical Science, Me dical College, Hunan Normal University, Changsha 410013, China
- Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha 410013, China
| | - Chang Xu
- Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha 410013, China
- Department of Pharmaceutical Science, Me dical College, Hunan Normal University, Changsha 410013, China
- Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha 410013, China
| | - Yimin Luo
- Pathology department, Medical College, University of South China, Hengyang 421001, China
| | - Lihua Liu
- Department of Pharmacology, Shenzhen People's Hospital 2nd Clinical Medical College of Jinan University, Shenzhen 518020, China
| | - Kun Song
- Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha 410013, China
| | - Guangqi Deng
- Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha 410013, China
| | - Mengjie Yang
- Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha 410013, China
| | - Jianguo Cao
- Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha 410013, China
- Department of Pharmaceutical Science, Me dical College, Hunan Normal University, Changsha 410013, China
- Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha 410013, China
| | - Liming Yuan
- Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha 410013, China
| | - Xiang Li
- Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha 410013, China
- Department of Pharmaceutical Science, Me dical College, Hunan Normal University, Changsha 410013, China
- Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha 410013, China
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27
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Chemopreventive Effect of Phytosomal Curcumin on Hepatitis B Virus-Related Hepatocellular Carcinoma in A Transgenic Mouse Model. Sci Rep 2019; 9:10338. [PMID: 31316146 PMCID: PMC6637187 DOI: 10.1038/s41598-019-46891-5] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 07/01/2019] [Indexed: 12/11/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a major risk factor for the development of hepatocellular carcinoma (HCC), a leading cause of cancer mortality worldwide. Hepatitis B X protein (HBx) and pre-S2 mutant have been proposed as the two most important HBV oncoproteins that play key roles in HCC pathogenesis. Curcumin is a botanical constituent displaying potent anti-inflammatory and anti-cancer properties without toxic side effects. Phytosomal formulation of curcumin has been shown to exhibit enhanced bioavailability, improved pharmacokinetics, and excellent efficacy against many human diseases. However, effectiveness of phytosomal curcumin for HCC treatment remains to be clarified. In this study, we evaluated chemopreventive effect of phytosomal curcumin on HBV-related HCC by using a transgenic mouse model specifically expressing both HBx and pre-S2 mutant in liver. Compared with unformulated curcumin, phytosomal curcumin exhibited significantly greater effects on suppression of HCC formation, improvement of liver histopathology, decrease of lipid accumulation and leukocyte infiltration, and reduction of total tumor volume in transgenic mice. Moreover, phytosomal curcumin exerted considerably stronger effects on activation of anti-inflammatory PPARγ as well as inhibition of pro-inflammatory NF-κB than unformulated curcumin. Furthermore, phytosomal curcumin showed a comparable effect on suppression of oncogenic mTOR activation to unformulated curcumin. Our data demonstrated that phytosomal curcumin has promise for HCC chemoprevention in patients with chronic HBV infection.
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28
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Zhang H, Zhang Y, Zhu X, Chen C, Zhang C, Xia Y, Zhao Y, Andrisani O, Kong L. DEAD Box Protein 5 Inhibits Liver Tumorigenesis by Stimulating Autophagy via Interaction with p62/SQSTM1. Hepatology 2019; 69:1046-1063. [PMID: 30281815 PMCID: PMC6411283 DOI: 10.1002/hep.30300] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 09/13/2018] [Indexed: 12/11/2022]
Abstract
In hepatocellular carcinoma (HCC), dysregulated expression of DDX5 (DEAD box protein 5) and impaired autophagy have been reported separately. However, the relationship between them has not been explored. Here we present evidence to show that, by interacting with autophagic receptor p62, DDX5 promotes autophagy and suppresses tumorigenesis. DDX5 inversely correlated with p62/sequestosome 1 (SQSTM1) expression in hepatitis B virus (HBV)-associated and non-HBV-associated HCCs. Patients with low DDX5 expression showed poor prognosis after tumor resection. We found that DDX5 overexpression induced, while DDX5 knockdown attenuated, autophagic flux in HepG2 and Huh7 cells. DDX5 promoted p62 degradation and markedly reduced the half-life of p62. Moreover, DDX5 overexpression dramatically reduced, while DDX5 knockdown promoted, cancer cell growth and tumorigenesis in vitro and in vivo. We found that DDX5 bound to p62 and interfered with p62/TRAF6 (tumor necrosis factor receptor-associated factor 6) interaction. Further findings revealed that the N-terminal domain of DDX5, involved in the interaction with p62, was sufficient to induce autophagy independent of its RNA binding and helicase activity. DDX5 overexpression decreased p62/TRAF6-mediated lysine 63-linked ubiquitination of mammalian target of rapamycin (mTOR) and subsequently inhibited the mTOR signaling pathway. Knockdown of TRAF6 blocked DDX5-induced autophagy. Furthermore, we showed that miR-17-5p downregulated DDX5 and impaired autophagy. Inhibition of miR-17-5p promoted autophagic flux and suppressed tumor growth in HCC xenograft models. Conclusion: Our findings define a noncanonical pathway that links miR-17-5p, DDX5, p62/TRAF6, autophagy, and HCC. These findings open an avenue for the treatment of HCC.
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Affiliation(s)
- Hao Zhang
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yanqiu Zhang
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xiaoyun Zhu
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Chen Chen
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Chao Zhang
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yuanzheng Xia
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yucheng Zhao
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Ourania Andrisani
- Department of Basic Medical Sciences and Purdue Center for Cancer Research, Purdue University, West Lafayette, IN
| | - Lingyi Kong
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
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Chaturvedi VK, Singh A, Dubey SK, Hetta HF, John J, Singh M. Molecular mechanistic insight of hepatitis B virus mediated hepatocellular carcinoma. Microb Pathog 2019; 128:184-194. [PMID: 30611768 DOI: 10.1016/j.micpath.2019.01.004] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Revised: 12/30/2018] [Accepted: 01/02/2019] [Indexed: 02/07/2023]
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30
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More than just oncogenes: mechanisms of tumorigenesis by human viruses. Curr Opin Virol 2018; 32:48-59. [PMID: 30268926 DOI: 10.1016/j.coviro.2018.09.003] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 09/05/2018] [Accepted: 09/14/2018] [Indexed: 12/18/2022]
Abstract
Most humans are infected with at least one of the known human cancer viruses during their lifetimes. While the initial infection with these viruses does not cause major disease, infected cells can acquire cancer hallmarks, particularly upon immunosuppression or exposure to co-carcinogenic stimuli. Even though cancer formation represents a rare outcome of a viral infection, approximately one out of eight human cancers has a viral etiology. Viral cancers present unique opportunities for prophylaxis, diagnosis, and therapy, as demonstrated by the success of HBV and HPV vaccines and HCV antivirals in decreasing the incidence of tumors that are caused by these viruses. Here we review common characteristics and mechanisms of action of the human oncogenic viruses.
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31
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Li Q, Deng C, Zhang T, Li X. Association of GSTP1 and P16 promoter methylation with the risk of HBV-related hepatocellular carcinoma: a meta-analysis. Onco Targets Ther 2018; 11:5789-5796. [PMID: 30254471 PMCID: PMC6140744 DOI: 10.2147/ott.s168444] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background Study on the relationship between glutathione-S-transferase Pi 1 (GSTP1) and P16 promoter region methylation and the risk of hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC) has produced inconsistent results. Objectives To assess the correlation between GSTP1 and P16 promoter methylation frequency and HBV-related HCC susceptibility. Methods All relevant studies were identified by searching PubMed, Embase, Web of Science, and China National Knowledge Infrastructure literature databases before December, 2017. The OR and the corresponding 95% CI were calculated to investigate the risk of GSTP1 and P16 promoter methylation rate and HBV-related HCC. Sensitivity analysis was performed and publication bias was estimated using the Begg’s and Egger’s test. Results Our meta-analysis identified the relationships of GSTP1 (six studies including 213 HBV-related HCC tumor tissues) and P16 (nine studies with 287 HBV-related HCC tumor tissue) promoter methylation with HCC risk. Compared with normal liver tissue and cirrhosis, the pooled ORs of GSTP1 promoter region methylation in HBV-related HCC cancer tissues were 6.05 (95% CI =1.20–30.52) and 5.21 (95% CI =2.19–12.41), respectively. Compared with paracancerous tissue, normal liver tissue, cirrhosis, and chronic hepatitis B as controls, the pooled ORs of P16 promoter region methylation in HBV-related HCC cancer tissues were 7.18 (95% CI =2.31–22.33), 24.89 (95% CI =3.38–183.03), 5.92 (95% CI =1.78–19.68), and 12.12 (95% CI =0.75–196.50). Conclusion In summary, our meta-analysis found strong associations between GSTP1 and P16 gene promoter methylation and an increased HBV-related HCC susceptibility. Moreover, GSTP1 and P16 methylation in promoter region could obviously increase the risk of HBV-related HCC in patients with cirrhosis, indicating that these would be promising biomarkers for early clinical diagnosis of HBV-related HCC.
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Affiliation(s)
- Qin Li
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, People's Republic of China
| | - Cunliang Deng
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, People's Republic of China
| | - Ting Zhang
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, People's Republic of China
| | - Xiang Li
- School of Pharmacy, The Southwest Medical University, Luzhou, Sichuan Province, People's Republic of China,
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32
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Mani SKK, Andrisani O. Interferon signaling during Hepatitis B Virus (HBV) infection and HBV-associated hepatocellular carcinoma. Cytokine 2018; 124:154518. [PMID: 30126685 DOI: 10.1016/j.cyto.2018.08.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 08/09/2018] [Accepted: 08/11/2018] [Indexed: 02/06/2023]
Abstract
Chronic Hepatitis B Virus (HBV) infection is linked to hepatocellular carcinoma (HCC) pathogenesis. The World Health Organization estimates that globally 257 million people are chronic HBV carriers at risk of developing liver cancer. Current therapies for prevention and treatment of HCC are inadequate. Although interferon-based treatment strategies hold great promise for combating chronic infection and HCC, many patients do not respond to the IFN-based drugs for reasons not completely understood. Interferon signaling plays key roles in activation of innate and adaptive immunity. However, HBV has evolved various mechanisms to suppress IFN signaling. In this review, we present the basics about HBV infection and interferon signaling. Next, we discuss mechanisms through which HBV downregulates the function -activity and transcription- of the transcription factor STAT1 during acute and chronic infection. STAT1 is activated in response to all types (I/II/III) of interferon signaling and is essential in mediating all types (I/II/III) of interferon responses. Lastly, we discuss emerging evidence from different human cancers linking loss of interferon signaling to aggressive cancer and cancer stem cells. Whether the same occurs during HBV-associated hepatocarcinogenesis is discussed and currently under investigation.
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Affiliation(s)
- Saravana Kumar Kailasam Mani
- Department of Basic Medical Sciences and Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
| | - Ourania Andrisani
- Department of Basic Medical Sciences and Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
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33
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Cheng W, Chen G, Jia H, He X, Jing Z. DDX5 RNA Helicases: Emerging Roles in Viral Infection. Int J Mol Sci 2018; 19:ijms19041122. [PMID: 29642538 PMCID: PMC5979547 DOI: 10.3390/ijms19041122] [Citation(s) in RCA: 40] [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: 02/17/2018] [Revised: 03/29/2018] [Accepted: 04/02/2018] [Indexed: 02/07/2023] Open
Abstract
Asp-Glu-Ala-Asp (DEAD)-box polypeptide 5 (DDX5), also called p68, is a prototypical member of the large ATP-dependent RNA helicases family and is known to participate in all aspects of RNA metabolism ranging from transcription to translation, RNA decay, and miRNA processing. The roles of DDX5 in cell cycle regulation, tumorigenesis, apoptosis, cancer development, adipogenesis, Wnt-β-catenin signaling, and viral infection have been established. Several RNA viruses have been reported to hijack DDX5 to facilitate various steps of their replication cycles. Furthermore, DDX5 can be bounded by the viral proteins of some viruses with unknown functions. Interestingly, an antiviral function of DDX5 has been reported during hepatitis B virus and myxoma virus infection. Thus, the precise roles of this apparently multifaceted protein remain largely obscure. Here, we provide a rapid and critical overview of the structure and functions of DDX5 with a particular emphasis on its role during virus infection.
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Affiliation(s)
- Wenyu Cheng
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Public Health of Agriculture Ministry, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, Gansu, China.
| | - Guohua Chen
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Public Health of Agriculture Ministry, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, Gansu, China.
| | - Huaijie Jia
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Public Health of Agriculture Ministry, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, Gansu, China.
| | - Xiaobing He
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Public Health of Agriculture Ministry, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, Gansu, China.
| | - Zhizhong Jing
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Public Health of Agriculture Ministry, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, Gansu, China.
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