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Arai J, Okumura A, Kimoto S, Sakamoto K, Kitada T, Kitano R, Inoue T, Nishimura S, Inden N, Muraki Y, Kato N, Ito K. Efficacy of measuring natural killer-activating receptor ligands to predict the pathogenesis of metabolic dysfunction-associated steatotic liver disease. Hepatol Int 2025:10.1007/s12072-025-10800-y. [PMID: 40085416 DOI: 10.1007/s12072-025-10800-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Accepted: 02/15/2025] [Indexed: 03/16/2025]
Abstract
OBJECTIVE The proportion of non-B/non-C hepatocellular carcinoma cases is increasing, and the principal cause is metabolic dysfunction-associated steatotic liver disease (MASLD). The degree of intrahepatic natural killer (NK) cell infiltration has been reported to correlate with MASLD progression. However, reports on MASLD are limited. We aimed to investigate the involvement of NK cell-activating receptor ligands in MASLD pathogenesis. METHODS This study cohort comprised 69 patients with biopsy-proven MASLD treated between 2012 and 2018 at our institute. The concentrations of major histocompatibility complex class I polypeptide-related sequences A and B (MICA and MICB, respectively) and B7H6 in patient sera were measured using enzyme-linked immunosorbent assay kits. Data were statistically compared between those with metabolic-associated steatotic liver (MASL, n = 25) and those with metabolic dysfunction-associated steatohepatitis (MASH, n = 44). The clinical characteristics related to higher concentrations of each NK cell-activating receptor ligand were also investigated. RESULTS The MASH group had a higher level of the ligands than the MASL group. Furthermore, the MASH group had a significantly higher level of the Mac-2-binding protein glycosylation isomer (M2BPGi) than the MASL group (p < 0.001). MICA and MICB were positively correlated, and all three ligands were strongly correlated with alpha-fetoprotein and protein induced by vitamin K absence 2. Although MICB levels positively correlated with aspartate transaminase and alanine transaminase levels (p < 0.005), patients with higher MICA and B7H6 levels had higher M2BPGi levels. Interestingly, concentrations of B7H6 were significantly correlated with portal inflammation (p < 0.001), rather than lobular inflammation. CONCLUSION The three NK-activating receptor ligands were higher in the sera of the MASH group than those of the MASL group and strongly correlated with tumor markers, indicating the potential for hepatocarcinogenesis. Higher concentrations of serum B7H6 were correlated with advanced fibrosis and the degree of portal inflammation, which is a potential biomarker for predicting the pathogenesis of MASH.
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Affiliation(s)
- Jun Arai
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan.
| | - Akinori Okumura
- Department of Microbiology and Immunology, Aichi Medical University, Nagakute, Aichi, Japan
| | - Satoshi Kimoto
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Kazumasa Sakamoto
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Tomoya Kitada
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Rena Kitano
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Tadahisa Inoue
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Sayaka Nishimura
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Noriko Inden
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Yukiko Muraki
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kiyoaki Ito
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
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Roberts LR. Surveillance for Hepatocellular Carcinoma. Clin Liver Dis 2025; 29:17-31. [PMID: 39608955 DOI: 10.1016/j.cld.2024.09.001] [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] [Indexed: 11/30/2024]
Abstract
This article reviews surveillance for the detection of early stage hepatocellular carcinoma, covering the rationale for surveillance, optimal selection of persons needing surveillance, methods and frequency of screening, strategies for addressing barriers to surveillance, and trends for future improvement in surveillance leading to more effective cancer control and improved patient outcomes. The importance of integrating liver cancer surveillance as a core component of national public health programs is emphasized. The impact of emerging technologies for identifying persons at risk, stratifying individual risk to improve the cost-effectiveness of surveillance programs, and improving the performance, accessibility, and convenience of surveillance are discussed.
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Affiliation(s)
- Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, 200 First Street Southwest, Rochester, MN 55905, USA.
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3
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Machraoui S, Hakmaoui A, Errafii K, Knidiri M, Essaadouni L, Krati K, Admou B. HLA Class I (A and B) Allele Polymorphism in a Moroccan Population Infected with Hepatitis C Virus. Curr Issues Mol Biol 2024; 46:14080-14094. [PMID: 39727970 DOI: 10.3390/cimb46120842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 11/28/2024] [Accepted: 12/10/2024] [Indexed: 12/28/2024] Open
Abstract
Hepatitis C virus (HCV) infection is one of the major health burdens worldwide. Its course depends on the virus itself and the host's immune responses. The latter are conditioned by immunogenetic factors, in particular human leukocyte antigens (HLAs), whose role in determining the outcome of infection varies according to populations and ethnic groups. The current study attempted to investigate the possible relationship between HLA-A and HLA-B allele polymorphism and its impacts on the clinical outcome of HCV for a better understanding of disease susceptibility and clearance. A cross-sectional and comparative study was carried out on 40 patients with hepatitis C and 100 ethnically matched healthy control subjects originating from southern Morocco. HLA class I alleles were typed using the high-resolution PCR-SSO method. The prevalence of certain HLA class I alleles differed significantly between HCV-infected individuals and healthy controls. In particular, HLA-A*02:01 was less prevalent in chronic HCV infection (p = 0.002), indicating a potential protective effect, while the higher prevalence of HLA-A*68:02, A*66:01 B*15:03, B*41:02, B*44:03, and B*50:01 in patients could indicate a predisposing factor. These findings support the association of these immunogenetic markers with HCV infection, indicating their possible role in determining clinical and genotype forms as well as the outcome of HCV infection. Thus, an in-depth analysis of these alleles could lead to a better understanding of HCV pathogenesis and potential targeted interventions.
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Affiliation(s)
- Safa Machraoui
- Laboratory of Immunology and Human Leukocyte Antigen, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco
- Biosciences Research Laboratory, Faculty of Medicine and Pharmacy, Cadi Ayyad University, Marrakech 40080, Morocco
- African Genome Center, Mohammed VI Polytechnic University (UM6P), Ben Guerir 43151, Morocco
| | - Abdelmalek Hakmaoui
- Laboratory of Immunology and Human Leukocyte Antigen, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco
| | - Khaoula Errafii
- African Genome Center, Mohammed VI Polytechnic University (UM6P), Ben Guerir 43151, Morocco
| | - Mehdi Knidiri
- African Genome Center, Mohammed VI Polytechnic University (UM6P), Ben Guerir 43151, Morocco
| | - Lamiaa Essaadouni
- Biosciences Research Laboratory, Faculty of Medicine and Pharmacy, Cadi Ayyad University, Marrakech 40080, Morocco
| | - Khadija Krati
- Gastroenterology Department, Arrazi Hospital, Mohammed VI University Hospital Center, Marrakech 40000, Morocco
| | - Brahim Admou
- Laboratory of Immunology and Human Leukocyte Antigen, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco
- Biosciences Research Laboratory, Faculty of Medicine and Pharmacy, Cadi Ayyad University, Marrakech 40080, Morocco
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Maekawa S, Takano S, Enomoto N. Risk of hepatocellular carcinoma after viral clearance achieved by DAA treatment. J Formos Med Assoc 2024; 123:1124-1130. [PMID: 38245398 DOI: 10.1016/j.jfma.2024.01.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 12/18/2023] [Accepted: 01/09/2024] [Indexed: 01/22/2024] Open
Abstract
The advent of direct-acting antiviral (DAA) therapy has revolutionized hepatitis C virus (HCV) treatment, enabling most HCV-infected patients to achieve a sustained viral response (SVR) easily and safely in a short period. On the other hand, it is gradually being recognized that a significant proportion of patients are still at risk of developing de novo and recurrent hepatocellular carcinoma (HCC), even after HCV elimination, and therefore, elucidation of the risk of de novo and recurrent HCC, investigation of its molecular basis, and construction of accurate prediction models are emerging as new important clinical topics. In this review, we present recent advances regarding these issues.
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Affiliation(s)
- Shinya Maekawa
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
| | - Shinichi Takano
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Nobuyuki Enomoto
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
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Huang S, Qin Z, Wang F, Kang Y, Ren B. A potential mechanism of tumor immune escape: Regulation and application of soluble natural killer group 2 member D ligands (Review). Oncol Rep 2024; 52:137. [PMID: 39155864 PMCID: PMC11358674 DOI: 10.3892/or.2024.8796] [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: 03/28/2024] [Accepted: 05/31/2024] [Indexed: 08/20/2024] Open
Abstract
The immune system is integral to the surveillance and eradication of tumor cells. Interactions between the natural killer group 2 member D (NKG2D) receptor and its ligands (NKG2DLs) are vital for activating NKG2D receptor‑positive immune cells, such as natural killer cells. This activation enables these cells to identify and destroy tumor cells presenting with NKG2DLs, which is an essential aspect of tumor immunity. However, tumor immune escape is facilitated by soluble NKG2DL (sNKG2DL) shed from the surface of tumor cells. The production of sNKG2DL is predominantly regulated by metalloproteinases [a disintegrin and metalloproteinases (ADAM) and matrix metalloproteinase (MMP) families] and exosomes. sNKG2DL not only diminish immune recognition on the tumor cell surface but also suppress the function of immune cells, such as NK cells, and reduce the expression of the NKG2D receptor. This process promotes immune evasion, progression, and metastasis of tumors. In this review, an in‑depth summary of the mechanisms and factors that influence sNKG2DL production and their contribution to immune suppression within the tumor microenvironment are provided. Furthermore, due to the significant link between sNKG2DLs and tumor progression and metastasis, they have great potential as novel biomarkers. Detectable via liquid biopsies, sNKG2DLs could assess tumor malignancy and prognosis, and act as pivotal targets for immunotherapy. This could lead to the discovery of new drugs or the enhancement of existing treatments. Thus, the application of sNKG2DLs in clinical oncology was explored, offering substantial theoretical support for the development of innovative immunotherapeutic strategies for sNKG2DLs.
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Affiliation(s)
- Shuhao Huang
- Hunan Center for Clinical Laboratory, Second People's Hospital of Hunan Province, Changsha, Hunan 410007, P.R. China
- Department of Clinical Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, P.R. China
| | - Zihao Qin
- Hunan Center for Clinical Laboratory, Second People's Hospital of Hunan Province, Changsha, Hunan 410007, P.R. China
- Department of Clinical Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, P.R. China
| | - Feiyang Wang
- Hunan Center for Clinical Laboratory, Second People's Hospital of Hunan Province, Changsha, Hunan 410007, P.R. China
- Department of Clinical Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, P.R. China
| | - Yiping Kang
- Hunan Center for Clinical Laboratory, Second People's Hospital of Hunan Province, Changsha, Hunan 410007, P.R. China
- Department of Clinical Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, P.R. China
| | - Biqiong Ren
- Hunan Center for Clinical Laboratory, Second People's Hospital of Hunan Province, Changsha, Hunan 410007, P.R. China
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Banerjee A, Farci P. Fibrosis and Hepatocarcinogenesis: Role of Gene-Environment Interactions in Liver Disease Progression. Int J Mol Sci 2024; 25:8641. [PMID: 39201329 PMCID: PMC11354981 DOI: 10.3390/ijms25168641] [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: 06/26/2024] [Revised: 07/23/2024] [Accepted: 07/29/2024] [Indexed: 09/02/2024] Open
Abstract
The liver is a complex organ that performs vital functions in the body. Despite its extraordinary regenerative capacity compared to other organs, exposure to chemical, infectious, metabolic and immunologic insults and toxins renders the liver vulnerable to inflammation, degeneration and fibrosis. Abnormal wound healing response mediated by aberrant signaling pathways causes chronic activation of hepatic stellate cells (HSCs) and excessive accumulation of extracellular matrix (ECM), leading to hepatic fibrosis and cirrhosis. Fibrosis plays a key role in liver carcinogenesis. Once thought to be irreversible, recent clinical studies show that hepatic fibrosis can be reversed, even in the advanced stage. Experimental evidence shows that removal of the insult or injury can inactivate HSCs and reduce the inflammatory response, eventually leading to activation of fibrolysis and degradation of ECM. Thus, it is critical to understand the role of gene-environment interactions in the context of liver fibrosis progression and regression in order to identify specific therapeutic targets for optimized treatment to induce fibrosis regression, prevent HCC development and, ultimately, improve the clinical outcome.
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Affiliation(s)
- Anindita Banerjee
- Department of Transfusion Transmitted Diseases, ICMR-National Institute of Immunohaematology, Mumbai 400012, Maharashtra, India;
| | - Patrizia Farci
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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Murakawa M, Nakagawa M, Nishimura H, Kaneko S, Miyoshi M, Kawai-Kitahata F, Nitta S, Tsuchiya J, Shimizu T, Watakabe K, Mochida T, Inada K, Iizuka Y, Sakai H, Sakurai Y, Sato A, Azuma S, Kawamura T, Maeyashiki C, Kurosaki M, Kusano F, Watanabe H, Kurata H, Karakama Y, Fujiwara T, Nagata Y, Tanaka T, Kakinuma S, Okamoto R, Asahina Y. High serum gamma-glutamyltransferase level after hepatitis C virus elimination is a risk factor for the development of hepatocellular carcinoma. Hepatol Res 2024. [PMID: 39073391 DOI: 10.1111/hepr.14094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 06/24/2024] [Accepted: 06/25/2024] [Indexed: 07/30/2024]
Abstract
AIM Gamma-glutamyltransferase (GGT) is known as an oxidative stress marker, induced by alcohol consumption and metabolic disorders, and is reported as a predictor of hepatocellular carcinoma (HCC) development after hepatitis C virus (HCV) elimination. However, it is not clear whether GGT serves simply as a surrogate marker for overlapping metabolic diseases or reflects HCV-specific carcinogenicity. We investigated the association between GGT and hepatocarcinogenesis after achieving a sustained viral response (SVR), accounting for drinking habits or diabetes, and examined predisposing factors associated with GGT levels after SVR. METHODS This is a prospective, multicenter, and observational study using the database of 1001 patients after HCV eradication with direct-acting antiviral agents. The association of GGT at SVR with cumulative HCC development was examined in a multivariate analysis using Cox proportional hazard models after adjustment for covariates including alcohol and diabetes. The association between oxidative stress markers or genetic factors and GGT levels was analyzed. RESULTS High GGT levels at SVR were associated with HCC development (HR] 2.38, 95% CI 1.10-5.17). This association was also significant when restricted to patients without alcohol consumption or diabetes (HR 8.38, 95% CI 2.87-24.47). GGT levels were correlated with serum growth differentiation factor 15 levels, a marker of mitochondrial dysfunction. Single-nucleotide polymorphisms of ZNF827 and GDF15 were associated with high GGT levels. CONCLUSIONS High GGT levels at SVR were associated with HCC development after accounting for alcohol consumption and diabetes. GGT levels are influenced by genetic predisposition and may reflect mitochondrial dysfunction after HCV eradication.
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Affiliation(s)
- Miyako Murakawa
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mina Nakagawa
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
- Institute of Education, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hisaaki Nishimura
- Department of Public Health, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shun Kaneko
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masato Miyoshi
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Fukiko Kawai-Kitahata
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Sayuri Nitta
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Jun Tsuchiya
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Taro Shimizu
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Keiya Watakabe
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tomohiro Mochida
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kento Inada
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yasuhiro Iizuka
- Department of Gastroenterology and Hepatology, Kashiwa Municipal Hospital, Chiba, Japan
| | - Hideki Sakai
- Department of Gastroenterology and Hepatology, Kashiwa Municipal Hospital, Chiba, Japan
| | - Yuki Sakurai
- Department of Gastroenterology and Hepatology, Showa General Hospital, Tokyo, Japan
| | - Ayako Sato
- Department of Gastroenterology and Hepatology, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan
| | - Seishin Azuma
- Department of Gastroenterology and Hepatology, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan
| | - Takahiro Kawamura
- Department of Gastroenterology and Hepatology, JA Toride Medical Center, Ibaraki, Japan
| | - Chiaki Maeyashiki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Fumihiko Kusano
- Department of Gastroenterology and Hepatology, Tsuchiura Kyodo General Hospital, Ibaraki, Japan
| | - Hideki Watanabe
- Department of Gastroenterology and Hepatology, Yokosuka Kyosai Hospital, Kanagawa, Japan
| | - Hitoshi Kurata
- Department of Gastroenterology and Hepatology, Tokyo Metropolitan Ohtsuka Hospital, Tokyo, Japan
| | - Yuko Karakama
- Department of Gastroenterology and Hepatology, Tokyo Kyosai Hospital, Tokyo, Japan
| | - Takeo Fujiwara
- Department of Public Health, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yuki Nagata
- Department of Human Genetics and Disease Diversity, Tokyo Medical Dental University, Tokyo, Japan
| | - Toshihiro Tanaka
- Department of Human Genetics and Disease Diversity, Tokyo Medical Dental University, Tokyo, Japan
| | - Sei Kakinuma
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Clinical and Diagnostic Laboratory Science, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ryuichi Okamoto
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yasuhiro Asahina
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
- Department for Liver Disease Control, Tokyo Medical and Dental University, Tokyo, Japan
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8
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Huang CF, Awad MH, Gal-Tanamy M, Yu ML. Unmet needs in the post-direct-acting antivirals era: The risk and molecular mechanisms of hepatocellular carcinoma after hepatitis C virus eradication. Clin Mol Hepatol 2024; 30:326-344. [PMID: 38665034 PMCID: PMC11261227 DOI: 10.3350/cmh.2024.0155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 04/26/2024] [Accepted: 04/26/2024] [Indexed: 07/20/2024] Open
Abstract
Hepatitis C virus (HCV) infection is one of the major etiologies of hepatocellular carcinoma (HCC) with approximately 30% of HCC being due to HCV infection worldwide. HCV eradication by antivirals greatly reduces the risk of HCC; nevertheless, HCC remains to occur in chronic hepatitis C (CHC) patients who have achieved a sustained virological response (SVR). The proportion of post-SVR HCC among newly diagnosed HCC patients is increasing in the direct-acting antiviral (DAA) era and might be due to preexisting inflammatory and fibrotic liver backgrounds, immune dysregulation between host and virus interactions, as well as host epigenetic scars, genetic predispositions and alternations. By means of applying surrogate markers and adopting risk stratification, HCC surveillance should be consistently performed in high-risk populations. In this review, we discuss the possible molecular mechanism, risk factors, and HCC surveillance strategy for HCC development after HCV eradication in CHC patients.
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Affiliation(s)
- Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Ph.D. Program in Translational Medicine, College of Medicine, Kaohsiung Medical University and Academia Sinica, Kaohsiung, Taiwan
| | - Manar Hijaze Awad
- Molecular Virology Lab, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Meital Gal-Tanamy
- Molecular Virology Lab, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- School of Medicine and Doctoral Program of Clinical and Experimental Medicine, College of Medicine and Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-sen University, Kaohsiung, Taiwan
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Zhang J, Zhang Q, Hu W, Liang Y, Jiang D, Chen H. A transcriptome-wide association study identified susceptibility genes for hepatocellular carcinoma in East Asia. Gastroenterol Rep (Oxf) 2024; 12:goae057. [PMID: 38846986 PMCID: PMC11153834 DOI: 10.1093/gastro/goae057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 03/07/2024] [Accepted: 04/30/2024] [Indexed: 06/09/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and is prevalent in East Asia. Although genome-wide association studies (GWASs) of HCC have identified 23 risk regions, the susceptibility genes underlying these associations largely remain unclear. To identify novel candidate genes for HCC, we conducted liver single-tissue and cross-tissue transcriptome-wide association studies (TWASs) in two populations of East Asia. METHODS GWAS summary statistics of 2,514 subjects (1,161 HCC cases and 1,353 controls) from the Chinese Qidong cohort and 161,323 subjects (2,122 HCC cases and 159,201 controls) from the BioBank Japan project were used to conduct TWAS analysis. The single-tissue and cross-tissue TWAS approaches were both used to detect the association between susceptible genes and the risk of HCC. TWAS identified genes were further annotated by Metascape, UALCAN, GEPIA2, and DepMap. RESULTS We identified 22 novel genes at 16 independent loci significantly associated with HCC risk after Bonferroni correction. Of these, 13 genes were located in novel regions. Besides, we found 83 genes overlapped in the Chinese and Japanese cohorts with P < 0.05, of which, three genes (NUAK2, HLA-DQA1, and ATP6V1G2) were discerned by both single-tissue and cross-tissue TWAS approaches. Among the genes identified through TWAS, a significant proportion of them exhibit a credible role in HCC biology, such as FAM96B, HSPA5, POLRMT, MPHOSPH10, and RABL2A. HLA-DQA1, NUAK2, and HSPA5 associated with the process of carcinogenesis in HCC as previously reported. CONCLUSIONS Our findings highlight the value of leveraging the gene expression data to identify new candidate genes beyond the GWAS associations and could further provide a genetic insight for the biology of HCC.
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Affiliation(s)
- Jingjing Zhang
- School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- School of Public Health (Shenzhen), Shenzhen campus of Sun Yat-sen University, Shenzhen, Guangdong, P. R. China
| | - Qingrong Zhang
- School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- School of Public Health (Shenzhen), Shenzhen campus of Sun Yat-sen University, Shenzhen, Guangdong, P. R. China
| | - Wenyan Hu
- School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- School of Public Health (Shenzhen), Shenzhen campus of Sun Yat-sen University, Shenzhen, Guangdong, P. R. China
| | - Yuxuan Liang
- School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- School of Public Health (Shenzhen), Shenzhen campus of Sun Yat-sen University, Shenzhen, Guangdong, P. R. China
| | - Deke Jiang
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P. R. China
| | - Haitao Chen
- School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- School of Public Health (Shenzhen), Shenzhen campus of Sun Yat-sen University, Shenzhen, Guangdong, P. R. China
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10
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Peruhova M, Banova-Chakarova S, Miteva DG, Velikova T. Genetic screening of liver cancer: State of the art. World J Hepatol 2024; 16:716-730. [PMID: 38818292 PMCID: PMC11135278 DOI: 10.4254/wjh.v16.i5.716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 02/14/2024] [Accepted: 04/09/2024] [Indexed: 05/22/2024] Open
Abstract
Liver cancer, primarily hepatocellular carcinoma, remains a global health challenge with rising incidence and limited therapeutic options. Genetic factors play a pivotal role in the development and progression of liver cancer. This state-of-the-art paper provides a comprehensive review of the current landscape of genetic screening strategies for liver cancer. We discuss the genetic underpinnings of liver cancer, emphasizing the critical role of risk-associated genetic variants, somatic mutations, and epigenetic alterations. We also explore the intricate interplay between environmental factors and genetics, highlighting how genetic screening can aid in risk stratification and early detection via using liquid biopsy, and advancements in high-throughput sequencing technologies. By synthesizing the latest research findings, we aim to provide a comprehensive overview of the state-of-the-art genetic screening methods for liver cancer, shedding light on their potential to revolutionize early detection, risk assessment, and targeted therapies in the fight against this devastating disease.
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Affiliation(s)
- Milena Peruhova
- Department of Gastroenterology, University Hospital "Heart and Brain", Burgas 8000, Bulgaria
| | - Sonya Banova-Chakarova
- Department of Gastroenterology, University Hospital "Heart and Brain", Burgas 8000, Bulgaria.
| | - Dimitrina Georgieva Miteva
- Department of Genetics, Faculty of Biology, Sofia University" St. Kliment Ohridski, Sofia 1164, Bulgaria
| | - Tsvetelina Velikova
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
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11
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Wang Y, Liu X, Zuo X, Wang C, Zhang Z, Zhang H, Zeng T, Chen S, Liu M, Chen H, Song Q, Li Q, Yang C, Le Y, Xing J, Zhang H, An J, Jia W, Kang L, Zhang H, Xie H, Ye J, Wu T, He F, Zhang X, Li Y, Zhou G. NRDE2 deficiency impairs homologous recombination repair and sensitizes hepatocellular carcinoma to PARP inhibitors. CELL GENOMICS 2024; 4:100550. [PMID: 38697125 PMCID: PMC11099347 DOI: 10.1016/j.xgen.2024.100550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 02/26/2024] [Accepted: 04/05/2024] [Indexed: 05/04/2024]
Abstract
To identify novel susceptibility genes for hepatocellular carcinoma (HCC), we performed a rare-variant association study in Chinese populations consisting of 2,750 cases and 4,153 controls. We identified four HCC-associated genes, including NRDE2, RANBP17, RTEL1, and STEAP3. Using NRDE2 (index rs199890497 [p.N377I], p = 1.19 × 10-9) as an exemplary candidate, we demonstrated that it promotes homologous recombination (HR) repair and suppresses HCC. Mechanistically, NRDE2 binds to the subunits of casein kinase 2 (CK2) and facilitates the assembly and activity of the CK2 holoenzyme. This NRDE2-mediated enhancement of CK2 activity increases the phosphorylation of MDC1 and then facilitates the HR repair. These functions are eliminated almost completely by the NRDE2-p.N377I variant, which sensitizes the HCC cells to poly(ADP-ribose) polymerase (PARP) inhibitors, especially when combined with chemotherapy. Collectively, our findings highlight the relevance of the rare variants to genetic susceptibility to HCC, which would be helpful for the precise treatment of this malignancy.
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Affiliation(s)
- Yahui Wang
- State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, P.R. China; State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, P.R. China
| | - Xinyi Liu
- State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, P.R. China
| | - Xianbo Zuo
- Department of Dermatology, Department of Pharmacy, China-Japan Friendship Hospital, Beijing, P.R. China
| | - Cuiling Wang
- State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, P.R. China
| | - Zheng Zhang
- State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, P.R. China
| | - Haitao Zhang
- State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, P.R. China
| | - Tao Zeng
- Faculty of Hepato-Biliary-Pancreatic Surgery, the First Medical Center of Chinese PLA General of Hospital, Beijing, P.R. China
| | - Shunqi Chen
- State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, P.R. China
| | - Mengyu Liu
- State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, P.R. China
| | - Hongxia Chen
- State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, P.R. China
| | - Qingfeng Song
- Affiliated Cancer Hospital of Guangxi Medical University, Nanning City, Guangxi Province, P.R. China
| | - Qi Li
- State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, P.R. China; Department of Neurosciences, School of Medicine, University of South China, Hengyang City, Hunan Province, P.R. China
| | - Chenning Yang
- State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, P.R. China
| | - Yi Le
- Department of Hepatobiliary Surgery, the 5th Medical Center of Chinese PLA General of Hospital, Beijing, P.R. China
| | - Jinliang Xing
- State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Air Force Medical University, Xi'an City, Shaanxi Province, P.R. China
| | - Hongxin Zhang
- Department of Pain Treatment, Tangdu Hospital, Air Force Medical University, Xi'an City, Shaanxi Province, P.R. China
| | - Jiaze An
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi'an City, Shaanxi Province, P.R. China
| | - Weihua Jia
- State Key Laboratory of Oncology in Southern China, Guangzhou City, Guangdong Province, P.R. China; Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou City, Guangdong Province, P.R. China
| | - Longli Kang
- Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, Key Laboratory of High Altitude Environment and Genes Related to Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang City, Shaanxi Province, P.R. China
| | - Hongxing Zhang
- State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, P.R. China
| | - Hui Xie
- Department of Interventional Oncology, the Fifth Medical Center of Chinese PLA General of Hospital, Beijing, P.R. China
| | - Jiazhou Ye
- Department of Hepatobiliary & Pancreatic Surgery, Guangxi Medical University Cancer Hospital, Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning City, Guangxi Province, P.R. China
| | - Tianzhun Wu
- Department of Hepatobiliary & Pancreatic Surgery, Guangxi Medical University Cancer Hospital, Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning City, Guangxi Province, P.R. China
| | - Fuchu He
- State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, P.R. China.
| | - Xuejun Zhang
- Department of Dermatology and Institute of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei City, Anhui Province, P.R. China.
| | - Yuanfeng Li
- State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, P.R. China.
| | - Gangqiao Zhou
- State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, P.R. China; Collaborative Innovation Center for Personalized Cancer Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing City, Jiangsu Province, P.R. China.
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12
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Arai J, Okumura A, Kato N, Ito K. Natural killer group 2D-major histocompatibility complex class I polypeptide-related sequence A activation enhances natural killer cell-mediated immunity against hepatocellular carcinoma: A review. Hepatol Res 2024; 54:420-428. [PMID: 38536662 DOI: 10.1111/hepr.14038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 02/26/2024] [Accepted: 03/09/2024] [Indexed: 05/03/2024]
Abstract
The recent clinical introduction of immune checkpoint inhibitors has improved therapeutic outcomes in patients with advanced hepatocellular carcinoma. However, these therapies targeting CD8+ T lymphocytes have a response rate of approximately 30%. In addition to CD8+ T lymphocytes, natural killer (NK) cells represent promising therapeutic targets for hepatocellular carcinoma, because they comprise 30%-50% of all lymphocytes in the liver and contribute to antitumor immunity. A recent meta-analysis revealed that the percentage of infiltrating NK cells in hepatocellular carcinoma correlates with a better patient outcome. Similarly, our previous genome-wide association study on chronic viral hepatitis showed that a single-nucleotide polymorphism of major histocompatibility complex class I polypeptide-related sequence A (MICA), a ligand to the NK activating receptor, plays a critical role in hepatocarcinogenesis. In this review, we summarize the mechanisms underlying the regulation of MICA and NK group 2D expression in chronic hepatitis. Furthermore, we describe recent reports on MICA single-nucleotide polymorphism-driven hepatocarcinogenesis. The suppression of MICA shedding could represent a promising approach for immunosurveillance, as increased expression of membrane-bound MICA achieved through the use of a MICA shedding inhibitor also enhances NK cell-mediated cytotoxicity.
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Affiliation(s)
- Jun Arai
- Department of Gastroenterology, Aichi Medical University, Nagakute, Aichi, Japan
| | - Akinori Okumura
- Department of Gastroenterology, Aichi Medical University, Nagakute, Aichi, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kiyoaki Ito
- Department of Gastroenterology, Aichi Medical University, Nagakute, Aichi, Japan
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13
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Fares S, Wehrle CJ, Hong H, Sun K, Jiao C, Zhang M, Gross A, Allkushi E, Uysal M, Kamath S, Ma WW, Modaresi Esfeh J, Linganna MW, Khalil M, Pita A, Kim J, Walsh RM, Miller C, Hashimoto K, Schlegel A, Kwon DCH, Aucejo F. Emerging and Clinically Accepted Biomarkers for Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:1453. [PMID: 38672535 PMCID: PMC11047909 DOI: 10.3390/cancers16081453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 04/03/2024] [Accepted: 04/08/2024] [Indexed: 04/28/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death and the sixth most diagnosed malignancy worldwide. Serum alpha-fetoprotein (AFP) is the traditional, ubiquitous biomarker for HCC. However, there has been an increasing call for the use of multiple biomarkers to optimize care for these patients. AFP, AFP-L3, and prothrombin induced by vitamin K absence II (DCP) have described clinical utility for HCC, but unfortunately, they also have well established and significant limitations. Circulating tumor DNA (ctDNA), genomic glycosylation, and even totally non-invasive salivary metabolomics and/or micro-RNAS demonstrate great promise for early detection and long-term surveillance, but still require large-scale prospective validation to definitively validate their clinical validity. This review aims to provide an update on clinically available and emerging biomarkers for HCC, focusing on their respective clinical strengths and weaknesses.
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Affiliation(s)
- Sami Fares
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Chase J. Wehrle
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Hanna Hong
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Keyue Sun
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Chunbao Jiao
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Mingyi Zhang
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Abby Gross
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Erlind Allkushi
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Melis Uysal
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Suneel Kamath
- Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.K.); (W.W.M.)
| | - Wen Wee Ma
- Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.K.); (W.W.M.)
| | - Jamak Modaresi Esfeh
- Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (J.M.E.); (M.W.L.)
| | - Maureen Whitsett Linganna
- Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (J.M.E.); (M.W.L.)
| | - Mazhar Khalil
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Alejandro Pita
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Jaekeun Kim
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - R. Matthew Walsh
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Charles Miller
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Koji Hashimoto
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Andrea Schlegel
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - David Choon Hyuck Kwon
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Federico Aucejo
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
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14
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Slowly M, Domingo-Relloso A, Santella RM, Haack K, Fallin DM, Terry MB, Rhoades DA, Herreros-Martinez M, Garcia-Esquinas E, Cole SA, Tellez-Plaza M, Navas-Acien A, Wu HC. Blood DNA methylation and liver cancer in American Indians: evidence from the Strong Heart Study. Cancer Causes Control 2024; 35:661-669. [PMID: 38010586 PMCID: PMC10960679 DOI: 10.1007/s10552-023-01822-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Accepted: 10/30/2023] [Indexed: 11/29/2023]
Abstract
PURPOSE Liver cancer incidence among American Indians/Alaska Natives has risen over the past 20 years. Peripheral blood DNA methylation may be associated with liver cancer and could be used as a biomarker for cancer risk. We evaluated the association of blood DNA methylation with risk of liver cancer. METHODS We conducted a prospective cohort study in 2324 American Indians, between age 45 and 75 years, from Arizona, Oklahoma, North Dakota and South Dakota who participated in the Strong Heart Study between 1989 and 1991. Liver cancer deaths (n = 21) were ascertained using death certificates obtained through 2017. The mean follow-up duration (SD) for non-cases was 25.1 (5.6) years and for cases, 11.0 (8.8) years. DNA methylation was assessed from blood samples collected at baseline using MethylationEPIC BeadChip 850 K arrays. We used Cox regression models adjusted for age, sex, center, body mass index, low-density lipoprotein cholesterol, smoking, alcohol consumption, and immune cell proportions to examine the associations. RESULTS We identified 9 CpG sites associated with liver cancer. cg16057201 annotated to MRFAP1) was hypermethylated among cases vs. non-cases (hazard ratio (HR) for one standard deviation increase in methylation was 1.25 (95% CI 1.14, 1.37). The other eight CpGs were hypomethylated and the corresponding HRs (95% CI) ranged from 0.58 (0.44, 0.75) for cg04967787 (annotated to PPRC1) to 0.77 (0.67, 0.88) for cg08550308. We also assessed 7 differentially methylated CpG sites associated with liver cancer in previous studies. The adjusted HR for cg15079934 (annotated to LPS1) was 1.93 (95% CI 1.10, 3.39). CONCLUSIONS Blood DNA methylation may be associated with liver cancer mortality and may be altered during the development of liver cancer.
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Affiliation(s)
- Monique Slowly
- Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, USA
| | - Arce Domingo-Relloso
- Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, USA
- Department of Chronic Diseases Epidemiology, National Center for Epidemiology, Carlos III Health Institute, Madrid, Spain
- Department of Statistics and Operations Research, University of Valencia, Valencia, Spain
| | - Regina M Santella
- Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA
| | - Karin Haack
- Population Health Program, Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Daniele M Fallin
- Department of Mental Health, Johns Hopkins University, Baltimore, MD, USA
- Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA
| | - Mary Beth Terry
- Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA
- Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY, USA
| | - Dorothy A Rhoades
- Department of Medicine, Stephenson Cancer Center, University of Oklahoma Health Sciences, Oklahoma City, OK, USA
| | | | - Esther Garcia-Esquinas
- Universidad Autónoma de Madrid, Madrid, Spain
- CIBERESP (CIBER of Epidemiology and Public Health), Madrid, Spain
| | - Shelley A Cole
- Population Health Program, Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Maria Tellez-Plaza
- Department of Chronic Diseases Epidemiology, National Center for Epidemiology, Carlos III Health Institute, Madrid, Spain
| | - Ana Navas-Acien
- Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, USA
| | - Hui-Chen Wu
- Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, USA.
- Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA.
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15
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Soliman N, Saharia A, Abdelrahim M, Connor AA. Molecular profiling in the management of hepatocellular carcinoma. Curr Opin Organ Transplant 2024; 29:10-22. [PMID: 38038621 DOI: 10.1097/mot.0000000000001124] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2023]
Abstract
PURPOSE OF REVIEW The purpose of this review is to both summarize the current knowledge of hepatocellular carcinoma molecular biology and to suggest a framework in which to prospectively translate this knowledge into patient care. This is timely as recent guidelines recommend increased use of these technologies to advance personalized liver cancer care. RECENT FINDINGS The main themes covered here address germline and somatic genetic alterations recently discovered in hepatocellular carcinoma, largely owing to next generation sequencing technologies, and nascent efforts to translate these into contemporary practice. SUMMARY Early efforts of translating molecular profiling to hepatocellular carcinoma care demonstrate a growing number of potentially actionable alterations. Still lacking are a consensus on what biomarkers and technologies to adopt, at what scale and cost, and how to integrate them most effectively into care.
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Chotiprasidhi P, Sato-Espinoza AK, Wangensteen KJ. Germline Genetic Associations for Hepatobiliary Cancers. Cell Mol Gastroenterol Hepatol 2023; 17:623-638. [PMID: 38163482 PMCID: PMC10899027 DOI: 10.1016/j.jcmgh.2023.12.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 12/19/2023] [Accepted: 12/20/2023] [Indexed: 01/03/2024]
Abstract
Hepatobiliary cancers (HBCs) include hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma, which originate from the liver, bile ducts, and gallbladder, respectively. They are responsible for a substantial burden of cancer-related deaths worldwide. Despite knowledge of risk factors and advancements in therapeutics and surgical interventions, the prognosis for most patients with HBC remains bleak. There is evidence from familial aggregation and case-control studies to suggest a familial risk component in HBC susceptibility. Recent progress in genomics research has led to the identification of germline variants including single nucleotide polymorphisms (SNPs) and pathogenic or likely pathogenic (P/LP) variants in cancer-associated genes associated with HBC risk. These findings emerged from genome-wide association studies and next-generation sequencing techniques such as whole-exome sequencing. Patients with other cancer types, including breast, colon, ovarian, prostate, and pancreatic cancer, are recommended by guidelines to undergo germline genetic testing, but similar recommendations are lagging in HBC. This prompts the question of whether multi-gene panel testing should be integrated into clinical guidelines for HBC management. Here, we review the hereditary genetics of HBC, explore studies investigating SNPs and P/LP variants in HBC patients, discuss the clinical implications and potential for personalized treatments and impact on patient's family members, and conclude that additional studies are needed to examine how genetic testing can be applied clinically.
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Affiliation(s)
- Perapa Chotiprasidhi
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | | | - Kirk J Wangensteen
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.
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17
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Seid E, Tessema L, Abebe T, Solomon A, Chindi A, Hirut B, Negash K, Shunka E, Mogse Z, Burgos G, Mendes T. Genetic Variability for Micronutrient Content and Tuber Yield Traits among Biofortified Potato ( Solanum tuberosum L.) Clones in Ethiopia. PLANTS (BASEL, SWITZERLAND) 2023; 12:2625. [PMID: 37514240 PMCID: PMC10383430 DOI: 10.3390/plants12142625] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 06/16/2023] [Accepted: 06/17/2023] [Indexed: 07/30/2023]
Abstract
Malnutrition is one of the global issues of public health concern, and iron and zinc deficiencies are at the top of the list. Iron deficiency affects more than 2 billion people in the world and is a major cause of anemia. Potato has the potential to be an important source of iron and zinc. This study assessed the nature and magnitude of genetic variability in Fe and Zn concentrations, tuber yield, and quality traits among biofortified tetraploid potato clones and their relationships through correlation and path analysis. A total of 45 potato genotypes, including the variety Gudanie, were grown in field trials in a 9 × 5 alpha lattice design with three replications. Significant differences in mineral, tuber quality, and yield traits were observed among the genotypes, and high broad-sense heritability was obtained for most traits, suggesting that progress through breeding can be achieved. However, negative correlations and direct effects on most of the traits with Fe and Zn contents are found both at genotypic and phenotypic levels. Therefore, attaining simultaneous genetic gain for yield and enhanced Fe and Zn concentrations will be challenging. Cluster analysis assembled them into five groups. Cluster II contained the most prominent genotypes, having better mean values compared to all other genotypes for micronutrient traits, viz., Fe (23.80 mg kg-1) and Zn (17.07 mg kg-1). The results of this study confirm the presence of sufficient genetic variation for iron and zinc mineral concentration and the possibility to make significant progress through breeding.
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Affiliation(s)
- Ebrahim Seid
- Ethiopia Institute of Agricultural Research, Holetta Agricultural Research Centre, Addis Ababa P.O. Box 2003, Ethiopia
| | - Lemma Tessema
- Ethiopia Institute of Agricultural Research, Holetta Agricultural Research Centre, Addis Ababa P.O. Box 2003, Ethiopia
| | - Tesfaye Abebe
- Ethiopia Institute of Agricultural Research, Holetta Agricultural Research Centre, Addis Ababa P.O. Box 2003, Ethiopia
| | - Atsede Solomon
- Ethiopia Institute of Agricultural Research, Holetta Agricultural Research Centre, Addis Ababa P.O. Box 2003, Ethiopia
| | - Abebe Chindi
- Ethiopia Institute of Agricultural Research, Holetta Agricultural Research Centre, Addis Ababa P.O. Box 2003, Ethiopia
| | - Betaw Hirut
- School of Integrative Plant Science, Plant Pathology and Plant-Microbe Biology (PPPMB) Section, Cornell University, Geneva, NY 14456, USA
| | - Kasaye Negash
- Ethiopia Institute of Agricultural Research, Holetta Agricultural Research Centre, Addis Ababa P.O. Box 2003, Ethiopia
| | - Egata Shunka
- Ethiopia Institute of Agricultural Research, Holetta Agricultural Research Centre, Addis Ababa P.O. Box 2003, Ethiopia
| | - Zewditu Mogse
- Ethiopia Institute of Agricultural Research, Holetta Agricultural Research Centre, Addis Ababa P.O. Box 2003, Ethiopia
| | | | - Thiago Mendes
- International Potato Centre (CIP), Nairobi 00100, Kenya
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18
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Alshahrani SH, Alameri AA, Kahar F, Alexis Ramírez-Coronel A, Fadhel Obaid R, Alsaikhan F, Zabibah RS, Qasim QA, Altalbawy FMA, Fakri Mustafa Y, Mirzaei R, Karampoor S. Overview of the role and action mechanism of microRNA-128 in viral infections. Microb Pathog 2023; 176:106020. [PMID: 36746316 DOI: 10.1016/j.micpath.2023.106020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 01/21/2023] [Accepted: 01/31/2023] [Indexed: 02/07/2023]
Abstract
Recently in vivo and in vitro studies have provided evidence establishing the significance of microRNAs (miRNAs) in both physiological and pathological conditions. In this regard, the role of miRNA-128 (miR-128) in health and diseases has been found, and its critical regulatory role in the context of some viral diseases has been recently identified. For instance, it has been found that miR-128 can serve as an antiviral mediator and significantly limit the replication and dissemination of human immunodeficiency virus type 1 (HIV-1). Besides, it has been noted that poliovirus receptor-related 4 (PVRL4) is post-transcriptionally regulated by miR-128, representing possible miRNA targets that can modulate measles virus infection. Of note, the downregulation of seminal exosomes eca-miR-128 is associated with the long-term persistence of Equine arteritis virus (EAV) in the reproductive tract, and this particular miRNA is a putative regulator of chemokine ligand 16 (C-X-C motif) as determined by target prediction analysis. In this review, the latest information on the role and action mechanism of miR-128 in viral infections will be summarized and discussed in detail.
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Affiliation(s)
- Shadia Hamoud Alshahrani
- Medical Surgical Nursing Department, King Khalid University, Almahala, Khamis Mushate, Saudi Arabia
| | - Ameer A Alameri
- Department of Chemistry, University of Babylon, Babylon, Iraq
| | - Fitriani Kahar
- Medic Technology Laboratory, Poltekkes Kemenkes Semarang, Indonesia
| | - Andrés Alexis Ramírez-Coronel
- National University of Education, Azogues, Ecuador; Catholic University of Cuenca, Azogues Campus, Ecuador; University of Palermo, Buenos Aires, Argentina; CES University, Colombia, Azogues, Ecuador
| | - Rasha Fadhel Obaid
- Department of Biomedical Engineering, Al-Mustaqbal University College, Babylon, Iraq
| | - Fahad Alsaikhan
- College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Kingdom of Saudi Arabia
| | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | | | - Farag M A Altalbawy
- National Institute of Laser Enhanced Sciences (NILES), Cairo University, Giza 12613, Egypt; Department of Chemistry, University College of Duba, Tabuk University, Duba 71911, Saudi Arabia
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul 41001, Iraq
| | - Rasoul Mirzaei
- Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran.
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19
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Genetic Susceptibility to Hepatocellular Carcinoma in Patients with Chronic Hepatitis Virus Infection. Viruses 2023; 15:v15020559. [PMID: 36851773 PMCID: PMC9964813 DOI: 10.3390/v15020559] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/13/2023] [Accepted: 02/14/2023] [Indexed: 02/22/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally. The risk factors for HCC include chronic hepatitis B and C virus infections, excessive alcohol consumption, obesity, metabolic disease, and aflatoxin exposure. In addition to these viral and environmental risk factors, individual genetic predisposition is a major determinant of HCC risk. Familial clustering of HCC has been observed, and a hereditary factor likely contributes to the risk of HCC development. The familial aggregation may depend on a shared environment and genetic background as well as the interactions of environmental and genetic factors. Genome-wide association studies (GWASs) are one of the most practical tools for mapping the patterns of inheritance for the most common form of genomic variation, single nucleotide polymorphisms. This approach is practical for investigating genetic variants across the human genome, which is affected by thousands of common genetic variants that do not follow Mendelian inheritance. This review article summarizes the academic knowledge of GWAS-identified genetic loci and their association with HCC. We summarize the GWASs in accordance with various chronic hepatitis virus infection statuses. This genetic profiling could be used to identify candidate biomarkers to refine HCC screening and management by enabling individual risk-based personalization and stratification. A more comprehensive understanding of the genetic mechanisms underlying individual predisposition to HCC may lead to improvements in the prevention and early diagnosis of HCC and the development of effective treatment strategies.
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20
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Arai J, Otoyama Y, Nozawa H, Kato N, Yoshida H. The immunological role of ADAMs in the field of gastroenterological chronic inflammatory diseases and cancers: a review. Oncogene 2023; 42:549-558. [PMID: 36572816 PMCID: PMC9937921 DOI: 10.1038/s41388-022-02583-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 12/09/2022] [Accepted: 12/13/2022] [Indexed: 12/27/2022]
Abstract
Metalloproteinases cleave transmembrane proteins that play critical roles in inflammation and cancers. Metalloproteinases include a disintegrin and metalloprotease (ADAM), which we previously examined using a fluorescence assay system, and described their association with resistance to systemic therapy in cancer patients. There are also many reports on the relation between ADAM expression and the prognosis of patients with gastroenterological chronic inflammatory diseases and cancers. Inhibiting their immunomodulating activity in chronic inflammation restores innate immunity and potentially prevents the development of various cancers. Among the numerous critical immune system-related molecules, we focus on major histocompatibility complex class I polypeptide-related sequence A (MICA), MICB, intracellular adhesion molecule (ICAM)-1, TNF-α, IL-6 receptor (IL-6R), and Notch. This review summarizes our current understanding of the role of ADAMs in gastroenterological diseases with regard to the immune system. Several Food and Drug Administration (FDA)-approved inhibitors of ADAMs have been identified, and potential therapies for targeting ADAMs in the treatment of chronic inflammatory diseases and cancers are discussed. Some ongoing clinical trials for cancers targeting ADAMs are also introduced.
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Affiliation(s)
- Jun Arai
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
| | - Yumi Otoyama
- grid.410714.70000 0000 8864 3422Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Hisako Nozawa
- grid.410714.70000 0000 8864 3422Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Naoya Kato
- grid.136304.30000 0004 0370 1101Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hitoshi Yoshida
- grid.410714.70000 0000 8864 3422Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
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21
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Tchacrome I, Zhu Q, Saleh MA, Zou Y. Diseases association with the polymorphic major histocompatibility complex class I related chain a: MICA gene. Transpl Immunol 2022; 75:101665. [PMID: 35809815 DOI: 10.1016/j.trim.2022.101665] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 06/29/2022] [Accepted: 07/04/2022] [Indexed: 11/17/2022]
Abstract
The Major Histocompatibility Complex class I chain-related molecule A (MICA) genes encode a highly polymorphic glycoprotein among the cell surface antigens that trigger an immune response after allograft transplantation. It is encoded by the MICA gene, a member of the glycosylated MIC genes. Discovered in 1994, the MICA gene is located within the MHC class I region. Moreover, its biological function is achieved through the interaction with the NKG2D receptor. Unlike the classical HLA molecules, MICA protein is not associated with β2- microglobulin nor binds peptides. MICA gene expression may result in a cytotoxic response and IFN-γ secretion through the up-regulation by heat shock proteins in response to infection (Human Cytomegalovirus HCMV), mediated by NKG2D-expressing cells. Anti-MICA antibodies were identified as significant risk factors for antibody mediated rejection after being detected in sera of patients with graft rejection. In addition, soluble MICA proteins (sMICA) has been detected in the serum of transplant recipients with cancers. Furthermore, the association of MICA polymorphisms with infectious diseases, various autoimmune diseases, cancer, and allograft rejection or graft-versus-host disease (GVHD) has been studied. Moreover, numerous advanced disease studies centered on MICA polymorphism are independent of HLA association. In this review, we discussed the up-to-date data about MICA and the association of MICA polymorphism with infections, autoimmune diseases, graft-versus-host disease, and cancer.
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Affiliation(s)
- Imane Tchacrome
- Department of Immunology, Xiangya School of Medicine, Central South University, Hunan, China
| | - Quan Zhu
- Department of Immunology, Xiangya School of Medicine, Central South University, Hunan, China
| | - Mohammad Abu Saleh
- Department of Immunology, Xiangya School of Medicine, Central South University, Hunan, China
| | - Yizhou Zou
- Department of Immunology, Xiangya School of Medicine, Central South University, Hunan, China.
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22
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Ohta A, Ogawa E, Murata M, Matsumoto Y, Yamasaki S, Ikezaki H, Furusyo N. Impact of the PNPLA3 genotype on the risk of hepatocellular carcinoma after hepatitis C virus eradication. J Med Virol 2022; 94:5007-5014. [PMID: 35652276 DOI: 10.1002/jmv.27904] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 05/20/2022] [Accepted: 05/31/2022] [Indexed: 11/05/2022]
Abstract
Almost all chronic hepatitis C (CHC) patients can achieve sustained virological response (SVR) with direct-acting antivirals. However, the development of hepatocellular carcinoma (HCC), even after the achievement of SVR, continues to be a serious problem. The aim of this study was to assess the association between host genetic factors and de novo HCC after SVR. This single-center, retrospective study consisted of 442 consecutive CHC patients without a history of HCC who achieved SVR through interferon (IFN)-based and IFN-free therapy. Predictive factors associated with the development of HCC were determined by the Cox proportional hazards model. The single nucleotide polymorphism (SNP) genotyping data of 223 patients were available for analysis. Of the seven SNPs analyzed in this study, only the patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 GG genotype was significantly, positively associated with the development of de novo HCC after adjusting for age, sex, and fibrosis status (adjusted hazard ratio [aHR] 5.66, P=0.003). In multivariable analysis, age (aHR 1.05, P=0.007), advanced fibrosis (aHR 2.69, P=0.019), α-fetoprotein at post-12 weeks of treatment ≥7.0 ng/mL (aHR 3.85, P=0.001), and PNPLA3 GG genotype (aHR 3.02, P=0.004) were extracted as independent predictors of the development of de novo HCC. In conclusion, the PNPLA3 genotype was independently associated with the de novo HCC of CHC patients who achieved SVR. Such detailed knowledge of host genetic factors will be useful for HCC surveillance after HCV elimination. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Azusa Ohta
- Department of Environmental Medicine and Infectious Disease, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.,Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Eiichi Ogawa
- Department of Environmental Medicine and Infectious Disease, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.,Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Masayuki Murata
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Yuji Matsumoto
- Department of Environmental Medicine and Infectious Disease, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.,Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Sho Yamasaki
- Department of Environmental Medicine and Infectious Disease, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.,Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Hiroaki Ikezaki
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan.,Department of Comprehensive General Internal Medicine, Kyushu University Graduate School of Medical Sciences, Faculty of Medical Sciences, Fukuoka, Japan
| | - Norihiro Furusyo
- General Internal Medicine, Taihaku Avenue Clinic, Fukuoka, Japan
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23
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DiMaio D, Emu B, Goodman AL, Mothes W, Justice A. Cancer Microbiology. J Natl Cancer Inst 2022; 114:651-663. [PMID: 34850062 PMCID: PMC9086797 DOI: 10.1093/jnci/djab212] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 08/18/2021] [Accepted: 11/15/2021] [Indexed: 12/12/2022] Open
Abstract
Microbes play important roles in cancer from direct carcinogenic effects to their use in treatment. Cancers caused by microorganisms account for approximately 15% of cancers, primarily in low- and middle-income countries. Unique features of infectious carcinogens include their transmissibility, mutability, and specific immune interactions, which provide challenges and opportunities for cancer prevention and treatment. For these agents, infection control through exposure reduction, antivirals, antibiotics, and vaccines is cancer control. In addition, developing evidence suggests that microorganisms including the human microbiome can indirectly modulate cancer formation and influence the effectiveness and toxicity of cancer treatments. Finally, microorganisms themselves can be used to prevent or treat cancer. The convergence of these factors signals the emergence of a new field, cancer microbiology. Recognition of cancer microbiology will spur research, stimulate cross-disciplinary training, inform drug development, and improve public health.
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Affiliation(s)
- Daniel DiMaio
- Department of Genetics, Yale School of Medicine, New Haven, CT, USA
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, USA
- Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT, USA
- Yale Cancer Center, New Haven, CT, USA
| | - Brinda Emu
- Yale Cancer Center, New Haven, CT, USA
- Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, USA
| | - Andrew L Goodman
- Yale Cancer Center, New Haven, CT, USA
- Department of Microbial Pathogenesis, Yale University, New Haven, CT, USA
| | - Walther Mothes
- Yale Cancer Center, New Haven, CT, USA
- Department of Microbial Pathogenesis, Yale University, New Haven, CT, USA
| | - Amy Justice
- Yale Cancer Center, New Haven, CT, USA
- Department of General Medicine, Yale University, VA Medical Center, New Haven, CT, USA
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24
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Arai J, Otoyama Y, Fujita KI, Goto K, Tojo M, Katagiri A, Nozawa H, Kubota Y, Takahashi T, Ishida H, Tsunoda T, Matsumoto N, Ogawa K, Nakagawa R, Muroyama R, Kato N, Yoshida H. Baseline soluble MICA levels act as a predictive biomarker for the efficacy of regorafenib treatment in colorectal cancer. BMC Cancer 2022; 22:428. [PMID: 35443621 PMCID: PMC9019943 DOI: 10.1186/s12885-022-09512-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Accepted: 04/04/2022] [Indexed: 11/25/2022] Open
Abstract
Background To evaluate the effect of regorafenib on soluble MHC class I polypeptide-related sequence A (MICA) (sMICA) level in vitro. In addition, we clinically examined whether its plasma levels were associated with regorafenib activity in terms of progression-free survival (PFS) in patients with CRC. Methods Human CRC cell line HCT116 and HT29 cells were treated with regorafenib and its pharmacologically active metabolites, M2 or M5 at the same concentrations as those in sera of patients. We also examined the sMICA levels and the area under the plasma concentration–time curve of regorafenib, M2 and M5. Results Regorafenib, M2, and M5 significantly suppressed shedding of MICA in human CRC cells without toxicity. This resulted in the reduced production of sMICA. In the clinical examination, patients with CRC who showed long median PFS (3.7 months) had significantly lower sMICA levels than those with shorter median PFS (1.2 months) (p = 0.045). Conclusions MICA is an attractive agent for manipulating the immunological control of CRC and baseline sMICA levels could be a predictive biomarker for the efficacy of regorafenib treatment.
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Affiliation(s)
- Jun Arai
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, Japan.
| | - Yumi Otoyama
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, Japan
| | - Ken-Ichi Fujita
- Division of Cancer Genome and Pharmacotherapy, Department of Clinical Pharmacy, Showa University School of Pharmacy, Tokyo, Japan
| | - Kaku Goto
- Institut de Recherche Sur Les Maladies Virales Et Hépatiques, INSERM, Strasbourg, France
| | - Masayuki Tojo
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, Japan
| | - Atsushi Katagiri
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, Japan
| | - Hisako Nozawa
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, Japan
| | - Yutaro Kubota
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Takehiro Takahashi
- Division of Medical Oncology, Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Hiroo Ishida
- Division of Internal Medicine, Department of Medicine, Showa University Hokubu Hospital, Yokohama, Japan
| | - Takuya Tsunoda
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Natsumi Matsumoto
- Division of Cancer Genome and Pharmacotherapy, Department of Clinical Pharmacy, Showa University School of Pharmacy, Tokyo, Japan
| | - Keita Ogawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Ryo Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Ryosuke Muroyama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hitoshi Yoshida
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, Japan
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25
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A Case of Rapidly Progressing Hepatocellular Carcinoma after Administration of JAK Inhibitors to Treat Rheumatoid Arthritis. Case Rep Rheumatol 2022; 2022:6852189. [PMID: 35391896 PMCID: PMC8983253 DOI: 10.1155/2022/6852189] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 03/14/2022] [Indexed: 11/20/2022] Open
Abstract
We report a case of rapidly progressing hepatocellular carcinoma after administration of Janus kinase (JAK) inhibitors to treat rheumatoid arthritis. A 76-year-old man was referred to our Department for pain in multiple joints and was diagnosed with rheumatoid arthritis. Blood tests revealed elevated hepatobiliary enzymes, but various tests revealed no signs suggestive of malignancy. He took baricitinib for 2 months followed by tofacitinib for 4 months. After that, he was diagnosed with hepatocellular carcinoma based on imaging findings and elevated tumor markers. This case showed the possibility of a causal relationship between JAK inhibitors and malignancy.
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26
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Wang C, Gao N, Yang L, Guo Y, Fang Y, Wang T, Xu C, Li GF, Zhou J, Zhang Y, Wen Q, Qiao H. Stat4 rs7574865 polymorphism promotes the occurrence and progression of hepatocellular carcinoma via the Stat4/CYP2E1/FGL2 pathway. Cell Death Dis 2022; 13:130. [PMID: 35136014 PMCID: PMC8826371 DOI: 10.1038/s41419-022-04584-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 01/06/2022] [Accepted: 01/20/2022] [Indexed: 12/25/2022]
Abstract
Although there are many studies on the relationship between genetic polymorphisms and the incidence of diseases, mechanisms are rarely known. We report the mechanism by which signal transducer and activator of transcription 4 (stat4) rs7574865 promotes the occurrence and progression of hepatocellular carcinoma (HCC). We found that the GG genotype at stat4 rs7574865 was a risk genotype, and STAT4 levels in serum and peritumoral tissue from HCC patients with the GG genotype were significantly higher than those found in TT or TG carriers. Furthermore, HCC patients with the GG genotype or elevated STAT4 levels had poor prognoses. In vitro experiments demonstrated that STAT4 silencing promoted apoptosis and inhibited the invasion and migration of HepG2 and L02 cells. Proteomic analysis of HCC peritumors identified 273 proteins related to STAT4, of which CYP2E1 activity and FGL2 content exhibited the highest positive correlation. The relationship between CYP2E1 and FGL2 was also confirmed in cyp2e1−/− mice and in CYP2E1 inhibitor-treated mice. In conclusion, this study elucidates the mechanism by which the stat4 rs7574865 polymorphism promotes the occurrence and progression of HCC via the Stat4/CYP2E1/FGL2 pathway.
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Affiliation(s)
- Caie Wang
- Institute of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, China.,Department of Pharmacy, the First Affiliated Hospital of Henan University of Science and Technology, Clinical Medical College of Henan University of Science and Technology, Luoyang, Henan, China
| | - Na Gao
- Institute of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Lukui Yang
- Department of Pharmacy, the First Affiliated Hospital of Henan University of Science and Technology, Clinical Medical College of Henan University of Science and Technology, Luoyang, Henan, China
| | - Yuanyuan Guo
- Institute of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Yan Fang
- Institute of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Tong Wang
- Institute of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Chen Xu
- Institute of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Gui Fang Li
- Department of Pharmacy, the First Affiliated Hospital of Henan University of Science and Technology, Clinical Medical College of Henan University of Science and Technology, Luoyang, Henan, China
| | - Jun Zhou
- Institute of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Yunfei Zhang
- Institute of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Qiang Wen
- Institute of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Hailing Qiao
- Institute of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, China.
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27
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Srivani Nagam L, Vadde R, Jinka R. Polymorphisms in hepatocellular carcinoma. THERANOSTICS AND PRECISION MEDICINE FOR THE MANAGEMENT OF HEPATOCELLULAR CARCINOMA 2022:125-133. [DOI: 10.1016/b978-0-323-98806-3.00013-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Ezzat R, Eltabbakh M, El Kassas M. Unique situation of hepatocellular carcinoma in Egypt: A review of epidemiology and control measures. World J Gastrointest Oncol 2021; 13:1919-1938. [PMID: 35070033 PMCID: PMC8713321 DOI: 10.4251/wjgo.v13.i12.1919] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/17/2021] [Accepted: 10/18/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common primary malignancy worldwide, and the third most common cause of death among cancers worldwide. HCC occurs in several pre-existing conditions, including hepatitis C, hepatitis B virus, and non-alcoholic cirrhosis. Egypt used to be the country with the heaviest hepatitis C virus (HCV) burden. The relationship between HCV and HCC is an important research area. In Egypt, HCC is a significant public health problem. A possible cause for the increasing rates of detection of HCC in Egypt is the mass screening program that was carried by the government for detecting and treating HCV. A multidisciplinary approach is now widely applied to HCC management in health centers all over Egypt. Different treatment modalities are available in Egypt, with success rates comparable to global rates. The Egyptian health authorities have made the elimination of HCV from Egypt a special priority, and this approach should lead to a decrease in number of HCC cases in the near future. In this article we review the current situation of HCC in Egypt, including epidemiological aspects, relevant risk factors for HCC development, strategies, and efforts established by health authorities for the screening and prevention of both HCV and HCC in Egypt. We highlight the different modalities for HCC treatment.
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Affiliation(s)
- Reem Ezzat
- Internal Medicine Department, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | - Mohamed Eltabbakh
- Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt
| | - Mohamed El Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo 11795, Cairo, Egypt
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Stickel F, Hampe J. Rs708113 in WNT3A-WNT9A and hepatocellular carcinoma risk. Lancet Oncol 2021; 23:14-16. [PMID: 34902337 DOI: 10.1016/s1470-2045(21)00663-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 11/05/2021] [Accepted: 11/09/2021] [Indexed: 12/14/2022]
Affiliation(s)
- Felix Stickel
- Department of Gastroenterology and Hepatology, University Hospital Zürich, CH-8091 Zürich, Switzerland.
| | - Jochen Hampe
- Medical Department 1, University Hospital Dresden, Technical University of Dresden, Dresden, Germany
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Wang Z, Budhu AS, Shen Y, Wong LL, Hernandez BY, Tiirikainen M, Ma X, Irwin ML, Lu L, Zhao H, Lim JK, Taddei T, Mishra L, Pawlish K, Stroup A, Brown R, Nguyen MH, Koshiol J, Hernandez MO, Forgues M, Yang H, Lee M, Huang Y, Iwasaki M, Goto A, Suzuki S, Matsuda K, Tanikawa C, Kamatani Y, Mann D, Guarnera M, Shetty K, Thomas CE, Yuan J, Khor CC, Koh W, Risch H, Wang XW, Yu H. Genetic susceptibility to hepatocellular carcinoma in chromosome 22q13.31, findings of a genome-wide association study. JGH Open 2021; 5:1363-1372. [PMID: 34950780 PMCID: PMC8674550 DOI: 10.1002/jgh3.12682] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 11/05/2021] [Accepted: 11/07/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND AIM Chronic hepatitis C virus (HCV) infection, long-term alcohol use, cigarette smoking, and obesity are the major risk factors for hepatocellular carcinoma (HCC) in the United States, but the disease risk varies substantially among individuals with these factors, suggesting host susceptibility to and gene-environment interactions in HCC. To address genetic susceptibility to HCC, we conducted a genome-wide association study (GWAS). METHODS Two case-control studies on HCC were conducted in the United States. DNA samples were genotyped using the Illumian microarray chip with over 710 000 single nucleotide polymorphisms (SNPs). We compared these SNPs between 705 HCC cases and 1455 population controls for their associations with HCC and verified our findings in additional studies. RESULTS In this GWAS, we found that two SNPs were associated with HCC at P < 5E-8 and six SNPs at P < 5E-6 after adjusting for age, sex, and the top three principal components (PCs). Five of the SNPs in chromosome 22q13.31, three in PNPLA3 (rs2281135, rs2896019, and rs4823173) and two in SAMM50 (rs3761472, rs3827385), were replicated in a small US case-control study and a cohort study in Singapore. The associations remained significant after adjusting for body mass index and HCV infection. Meta-analysis of multiple datasets indicated that these SNPs were significantly associated with HCC. CONCLUSIONS SNPs in PNPLA3 and SAMM50 are known risk loci for nonalcoholic fatty liver disease (NAFLD) and are suspected to be associated with HCC. Our GWAS demonstrated the associations of these SNPs with HCC in a US population. Biological mechanisms underlying the relationship remain to be elucidated.
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Affiliation(s)
- Zhanwei Wang
- University of Hawaii Cancer CenterHonoluluHawaiiUSA
| | - Anuradha S Budhu
- Laboratory of Human Carcinogenesis, Liver Cancer Program, Center for Cancer ResearchNational Cancer InstituteBethesdaMarylandUSA
| | - Yi Shen
- University of Hawaii Cancer CenterHonoluluHawaiiUSA
| | | | | | | | - Xiaomei Ma
- Yale School of Public HealthNew HavenConnecticutUSA
| | | | - Lingeng Lu
- Yale School of Public HealthNew HavenConnecticutUSA
| | - Hongyu Zhao
- Yale School of Public HealthNew HavenConnecticutUSA
| | | | | | - Lopa Mishra
- Center for Translational Medicine, Department of SurgeryThe George Washington UniversityWashingtonDistrict of ColumbiaUSA
| | - Karen Pawlish
- New Jersey State Cancer Registry, New Jersey Department of HealthTrentonNew JerseyUSA
| | - Antoinette Stroup
- Rutgers Cancer Institute, and Rutgers School of Public HealthNew BrunswickNew JerseyUSA
| | - Robert Brown
- Weill Cornell Medical College, and College of Physicians and Surgeons, Columbia UniversityNew YorkNew YorkUSA
| | - Mindie H Nguyen
- Division of Gastroenterology and HepatologyStanford University Medical CenterPalo AltoCaliforniaUSA
| | - Jill Koshiol
- Division of Cancer Epidemiology and GeneticsNational Cancer InstituteBethesdaMarylandUSA
| | - Maria O Hernandez
- Laboratory of Human CarcinogenesisCenter for Cancer Research, National Cancer InstituteBethesdaMarylandUSA
| | - Marshonna Forgues
- Laboratory of Human CarcinogenesisCenter for Cancer Research, National Cancer InstituteBethesdaMarylandUSA
| | - Hwai‐I Yang
- Genomics Research Center, Academia SinicaTaipeiTaiwan
- Institute of Clinical Medicine, National Yang Ming UniversityTaipeiTaiwan
| | - Mei‐Hsuan Lee
- Institute of Clinical Medicine, National Yang Ming UniversityTaipeiTaiwan
| | - Yu‐Han Huang
- Institute of Clinical Medicine, National Yang Ming UniversityTaipeiTaiwan
| | - Motoki Iwasaki
- Division of EpidemiologyCenter for Public Health Sciences, National Cancer CenterTokyoJapan
| | - Atsushi Goto
- Division of EpidemiologyCenter for Public Health Sciences, National Cancer CenterTokyoJapan
| | - Shiori Suzuki
- Division of EpidemiologyCenter for Public Health Sciences, National Cancer CenterTokyoJapan
| | - Koichi Matsuda
- Graduate School of Frontier Sciences, and Institute of Medical Science, University of TokyoTokyoJapan
| | - Chizu Tanikawa
- Graduate School of Frontier Sciences, and Institute of Medical Science, University of TokyoTokyoJapan
| | - Yoichiro Kamatani
- Graduate School of Frontier Sciences, and Institute of Medical Science, University of TokyoTokyoJapan
| | - Dean Mann
- Department of PathologyUniversity of Maryland School of MedicineBaltimoreMarylandUSA
| | - Maria Guarnera
- Department of PathologyUniversity of Maryland School of MedicineBaltimoreMarylandUSA
| | - Kirti Shetty
- Department of Gastroenterology and HepatologyUniversity of Maryland School of MedicineBaltimoreMarylandUSA
| | - Claire E Thomas
- Division of Cancer Control and Population SciencesUniversity of Pittsburgh Medical Center (UPMC) Hillman Cancer CenterPittsburghPennsylvaniaUSA
- Department of EpidemiologyGraduate School of Public Health, University of PittsburghPittsburghPennsylvaniaUSA
| | - Jian‐Min Yuan
- Division of Cancer Control and Population SciencesUniversity of Pittsburgh Medical Center (UPMC) Hillman Cancer CenterPittsburghPennsylvaniaUSA
- Department of EpidemiologyGraduate School of Public Health, University of PittsburghPittsburghPennsylvaniaUSA
| | - Chiea Chuen Khor
- Genome Institute of Singapore, Agency for Science, Technology and ResearchSingaporeSingapore
- Singapore Eye Research InstituteSingaporeSingapore
| | - Woon‐Puay Koh
- Health Systems and Services Research, Duke‐NUS Medical School SingaporeSingaporeSingapore
- Saw Swee Hock School of Public Health, National University of SingaporeSingaporeSingapore
| | - Harvey Risch
- Yale School of Public HealthNew HavenConnecticutUSA
| | - Xin Wei Wang
- Laboratory of Human Carcinogenesis, Liver Cancer Program, Center for Cancer ResearchNational Cancer InstituteBethesdaMarylandUSA
| | - Herbert Yu
- University of Hawaii Cancer CenterHonoluluHawaiiUSA
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Wang H, Yang B, Cai X, Cheng X, Shen N, Liu L, Li J, Wang Y, He H, Ying P, Li B, Lu Z, Yang N, Wang X, Zhang F, Li Y, Wang W, Ning C, Zhu Y, Chang J, Miao X, Tian J, Zhong R. Hepatocellular carcinoma risk variant modulates lncRNA HLA-DQB1-AS1 expression via a long-range enhancer-promoter interaction. Carcinogenesis 2021; 42:1347-1356. [PMID: 34665859 DOI: 10.1093/carcin/bgab095] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 09/15/2021] [Accepted: 10/18/2021] [Indexed: 01/01/2023] Open
Abstract
Substantial evidence highlighted the critical role of long non-coding RNAs (lncRNA) in driving hepatocarcinogenesis. We hypothesized that functional variants in genome-wide association studies (GWASs) associated loci might alter the expression levels of lncRNAs and contribute to the development of hepatocellular carcinoma (HCC). Here, we prioritized potentially cis-expression quantitative trait loci-based single nucleotide polymorphism (SNP)-lncRNA association together with the physical interaction by the analyses from Hi-C data in GWAS loci of chronic hepatitis B and HCC. Subsequently, by leveraging two-stage case-control study (1738 hepatitis B [HBV]) related HCC cases and 1988 HBV persistent carriers) and biological assays, we identified that rs2647046 was significantly associated with HCC risk (odds ratio = 1.26, 95% CI = 1.11 to 1.43, P = 4.14 × 10-4). Luciferase reporter assays and electrophoretic mobility shift assays showed that rs2647046 A allele significantly increased transcriptional activity via influencing transcript factor binding affinity. Allele-specific chromosome conformation capture assays revealed that enhancer with rs2647046 interacted with the HLA-DQB1-AS1 promoter to allele-specifically influence its expression by CTCF-mediated long-range loop. Cell proliferation assays indicated that HLA-DQB1-AS1 is a potential oncogene in HCC. Our study showed HLA-DQB1-AS1 regulated by a causal SNP in a long-range interaction manner conferred the susceptibility to HCC, suggesting an important mechanism of modulating lncRNA expression for risk-associated SNPs in the etiology of HCC.
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Affiliation(s)
- Haoxue Wang
- Department of Epidemiology and Biostatistics and Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Beifang Yang
- Hubei Institute for Infectious Disease Control and Prevention, Hubei Provincial Center for Disease Control and Prevention, Wuhan, Hubei, China
| | - Xiaomin Cai
- Department of Epidemiology and Biostatistics and Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Xiang Cheng
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Na Shen
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Li Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jiaoyuan Li
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ying Wang
- Department of Virology, Wuhan Centers for Disease Prevention and Control, Wuhan, Hubei, China
| | - Heng He
- Department of Epidemiology and Biostatistics and Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Pingting Ying
- Department of Epidemiology and Biostatistics and Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Bin Li
- Department of Epidemiology and Biostatistics and Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Zequn Lu
- Department of Epidemiology and Biostatistics and Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Nan Yang
- Department of Epidemiology and Biostatistics and Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Xiaoyang Wang
- Department of Epidemiology and Biostatistics and Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Fuwei Zhang
- Department of Epidemiology and Biostatistics and Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Yanmin Li
- Department of Epidemiology and Biostatistics and Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Wenzhuo Wang
- Department of Epidemiology and Biostatistics and Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Caibo Ning
- Department of Epidemiology and Biostatistics and Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Ying Zhu
- School of Health Sciences, Wuhan University, Wuhan 430071, Hubei, China
| | - Jiang Chang
- Department of Epidemiology and Biostatistics and Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Xiaoping Miao
- School of Health Sciences, Wuhan University, Wuhan 430071, Hubei, China
| | - Jianbo Tian
- School of Health Sciences, Wuhan University, Wuhan 430071, Hubei, China
| | - Rong Zhong
- Department of Epidemiology and Biostatistics and Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
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Schoenberg MB, Li X, Li X, Han Y, Börner N, Koch D, Guba MO, Werner J, Bazhin AV. The interactions between major immune effector cells and Hepatocellular Carcinoma: A systematic review. Int Immunopharmacol 2021; 101:108220. [PMID: 34673334 DOI: 10.1016/j.intimp.2021.108220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Revised: 09/13/2021] [Accepted: 09/30/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most common liver neoplasm with high morbidity and mortality. Tumor immunotherapy might be promising adjuvant therapy for HCC after surgery. To better develop HCC immunotherapy, comprehensive understanding of cell-cell interactions between immune effector cells and HCC cells remains crucial. AIM To review the existing studies to summarize the cell-cell interactions between major immune effector cells and HCC cells providing new data for HCC immunotherapy. METHODS A systematic review was conducted by searching PubMed database covering all papers published in recent five years up to January 2020. The guidelines of the preferred reporting items for systematic reviews were firmly followed. RESULTS There are 9 studies researching the interactions between CD8+ T lymphocytes and HCC cells and 22 studies researching that between natural killer (NK) cells and HCC cells. Among the 9 studies, 6 studies reported that CD8+ T lymphocytes showed cytotoxicity towards HCC cells while 3 studies found CD8+ T lymphocytes were impaired by HCC cells. Among the 22 studies, 20 studies presented that NK cells could inhibit HCC cells. Two studies were found to report NK cell dysfunction in HCC. CONCLUSION Based on the systematic analysis, we concluded that CD8+ T lymphocytes and NK cells can inhibit HCC cells. While in turn, HCC cells can also result in the dysfunction of those effector cells through various mechanisms. Organoids and direct contact cell co-culture with primary HCC cells and TILs should be the most innovative way to investigate the interactions and develop novel immunotherapy.
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Affiliation(s)
- Markus Bo Schoenberg
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Xiaokang Li
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany; Department of Dermatology, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xinyu Li
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany; Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Yongsheng Han
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Nikolaus Börner
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Dominik Koch
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Markus Otto Guba
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany; Transplantation Center Munich, Hospital of the LMU, Campus Grosshadern, Munich, Germany
| | - Jens Werner
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany; Bavarian Cancer Research Center (BZKF), Munich, Germany
| | - Alexandr V Bazhin
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany.
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Xu Y, Wang T, Zeng J, Wang B, Zhou L, Yang M, Zhang L, Zhang N. Integrative Functional Genomics Implicated the Key T-/B-Cell Deficiency Regulator RAG1 in Transarterial Chemoembolization of Hepatocellular Carcinoma. Front Cell Dev Biol 2021; 9:720791. [PMID: 34646823 PMCID: PMC8502842 DOI: 10.3389/fcell.2021.720791] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Accepted: 08/30/2021] [Indexed: 01/22/2023] Open
Abstract
Transarterial chemoembolization (TACE) has significantly prolonged overall survival (OS) of unresectable hepatocellular carcinoma (HCC) patients. Unfortunately, there are still a portion of patients without therapeutic responses to TACE. Although genome-wide association studies identified multiple HCC susceptibility SNPs, it is still largely unclear how genome-wide identified functional SNPs impacting gene expression contribute to the prognosis of TACE-treated HCC patients. In this study, we developed an integrative functional genomics methodology to identify gene expression-related SNPs significantly contributing to prognosis of TACE-treated HCC patients across the whole genome. Employing integration of data from expression quantitative trait locus (eQTLs) analyses of The Cancer Genome Atlas (TCGA) liver hepatocellular carcinoma (LIHC) as well as the 1000 Genomes project, we successfully annotated 60 gene expression-related SNPs which are associated with OS of the TCGA patients. After genotyping these 60 SNPs in our TACE cohort, we identified four SNPs (rs12574873, rs12513391, rs34597395, and rs35624901) which are significantly associated with OS of HCC patients treated with TACE. For instance, multivariate Cox proportional hazards model indicated that the rs35624901 Deletion.Deletion (Del.Del) genotype carriers had markedly prolonged OS and a 55% decreased death risk compared with individuals with the GG genotype after TACE therapy (p = 8.3 × 10–5). In support of this, the rs35624901 Del.Del genotype is correlated to higher expression of RAG1, a key T-/B-cell deficiency regulator. Our findings reported the first evidence supporting the prognostic value of four eQTL SNPs in TACE-treated HCC patients. Importantly, our data implicated that antitumor immunity might contribute to TACE efficiency for unresectable HCC patients.
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Affiliation(s)
- Yeyang Xu
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Teng Wang
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jiajia Zeng
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Bowen Wang
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Liqing Zhou
- Department of Radiation Oncology, Huaian No. 2 Hospital, Huaian, China
| | - Ming Yang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Li Zhang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Nasha Zhang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
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Demirtas CO, Brunetto MR. Surveillance for hepatocellular carcinoma in chronic viral hepatitis: Is it time to personalize it? World J Gastroenterol 2021; 27:5536-5554. [PMID: 34588750 PMCID: PMC8433616 DOI: 10.3748/wjg.v27.i33.5536] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 04/28/2021] [Accepted: 08/02/2021] [Indexed: 02/06/2023] Open
Abstract
Surveillance with abdominal ultrasound with or without alpha-fetoprotein is recommended by clinical practice guidelines for patients who are considered to be at risk of developing hepatocellular carcinoma (HCC), including those with cirrhosis, advanced fibrosis and special subgroups of chronic hepatitis B (CHB). Application of the standard surveillance strategy to all patients with chronic liver disease (CLD) with or without cirrhosis imposes major sustainability and economic burdens on healthcare systems. Thus, a number of HCC risk scores were constructed, mainly from Asian cohorts, to stratify the HCC prediction in patients with CHB. Similarly, even if less than for CHB, a few scoring systems were developed for chronic hepatitis C patients or cirrhotic patients with CLD of different etiologies. Recently, a few newsworthy HCC-risk algorithms were developed for patients with cirrhosis using the combination of serologic HCC markers and clinical parameters. Overall, the HCC risk stratification appears at hand by several validated multiple score systems, but their optimal performance is obtained only in populations who show highly homogenous clinic-pathologic, epidemiologic, etiologic and therapeutic characteristics and this limitation poses a major drawback to their sustainable use in clinical practice. A better understanding of the dynamic process driving the progression from CLD to HCC derived from studies based on molecular approaches and genetics, epigenetics and liquid biopsy will enable the identification of new biomarkers to define the individual risk of HCC in the near future, with the possibility to achieve a real and cost/effective personalization of surveillance.
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Affiliation(s)
- Coskun Ozer Demirtas
- Department of Gastroenterology and Hepatology, Marmara University, School of Medicine, Istanbul 34854, Turkey
| | - Maurizia Rossana Brunetto
- Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa 56125, Italy
- Hepatology Unit, University Hospital of Pisa, Pisa 56125, Italy
- Biostructure and Bio-imaging Institute, National Research Council of Italy, Naples 56125, Italy
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35
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Liu PC, Chan C, Huang YH, Chen YJ, Liao SF, Lin YJ, Huang C, Lu SN, Jen CL, Wang LY, Yang HI, Shen CY, Chen CJ, Lee MH. Genetic variants associated with serum alanine aminotransferase levels among patients with hepatitis C virus infection: A genome-wide association study. J Viral Hepat 2021; 28:1265-1273. [PMID: 34003538 DOI: 10.1111/jvh.13550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/12/2021] [Accepted: 04/17/2021] [Indexed: 12/09/2022]
Abstract
Information on genetic variants associated with elevated serum alanine aminotransferase (ALT) levels remains limited. A genome-wide association study was performed to identify single-nucleotide polymorphisms (SNPs) associated with ALT levels. The ALT-associated SNP was further evaluated for hepatocellular carcinoma (HCC) risk. A cohort of 892 anti-HCV seropositive patients was used for genome-wide SNP array to examine the associations with baseline ALT levels. SNPs <10-5 were further tested for associations with serial ALT levels then validated in 486 anti-HCV seropositives. Multinomial logistic regressions were used to estimate odds ratios (ORs) and 95% confidence intervals of SNPs associated with ALT. The SNP was evaluated for HCC risk by using Cox's proportional hazards models. After quality control, 803 participants with 564,464 SNPs were included in the analysis. Of these, 12 SNPs were associated with ALT (p < 10-5 ). Among the participants, 158 (19.7%) had ALT persistently ≤15 U/L, 327 (40.7%) ever >15 U/L but never >45 U/L, and 318 (39.6%) ever >45 U/L during follow-up. The rs568800 was associated with serial ALT levels, and this was replicated in the external population significantly (p < .05). The A allele (vs C) of rs568800 was associated with ALT >15 U/L but ≤45 U/L and ALT >45 U/L, with the adjusted ORs of 1.41 (1.11-1.78) and 1.86 (1.34-2.60), respectively. The adjusted HRs for HCC were 2.09 (0.90-4.89) for AC and 2.64 (1.13-6.17) for AA (CC as a reference). In conclusion, the rs568800 was associated with serum ALT levels and HCC risk. Clinical utility should be evaluated among patients who have received antivirals.
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Affiliation(s)
- Po-Chun Liu
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chi Chan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yu-Han Huang
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yen-Ju Chen
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Shu-Fen Liao
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Yu-Ju Lin
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Claire Huang
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Sheng-Nan Lu
- Department of Gastroenterology, Chang-Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chin-Lan Jen
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Li-Yu Wang
- Department of Medicine, Mackay Medical College, Taipei, Taiwan
| | - Hwai-I Yang
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Chen-Yang Shen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Chien-Jen Chen
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Mei-Hsuan Lee
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
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Alves E, McLeish E, Blancafort P, Coudert JD, Gaudieri S. Manipulating the NKG2D Receptor-Ligand Axis Using CRISPR: Novel Technologies for Improved Host Immunity. Front Immunol 2021; 12:712722. [PMID: 34456921 PMCID: PMC8397441 DOI: 10.3389/fimmu.2021.712722] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 07/28/2021] [Indexed: 12/26/2022] Open
Abstract
The activating immune receptor natural killer group member D (NKG2D) and its cognate ligands represent a fundamental surveillance system of cellular distress, damage or transformation. Signaling through the NKG2D receptor-ligand axis is critical for early detection of viral infection or oncogenic transformation and the presence of functional NKG2D ligands (NKG2D-L) is associated with tumor rejection and viral clearance. Many viruses and tumors have developed mechanisms to evade NKG2D recognition via transcriptional, post-transcriptional or post-translational interference with NKG2D-L, supporting the concept that circumventing immune evasion of the NKG2D receptor-ligand axis may be an attractive therapeutic avenue for antiviral therapy or cancer immunotherapy. To date, the complexity of the NKG2D receptor-ligand axis and the lack of specificity of current NKG2D-targeting therapies has not allowed for the precise manipulation required to optimally harness NKG2D-mediated immunity. However, with the discovery of clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR-associated (Cas) proteins, novel opportunities have arisen in the realm of locus-specific gene editing and regulation. Here, we give a brief overview of the NKG2D receptor-ligand axis in humans and discuss the levels at which NKG2D-L are regulated and dysregulated during viral infection and oncogenesis. Moreover, we explore the potential for CRISPR-based technologies to provide novel therapeutic avenues to improve and maximize NKG2D-mediated immunity.
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Affiliation(s)
- Eric Alves
- School of Human Sciences, The University of Western Australia, Perth, WA, Australia
- Cancer Epigenetics Laboratory, The Harry Perkins Institute of Medical Research, Perth, WA, Australia
| | - Emily McLeish
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA, Australia
| | - Pilar Blancafort
- School of Human Sciences, The University of Western Australia, Perth, WA, Australia
- Cancer Epigenetics Laboratory, The Harry Perkins Institute of Medical Research, Perth, WA, Australia
- The Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Jerome D. Coudert
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA, Australia
- Perron Institute for Neurological and Translational Science, Perth, WA, Australia
- School of Medicine, University of Notre Dame, Fremantle, WA, Australia
| | - Silvana Gaudieri
- School of Human Sciences, The University of Western Australia, Perth, WA, Australia
- Institute for Immunology and Infectious Diseases, Murdoch University, Perth, WA, Australia
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
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Araujo OC, de Paula VS, do Ó KM, Villela-Nogueira CA, Araujo NM. Association of Polymorphisms in the Glutathione S-Transferase Theta-1 Gene with Cirrhosis and Hepatocellular Carcinoma in Brazilian Patients with Chronic Hepatitis C. Vaccines (Basel) 2021; 9:831. [PMID: 34451956 PMCID: PMC8402309 DOI: 10.3390/vaccines9080831] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 07/14/2021] [Accepted: 07/20/2021] [Indexed: 12/15/2022] Open
Abstract
Oxidative stress contributes to hepatitis C virus (HCV)-induced liver damage. Host genetic factors may be involved in progression of HCV infection. The present study was conducted to determine the influence of glutathione S-transferase (GST)-M1 and T1 gene polymorphisms during different stages of HCV infection, including chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The study population comprised 190 patients (47 with chronic hepatitis, 83 with cirrhosis (without HCC), and 60 with HCC). GSTM1 and GSTT1 gene polymorphisms were analyzed via multiplex polymerase chain reaction. The GSTT1-null genotype was more commonly detected in patients with cirrhosis (n = 17; 20.5%) and HCC (n = 13; 21.7%) than those with chronic hepatitis (n = 3; 6.4%). The differences in GSTT1-null genotype frequencies were significant for cirrhosis vs. chronic hepatitis (odds ratio, OR, 3.778 (95% confidence interval, CI, 1.045-13.659); p = 0.043) and HCC vs. chronic hepatitis (OR, 4.057 (95% CI, 1.083-15.201); p = 0.038) groups. However, the incidence of individual GSTM1-null or combined GSTM1/GSTT1 double-null genotypes did not vary significantly between the groups. Our collective findings support the utility of the GSTT1-null genotype as a useful biomarker for liver disease progression in Brazilian patients with chronic hepatitis C.
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Affiliation(s)
- Oscar C. Araujo
- Laboratory of Molecular Virology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 21040-360, Brazil; (O.C.A.); (V.S.d.P.)
| | - Vanessa S. de Paula
- Laboratory of Molecular Virology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 21040-360, Brazil; (O.C.A.); (V.S.d.P.)
| | | | - Cristiane A. Villela-Nogueira
- Hepatology Division, Clementino Fraga Filho University Hospital, School of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-617, Brazil;
| | - Natalia M. Araujo
- Laboratory of Molecular Virology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 21040-360, Brazil; (O.C.A.); (V.S.d.P.)
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Song Y, Xing H, Zhou L, Zhang N, Yang M. LncRNA H19 modulated by miR-146b-3p/miR-1539-mediated allelic regulation in transarterial chemoembolization of hepatocellular carcinoma. Arch Toxicol 2021; 95:3063-3070. [PMID: 34251499 DOI: 10.1007/s00204-021-03119-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 07/07/2021] [Indexed: 12/19/2022]
Abstract
Transarterial chemoembolization (TACE) is an effective treatment for unresectable hepatocellular carcinoma (HCC) patients. Although overall survival (OS) of TACE-treated patients has been evidently prolonged, not all unresectable HCC patients can benefit from TACE. Genome-wide association studies identified multiple HCC susceptibility single nucleotide polymorphisms (SNPs). However, it is still unclear how lncRNAs and their functional SNPs impact therapeutic responses of TACE. In the study, we hypothesized that the functional lncRNA H19 SNP(s) might impact H19 expression and, thus, prognosis of TACE-treated HCC patients. We found that the H19 rs3741219 SNP was significantly associated with OS of HCC patients received TACE. Cox proportional hazards model demonstrated that the rs3741219 CC genotype was associated with longer OS and a 37% decreased death risk compared with the TT carriers after TACE therapy (P = 0.001). Interestingly, the rs3741219 T-to-C change led to allelic down-regulation of lncRNA H19 expression via creating the binding sites of miR-146b-3p and miR-1539. Luciferase reporter gene assays indicated that miR-146b-3p and miR-1539 could markedly silence the rs3741219 C-allelic H19 expression but not lncRNA H19 with the T allele. Consistently, there was significantly reduced expression of lncRNA H19 in HCC and normal tissues of the C allele carriers compared with the H19 levels in patients with the T allele. Knock-down of lncRNA H19 significantly promoted the anti-viability efficiency of oxaliplatin (the main chemotherapy drug used in TACE) to HCC cells. In view of these results, we assume that lncRNA H19 might be a potential therapeutic target for unresectable HCC patients.
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Affiliation(s)
- Yemei Song
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Huaixin Xing
- Department of Anesthesiology, Shandong Cancer Hospital and Institute, Shandong First Medical University, and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Liqing Zhou
- Department of Radiation Oncology, Huaian No. 2 Hospital, Huaian, Jiangsu Province, China
| | - Nasha Zhang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Ming Yang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China.
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Reungoat E, Grigorov B, Zoulim F, Pécheur EI. Molecular Crosstalk between the Hepatitis C Virus and the Extracellular Matrix in Liver Fibrogenesis and Early Carcinogenesis. Cancers (Basel) 2021; 13:cancers13092270. [PMID: 34065048 PMCID: PMC8125929 DOI: 10.3390/cancers13092270] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/01/2021] [Accepted: 05/03/2021] [Indexed: 12/16/2022] Open
Abstract
Simple Summary In the era of direct-acting antivirals against the hepatitis C virus (HCV), curing chronic hepatitis C has become a reality. However, while replicating chronically, HCV creates a peculiar state of inflammation and oxidative stress in the infected liver, which fuels DNA damage at the onset of HCV-induced hepatocellular carcinoma (HCC). This cancer, the second leading cause of death by cancer, remains of bad prognosis when diagnosed. This review aims to decipher how HCV durably alters elements of the extracellular matrix that compose the liver microenvironment, directly through its viral proteins or indirectly through the induction of cytokine secretion, thereby leading to liver fibrosis, cirrhosis, and, ultimately, HCC. Abstract Chronic infection by the hepatitis C virus (HCV) is a major cause of liver diseases, predisposing to fibrosis and hepatocellular carcinoma. Liver fibrosis is characterized by an overly abundant accumulation of components of the hepatic extracellular matrix, such as collagen and elastin, with consequences on the properties of this microenvironment and cancer initiation and growth. This review will provide an update on mechanistic concepts of HCV-related liver fibrosis/cirrhosis and early stages of carcinogenesis, with a dissection of the molecular details of the crosstalk during disease progression between hepatocytes, the extracellular matrix, and hepatic stellate cells.
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Liu WY, Eslam M, Zheng KI, Ma HL, Rios RS, Lv MZ, Li G, Tang LJ, Zhu PW, Wang XD, Byrne CD, Targher G, George J, Zheng MH. Associations of Hydroxysteroid 17-beta Dehydrogenase 13 Variants with Liver Histology in Chinese Patients with Metabolic-associated Fatty Liver Disease. J Clin Transl Hepatol 2021; 9:194-202. [PMID: 34007801 PMCID: PMC8111109 DOI: 10.14218/jcth.2020.00151] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 01/24/2021] [Accepted: 02/07/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND AIMS In Europeans, variants in the hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) gene impact liver histology in metabolic-associated fatty liver disease (MAFLD). The impact of these variants in ethnic Chinese is unknown. The aim of this study was to investigate the potential associations in Chinese patients. METHODS In total, 427 Han Chinese with biopsy-confirmed MAFLD were enrolled. Two single nucleotide polymorphisms in HSD17B13 were genotyped: rs72613567 and rs6531975. Logistic regression was used to test the association between the single nucleotide polymorphisms and liver histology. RESULTS In our cohort, the minor allele TA of the rs72613567 variant was related to an increased risk of fibrosis [odds ratio (OR): 2.93 (1.20-7.17), p=0.019 for the additive model; OR: 3.32 (1.39-7.91), p=0.007 for the recessive model], representing an inverse association as compared to the results from European cohorts. In contrast, we observed a protective effect on fibrosis for the minor A allele carriers of the HSD17B13 rs6531975 variant [OR: 0.48 (0.24-0.98), p=0.043 for the additive model; OR: 0.62 (0.40-0.94), p=0.025 for the dominant model]. HSD17B13 variants were only associated with fibrosis but no other histological features. Furthermore, HSD17B13 rs6531975 modulated the effect of PNPLA3 rs738409 on hepatic steatosis. CONCLUSIONS HSD17B13 rs72613567 is a risk variant for fibrosis in a Han Chinese MAFLD population but with a different direction for allelic association to that seen in Europeans. These data exemplify the need for studying diverse populations in genetic studies in order to fine map genome-wide association studies signals.
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Affiliation(s)
- Wen-Yue Liu
- Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, Sydney, Australia
| | - Kenneth I. Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Hong-Lei Ma
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Rafael S. Rios
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Min-Zhi Lv
- Department of Biostatistics, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Gang Li
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Liang-Jie Tang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Pei-Wu Zhu
- Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiao-Dong Wang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Christopher D. Byrne
- Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, Sydney, Australia
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, Zhejiang, China
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Eldafashi N, Darlay R, Shukla R, McCain MV, Watson R, Liu YL, McStraw N, Fathy M, Fawzy MA, Zaki MYW, Daly AK, Maurício JP, Burt AD, Haugk B, Cordell HJ, Bianco C, Dufour JF, Valenti L, Anstee QM, Reeves HL. A PDCD1 Role in the Genetic Predisposition to NAFLD-HCC? Cancers (Basel) 2021; 13:1412. [PMID: 33808740 PMCID: PMC8003582 DOI: 10.3390/cancers13061412] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 03/12/2021] [Accepted: 03/16/2021] [Indexed: 12/13/2022] Open
Abstract
Obesity and non-alcoholic fatty liver disease (NAFLD) are contributing to the global rise in deaths from hepatocellular carcinoma (HCC). The pathogenesis of NAFLD-HCC is not well understood. The severity of hepatic steatosis, steatohepatitis and fibrosis are key pathogenic mechanisms, but animal studies suggest altered immune responses are also involved. Genetic studies have so far highlighted a major role of gene variants promoting fat deposition in the liver (PNPLA3 rs738409; TM6SF2 rs58542926). Here, we have considered single-nucleotide polymorphisms (SNPs) in candidate immunoregulatory genes (MICA rs2596542; CD44 rs187115; PDCD1 rs7421861 and rs10204525), in 594 patients with NAFLD and 391 with NAFLD-HCC, from three European centres. Associations between age, body mass index, diabetes, cirrhosis and SNPs with HCC development were explored. PNPLA3 and TM6SF2 SNPs were associated with both progression to cirrhosis and NAFLD-HCC development, while PDCD1 SNPs were specifically associated with NAFLD-HCC risk, regardless of cirrhosis. PDCD1 rs7421861 was independently associated with NAFLD-HCC development, while PDCD1 rs10204525 acquired significance after adjusting for other risks, being most notable in the smaller numbers of women with NAFLD-HCC. The study highlights the potential impact of inter individual variation in immune tolerance induction in patients with NAFLD, both in the presence and absence of cirrhosis.
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Affiliation(s)
- Nardeen Eldafashi
- Translational and Clinical Research Institute, Faculty of Medical Sciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK; (N.E.); (M.V.M.); (R.W.); (Y.L.L.); (M.Y.W.Z.); (A.K.D.); (J.P.M.); (A.D.B.); (Q.M.A.)
- Biochemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt; (M.F.); (M.A.F.)
| | - Rebecca Darlay
- Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, International Centre for Life, Newcastle upon Tyne NE1 3BZ, UK; (R.D.); (H.J.C.)
| | - Ruchi Shukla
- Biosciences Institute, Faculty of Medical Sciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK; (R.S.); (N.M.)
| | - Misti Vanette McCain
- Translational and Clinical Research Institute, Faculty of Medical Sciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK; (N.E.); (M.V.M.); (R.W.); (Y.L.L.); (M.Y.W.Z.); (A.K.D.); (J.P.M.); (A.D.B.); (Q.M.A.)
| | - Robyn Watson
- Translational and Clinical Research Institute, Faculty of Medical Sciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK; (N.E.); (M.V.M.); (R.W.); (Y.L.L.); (M.Y.W.Z.); (A.K.D.); (J.P.M.); (A.D.B.); (Q.M.A.)
| | - Yang Lin Liu
- Translational and Clinical Research Institute, Faculty of Medical Sciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK; (N.E.); (M.V.M.); (R.W.); (Y.L.L.); (M.Y.W.Z.); (A.K.D.); (J.P.M.); (A.D.B.); (Q.M.A.)
| | - Nikki McStraw
- Biosciences Institute, Faculty of Medical Sciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK; (R.S.); (N.M.)
| | - Moustafa Fathy
- Biochemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt; (M.F.); (M.A.F.)
| | - Michael Atef Fawzy
- Biochemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt; (M.F.); (M.A.F.)
| | - Marco Y. W. Zaki
- Translational and Clinical Research Institute, Faculty of Medical Sciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK; (N.E.); (M.V.M.); (R.W.); (Y.L.L.); (M.Y.W.Z.); (A.K.D.); (J.P.M.); (A.D.B.); (Q.M.A.)
- Biochemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt; (M.F.); (M.A.F.)
| | - Ann K. Daly
- Translational and Clinical Research Institute, Faculty of Medical Sciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK; (N.E.); (M.V.M.); (R.W.); (Y.L.L.); (M.Y.W.Z.); (A.K.D.); (J.P.M.); (A.D.B.); (Q.M.A.)
| | - João P. Maurício
- Translational and Clinical Research Institute, Faculty of Medical Sciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK; (N.E.); (M.V.M.); (R.W.); (Y.L.L.); (M.Y.W.Z.); (A.K.D.); (J.P.M.); (A.D.B.); (Q.M.A.)
| | - Alastair D. Burt
- Translational and Clinical Research Institute, Faculty of Medical Sciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK; (N.E.); (M.V.M.); (R.W.); (Y.L.L.); (M.Y.W.Z.); (A.K.D.); (J.P.M.); (A.D.B.); (Q.M.A.)
| | - Beate Haugk
- Department of Cellular Pathology, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle NE1 4LP, UK;
| | - Heather J. Cordell
- Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, International Centre for Life, Newcastle upon Tyne NE1 3BZ, UK; (R.D.); (H.J.C.)
| | - Cristiana Bianco
- Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (C.B.); (L.V.)
| | - Jean-François Dufour
- University Clinic for Visceral Surgery and Medicine, University Hospital of Bern, 3010 Bern, Switzerland;
- Hepatology, Department of Biomedical Research, University of Bern, 3012 Bern, Switzerland
| | - Luca Valenti
- Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (C.B.); (L.V.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Quentin M. Anstee
- Translational and Clinical Research Institute, Faculty of Medical Sciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK; (N.E.); (M.V.M.); (R.W.); (Y.L.L.); (M.Y.W.Z.); (A.K.D.); (J.P.M.); (A.D.B.); (Q.M.A.)
- The Liver Unit, Freeman Hospital, Freeman Road, Newcastle upon Tyne Hospitals NHS Foundation Trust, Heaton NE7 7DN, UK
| | - Helen L. Reeves
- Translational and Clinical Research Institute, Faculty of Medical Sciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK; (N.E.); (M.V.M.); (R.W.); (Y.L.L.); (M.Y.W.Z.); (A.K.D.); (J.P.M.); (A.D.B.); (Q.M.A.)
- The Liver Unit, Freeman Hospital, Freeman Road, Newcastle upon Tyne Hospitals NHS Foundation Trust, Heaton NE7 7DN, UK
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Tani R, Ito N, Matsui K, Yamasaki S, Hamada A, Tokumaru K, Toratani S, Okamoto T. MICA A5.1 homozygous genotype is associated with a risk for early-onset oral cancer. Oral Oncol 2021; 116:105256. [PMID: 33730629 DOI: 10.1016/j.oraloncology.2021.105256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 02/25/2021] [Accepted: 02/27/2021] [Indexed: 11/26/2022]
Abstract
OBJECTIVES Genetic predisposition is reportedly involved in early-onset oral cancer, although the genetic basis of this cancer remains unclear. The major histocompatibility complex class I-related chain A (MICA) plays a crucial role in eliminating malignant tumors by activating NKG2D, the natural killer (NK) receptor. MICA polymorphism might affect its binding to NKG2D. We aimed to find whether MICA gene microsatellite polymorphism is involved in the risk of oral squamous cell carcinoma (OSCC) development in a Japanese population. MATERIALS AND METHODS We recruited 386 patients with OSCC and 103 healthy controls. Genomic DNA was analyzed by PCR for microsatellite repeat polymorphism in the transmembrane region of the MICA gene. The groups were compared for the prevalence of various alleles and their association with disease prognosis and survival. RESULTS We found that adolescents and young adults (AYA) with OSCC were more likely to have the MICA A5.1 homozygous genotype than healthy controls (P = 0.0001), but their survival rate was higher than with other MICA genotypes (P = 0.0185). CONCLUSION These results suggest that cancer's immune escape is facilitated by MICA's failure to activate the NK cells. MICA A5.1 homozygosity plays a role in individual susceptibility to OSCC, increasing the risk of early-onset oral cancer. However, such patients have a better prognosis than those with other MICA genotypes.
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Affiliation(s)
- Ryouji Tani
- Oral and Maxillofacial Surgery, Hiroshima University Hospital, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan.
| | - Nanako Ito
- Oral and Maxillofacial Surgery, Hiroshima University Hospital, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan
| | - Kensaku Matsui
- Oral and Maxillofacial Surgery, Hiroshima University Hospital, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan
| | - Sachiko Yamasaki
- Oral and Maxillofacial Surgery, Hiroshima University Hospital, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan
| | - Atsuko Hamada
- Oral and Maxillofacial Surgery, Hiroshima University Hospital, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan
| | - Koichiro Tokumaru
- NIHON KEFIA Co., Ltd, 13-16, Asahicho, Fujisawa-shi, Kanagawa 251-0054, Japan
| | - Shigeaki Toratani
- Dept. of Molecular Oral Medicine and Maxillofacial Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan
| | - Tetsuji Okamoto
- Dept. of Molecular Oral Medicine and Maxillofacial Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan; School of Medical Sciences, University of East Asia, 2-1 Ichinomiyagakuenchō, Shimonoseki-shi, Yamaguchi 751-8503, Japan
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Viet NH, Trung NQ, Dong LT, Trung LQ, Espinoza JL. Genetic variants in NKG2D axis and susceptibility to Epstein-Barr virus-induced nasopharyngeal carcinoma. J Cancer Res Clin Oncol 2021; 147:713-723. [PMID: 33392659 DOI: 10.1007/s00432-020-03475-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 11/18/2020] [Indexed: 12/31/2022]
Abstract
BACKGROUND Nasopharyngeal carcinoma (NPC) is a rare epithelial carcinoma arising from the nasopharyngeal region. The pathogenesis of NPC is linked to Epstein-Barr virus (EBV) infection, although genetics and lifestyle factors appears to be also implicated. NKG2D is an immunoreceptor expressed by NK and T-cell subsets that recognizes MICA protein and other ligands on tumor cells. NKG2D interaction with MICA plays a role in the immunosurveillance to viruses and cancer. METHODS We investigated potential associations between functional polymorphisms in NKG2D and MICA genes with NPC susceptibility. We conducted a case-control study including 255 Vietnamese patients with EBV + non-differentiated NPC and 220 healthy controls. RESULTS We observed a significant association between the LNK/LNK genotype of rs1049174 (a variant associated with lower NKG2D receptor expression and reduced NK cell cytotoxicity) and increased susceptibility to NPC (adjusted OR = 1.66, 95% CI 1.07-2.59; p = 0.024). Similarly, the AA genotype of MICA rs2596542 was significantly associated with NPC (adjusted OR = 2.12; 95% CI 1.22-3.81; p = 0.009). In addition, tumor specimens of NPC patients with the AA genotype displayed a higher expression level of MICA proteins and showed higher EBV titers compared with tumor tissues from patients with the GG or GA genotypes. Higher EBV copy numbers were also observed in tumors with the A allele of MICA rs1051792 (also known as MICA-129 Met/Val) compared with those with the G allele; however, MICA rs1051792 variants were not associated with NPC susceptibility. These results suggest that genetic variants in components of the NKG2D axis may influence the individual susceptibility to EBV-induced NPC.
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Affiliation(s)
- Nguyen Hoang Viet
- Faculty of Medical Technology, Hanoi Medical University, Hanoi, Vietnam
- Center for Gene-Protein Research, Hanoi Medical University, Hanoi, Vietnam
| | - Nguyen Quang Trung
- Department of Otorhinolaryngology, Hanoi Medical University, Hanoi, Vietnam
| | - Le Thanh Dong
- Faculty of Medical Technology, Hanoi Medical University, Hanoi, Vietnam
| | - Ly Quoc Trung
- Faculty of Medicine and Pharmacy, Soc Trang Community College, Soc Trang, Vietnam
| | - J Luis Espinoza
- Faculty of Health Sciences, Kanazawa University, Kodatsuno 5-11-80, Kanazawa, 920-0942, Japan.
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McGlynn KA, Petrick JL, El-Serag HB. Epidemiology of Hepatocellular Carcinoma. Hepatology 2021; 73 Suppl 1:4-13. [PMID: 32319693 PMCID: PMC7577946 DOI: 10.1002/hep.31288] [Citation(s) in RCA: 1281] [Impact Index Per Article: 320.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 03/22/2020] [Accepted: 04/10/2020] [Indexed: 02/06/2023]
Abstract
Liver cancer is a major contributor to the worldwide cancer burden. Incidence rates of this disease have increased in many countries in recent decades. As the principal histologic type of liver cancer, hepatocellular carcinoma (HCC) accounts for the great majority of liver cancer diagnoses and deaths. Hepatitis B virus (HBV) and hepatitis C virus (HCV) remain, at present, the most important global risk factors for HCC, but their importance will likely decline in the coming years. The effect of HBV vaccination of newborns, already seen in young adults in some countries, will be more notable as vaccinated cohorts age. In addition, effective treatments for chronic infections with both HBV and HCV should contribute to declines in the rates of viral-associated HCC. Unfortunately, the prevalence of metabolic risk factors for HCC, including metabolic syndrome, obesity, type II diabetes and non-alcoholic fatty liver disease (NAFLD) are increasing and may jointly become the major cause of HCC globally. Excessive alcohol consumption also remains an intractable risk factor, as does aflatoxin contamination of food crops in some parts of the world. While significant efforts in early diagnosis and better treatment are certainly needed for HCC, primary prevention efforts aimed at decreasing the prevalence of obesity and diabetes and controlling mycotoxin growth, are just as urgently required.
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Affiliation(s)
- Katherine A McGlynn
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
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Moaz IM, Abdallah AR, Yousef MF, Ezzat S. Main insights of genome wide association studies into HCV-related HCC. EGYPTIAN LIVER JOURNAL 2020. [DOI: 10.1186/s43066-019-0013-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Abstract
Background
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-mortality globally. Hepatocarcinogenesis is a complex multifactorial process. Host genetic background appeared to play a crucial role in the progression of HCC among chronic hepatitis C patients, especially in the era of Genome Wide Association Studies (GWAS) which allowed us to study the association of millions of single nucleotide polymorphisms (SNPs) with different complex diseases. This article aimed to review the discovered SNPs associated with the risk of HCV-related HCC development which was reported in the published GWA studies and subsequent validation studies and also try to explain the possible functional pathways.
Main text
We reviewed the recent GWA studies which reported several new loci associated with the risk of HCV-related HCC, such as (SNPs) in MHC class I polypeptide-related sequence A (MICA), DEP domain-containing 5 (DEPDC5), Tolloid-like protein 1 (TLL1), and human leukocyte antigen (HLA) genes. We also explained the possible underlying biological mechanisms that affect the host immune response pathways. Additionally, we discussed the controversial results reported by the subsequent validation studies of different ethnicities.
Conclusions
Although GWA studies reported strong evidence of the association between the identified SNPs and the risk of HCV-related HCC development, more functional experiments are necessary to confirm the defined roles of these genetic mutations for the future clinical application in different populations.
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PNPLA3 and HLA-DQB1 polymorphisms are associated with hepatocellular carcinoma after hepatitis C virus eradication. J Gastroenterol 2020; 55:1162-1170. [PMID: 33057914 DOI: 10.1007/s00535-020-01731-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 09/13/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Even though both interferon (IFN)-based and direct-acting antiviral (DAA) therapies against hepatitis C virus (HCV) reduce the risk of hepatocellular carcinoma (HCC), post-sustained virological response (SVR) patients remain at elevated risk of HCC. METHODS A total of 4620 patients who achieved SVR were enrolled in this retrospective cohort study. After excluding patients who had a history of HCC or developed HCC within 1 year and whose follow-up period was less than 1 year and who were positive for HBsAg, we investigated the association between clinical characteristics and HCC development after SVR in the remaining 3771 patients. RESULTS Median observation period was 41 months. We confirmed known risk factors. In addition, we found that PNPLA3 and HLA-DQB1 polymorphisms were associated with HCC after SVR. Finally, we propose an estimation model for the incidence of HCC after SVR. Based on gender, FIB-4 index, AFP, and PNPLA3 polymorphism, about 18% of all patients were classified as having high risk, with a cumulative incidence rate (CIR) at 5 years of 16.5%. Another 17% were classified as having moderate risk with a CIR of 7.6%. The remaining 65% showed a CIR of 0.5%. The effect of PNPLA3 polymorphism might be more pronounced in patients with lower body mass index (BMI) and without diabetes mellitus compared to those with higher BMI and diabetes mellitus. CONCLUSIONS We demonstrated that PNPLA3 and HLA-DQB1 polymorphisms were associated with HCC after SVR. These findings might be useful to inform risk stratification for HCC surveillance after SVR.
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Kubota N, Fujiwara N, Hoshida Y. Clinical and Molecular Prediction of Hepatocellular Carcinoma Risk. J Clin Med 2020; 9:jcm9123843. [PMID: 33256232 PMCID: PMC7761278 DOI: 10.3390/jcm9123843] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 11/20/2020] [Accepted: 11/23/2020] [Indexed: 02/07/2023] Open
Abstract
Prediction of hepatocellular carcinoma (HCC) risk becomes increasingly important with recently emerging HCC-predisposing conditions, namely non-alcoholic fatty liver disease and cured hepatitis C virus infection. These etiologies are accompanied with a relatively low HCC incidence rate (~1% per year or less), while affecting a large patient population. Hepatitis B virus infection remains a major HCC risk factor, but a majority of the patients are now on antiviral therapy, which substantially lowers, but does not eliminate, HCC risk. Thus, it is critically important to identify a small subset of patients who have elevated likelihood of developing HCC, to optimize the allocation of limited HCC screening resources to those who need it most and enable cost-effective early HCC diagnosis to prolong patient survival. To date, numerous clinical-variable-based HCC risk scores have been developed for specific clinical contexts defined by liver disease etiology, severity, and other factors. In parallel, various molecular features have been reported as potential HCC risk biomarkers, utilizing both tissue and body-fluid specimens. Deep-learning-based risk modeling is an emerging strategy. Although none of them has been widely incorporated in clinical care of liver disease patients yet, some have been undergoing the process of validation and clinical development. In this review, these risk scores and biomarker candidates are overviewed, and strategic issues in their validation and clinical translation are discussed.
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Li S, Saviano A, Erstad DJ, Hoshida Y, Fuchs BC, Baumert T, Tanabe KK. Risk Factors, Pathogenesis, and Strategies for Hepatocellular Carcinoma Prevention: Emphasis on Secondary Prevention and Its Translational Challenges. J Clin Med 2020; 9:E3817. [PMID: 33255794 PMCID: PMC7760293 DOI: 10.3390/jcm9123817] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 11/11/2020] [Accepted: 11/17/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated mortality globally. Given the limited therapeutic efficacy in advanced HCC, prevention of HCC carcinogenesis could serve as an effective strategy. Patients with chronic fibrosis due to viral or metabolic etiologies are at a high risk of developing HCC. Primary prevention seeks to eliminate cancer predisposing risk factors while tertiary prevention aims to prevent HCC recurrence. Secondary prevention targets patients with baseline chronic liver disease. Various epidemiological and experimental studies have identified candidates for secondary prevention-both etiology-specific and generic prevention strategies-including statins, aspirin, and anti-diabetic drugs. The introduction of multi-cell based omics analysis along with better characterization of the hepatic microenvironment will further facilitate the identification of targets for prevention. In this review, we will summarize HCC risk factors, pathogenesis, and discuss strategies of HCC prevention. We will focus on secondary prevention and also discuss current challenges in translating experimental work into clinical practice.
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Affiliation(s)
- Shen Li
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114, USA; (S.L.); (D.J.E.); (B.C.F.)
| | - Antonio Saviano
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, 67000 Strasbourg, France;
| | - Derek J. Erstad
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114, USA; (S.L.); (D.J.E.); (B.C.F.)
| | - Yujin Hoshida
- Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Department of Internal Medicine, Dallas, TX 75390, USA;
| | - Bryan C. Fuchs
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114, USA; (S.L.); (D.J.E.); (B.C.F.)
| | - Thomas Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, 67000 Strasbourg, France;
| | - Kenneth K. Tanabe
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114, USA; (S.L.); (D.J.E.); (B.C.F.)
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Abstract
Liver cancer is a global problem and hepatocellular carcinoma (HCC) accounts for about 85% of this cancer. In the USA, etiologies and risk factors for HCC include chronic hepatitis C virus (HCV) infection, diabetes, non-alcoholic steatohepatitis (NASH), obesity, excessive alcohol drinking, exposure to tobacco smoke, and genetic factors. Chronic HCV infection appears to be associated with about 30% of HCC. Chronic HCV infection induces multistep changes in liver, involving metabolic disorders, steatosis, cirrhosis and HCC. Liver carcinogenesis requires initiation of neoplastic clones, and progression to clinically diagnose malignancy. Tumor progression associates with profound exhaustion of tumor-antigen-specific CD8+T cells, and accumulation of PD-1hi CD8+T cells and Tregs. In this chapter, we provide a brief description of HCV and environmental/genetic factors, immune regulation, and highlight mechanisms of HCV associated HCC. We also underscore HCV treatment and recent paradigm of HCC progression, highlighted the current treatment and potential future therapeutic opportunities.
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Wang H, Wang B, Wang T, Fan R. A genetic variant in the promoter region of miR-877 is associated with an increased risk of hepatocellular carcinoma. Clin Res Hepatol Gastroenterol 2020; 44:692-698. [PMID: 32113822 DOI: 10.1016/j.clinre.2020.01.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 01/17/2020] [Accepted: 01/29/2020] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Genome wide association study has identified chromosome 6p21.33 as a risk locus of hepatocellular carcinoma (HCC). MiR-877 is located on this region, functioning as a tumor suppressor. The aim of this study was to investigate the association between rs1264440 in the promoter of miR-877 and HCC risk. MATERIALS AND METHODS A total of 352 HCC patients and 359 age, gender, ethnicity and living area matched controls were enrolled in this study. The rs1264440 was genotyped using the TaqMan allelic discrimination assay. MiR-877 expression in HCC tissues was examined using quantitative PCR. RESULTS After Adjustment for age, sex, smoking status, drinking status and HBsAg status, this study showed a significant association between the rs1264440 and HCC risk. Subjects with the rs1264440 TT genotype and T allele showed a 2.20- and 1.44-fold increased risk to develop HCC, respectively (TT vs. CC: 95% CI, 1.18-4.11, P=0.01;T vs. C: 95% CI, 1.07-1.94, P=0.02). The increased risk was also observed in smokers and nondrinkers subgroup. The rs1264440 TT carriers had lower levels of miR-877. CONCLUSION The rs1264440 in the promoter region of miR-877 may regulate miR-877 expression and serve as an independent biomarker for the risk of HCC.
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Affiliation(s)
- Hongtu Wang
- Department of Infections Disease, the First Affiliated Hospital of Kunming Medical University, 650032 Kunming, Yunnan, China
| | - Bo Wang
- Department of Neurosurgery, the First Affiliated Hospital of Kunming Medical University, 650032 Kunming, Yunnan, China
| | - Tao Wang
- Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital of Kunming Medical University, 650101 Kunming, Yunnan, China
| | - Ruixuan Fan
- Department of Infections Disease, the First Affiliated Hospital of Kunming Medical University, 650032 Kunming, Yunnan, China.
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