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Shinde S, Bigogno CM, Simmons A, Kathuria N, Ghose A, Apte V, Lapitan P, Makker S, Caglayan A, Boussios S. Precision oncology through next generation sequencing in hepatocellular carcinoma. Heliyon 2025; 11:e42054. [PMID: 39927143 PMCID: PMC11804570 DOI: 10.1016/j.heliyon.2025.e42054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 01/08/2025] [Accepted: 01/15/2025] [Indexed: 02/11/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a primary liver cancer that originates from underlying inflammation, often associated with Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infections. Despite the availability of treatments, there are high rates of tumour relapse due to the development of drug resistance in infected cells. Next-Generation Sequencing (NGS) plays a crucial role in overcoming this issue by sequencing both viral and host genomes to identify mutations and genetic heterogeneity. The knowledge gained from sequencing is then utilised to develop countermeasures against these mutants through different combination therapies. Advances in NGS have led to sequencing with higher accuracy and throughput, thereby enabling personalized and effective treatments. The purpose of this article is to highlight how NGS has contributed to precision medicine in HCC and the possible integration of artificial intelligence (AI) to bolster the advancement.
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Affiliation(s)
- Sayali Shinde
- Barts Cancer Institute, Queen Mary University of London, Cancer Research UK Barts Centre, London, UK
| | - Carola Maria Bigogno
- Department of Medical Oncology, St. Bartholomew's Hospital, Barts Health NHS Trust, London, UK
- British Oncology Network for Undergraduate Societies (BONUS), UK
| | - Ana Simmons
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- QIAGEN Manchester, Manchester, UK
| | - Nikita Kathuria
- Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Aruni Ghose
- Department of Medical Oncology, St. Bartholomew's Hospital, Barts Health NHS Trust, London, UK
- Department of Medical Oncology, Medway NHS Foundation Trust, Kent, UK
- Department of Medical Oncology, Mount Vernon Cancer Centre, East and North Hertfordshire NHS Trust, London, UK
| | - Vedika Apte
- University College London Medical School, London, UK
- University College London Oncology Society, London, UK
| | - Patricia Lapitan
- School of Medical Sciences, The University of Manchester, Manchester, UK
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Surrey, UK
- University College London Cancer Institute, London, UK
| | - Shania Makker
- University College London Cancer Institute, London, UK
- Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Barts and the London Oncology Society, London, UK
| | - Aydin Caglayan
- Department of Medical Oncology, Medway NHS Foundation Trust, Kent, UK
| | - Stergios Boussios
- Department of Medical Oncology, Medway NHS Foundation Trust, Kent, UK
- Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, King's College London, Strand, London, UK
- Kent and Medway Medical School, University of Kent, Canterbury, UK
- Faculty of Medicine, Health, and Social Care, Canterbury Christ Church University, Canterbury, UK
- AELIA Organization, 9th Km Thessaloniki–Thermi, 57001 Thessaloniki, Greece
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Kang X, Zhao S, Lin S, Li J, Wang S. Synergistic upregulation of PD‑L1 in tumor cells and CD39 in tumor‑infiltrating CD8 + T cells leads to poor prognosis in patients with hepatocellular carcinoma. Oncol Lett 2024; 28:368. [PMID: 38933811 PMCID: PMC11200054 DOI: 10.3892/ol.2024.14501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 05/16/2024] [Indexed: 06/28/2024] Open
Abstract
The immune escape of tumor cells and functional status of tumor-infiltrating T cells may serve pivotal roles in the tumor immune microenvironment and progression of hepatocellular carcinoma (HCC). The present study enrolled 91 patients with HCC and examined programmed cell death ligand 1 (PD-L1) expression in tumor cells and CD39 expression in tumor-infiltrating CD8+ T cells in patient samples using multiplex immunofluorescence assays. The impact of PD-L1 and CD39 expression levels on the prognosis of patients with HCC was investigated utilizing Kaplan-Meier analyses. The individual upregulation of PD-L1 in tumor cells, as well as the individual upregulation of CD39 expression in tumor-infiltrating CD8+ T cells did not significantly affect the prognosis of patients with HCC. However, the simultaneous upregulation of both PD-L1 in tumor cells and CD39 in tumor-infiltrating CD8+ T cells was associated with reduced overall survival in patients with HCC. Therefore, the results of the present study suggested that the interplay between tumor cell immune escape and tumor-infiltrating immune cell functional status within the tumor immune microenvironment may have had a substantial impact on the prognosis of patients with HCC. Mechanistically, increased expression levels of PD-L1 in tumor cells may improve the immune escape capacity of tumors, whilst upregulation of CD39 in tumor-infiltrating T cells may be associated with T cell exhaustion. Therefore, the upregulation of PD-L1 expression in tumor cells, in conjunction with the exhaustion of tumor-infiltrating CD8+ T cells, could serve as a future potential prognostic indicator of patients with HCC.
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Affiliation(s)
- Xi Kang
- Department of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Sinan Zhao
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang, Heibei 050000, P.R. China
| | - Shan Lin
- Department of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
- Department of General Surgery, Cangzhou Central Hospital, Cangzhou, Hebei 061000, P.R. China
| | - Jing Li
- Department of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
- Department of General Surgery, Chengde Central Hospital, Chengde, Hebei 067000, P.R. China
| | - Shunxiang Wang
- Department of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
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Yüregir Y, Kaçaroğlu D, Yaylacı S. Regulation of Hepatocellular Carcinoma Epithelial-Mesenchymal Transition Mechanism and Targeted Therapeutic Approaches. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1450:93-102. [PMID: 37452258 DOI: 10.1007/5584_2023_781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/18/2023]
Abstract
Hepatocellular carcinoma (HCC) is a primary liver malignancy that accounts for the majority of liver cancer cases, with multiple risk factors including chronic hepatitis B and C infections, alcohol abuse, and non-alcoholic fatty liver disease (NAFLD). Despite advancements in diagnosis and treatment, the survival rate of patients with advanced HCC remains low, creating an urgent need for new therapeutic targets and strategies.One biological process crucial to HCC progression is the epithelial-mesenchymal transition (EMT). EMT is a process that enables epithelial cells to acquire mesenchymal properties, including motility and invasiveness, by losing their cell-cell adhesion. Various signaling pathways, including TGF-β, Wnt/β-catenin, and Notch, have been implicated in regulating EMT in HCC.To inhibit EMT, targeted therapeutic approaches have been developed, and preclinical studies suggest that the inhibition of the TGF-β, Wnt/β-catenin, and Notch signaling pathways is promising. TGF-β receptor inhibitors, Wnt/β-catenin pathway inhibitors, and gamma-secretase inhibitors have shown efficacy in preclinical studies by inhibiting EMT and reducing tumor growth in HCC models. However, further clinical studies are necessary to determine their effectiveness in human patients.In addition to these approaches, further research is needed to identify other novel therapeutic targets and develop new treatment strategies for HCC. This review emphasizes the critical role of EMT in HCC progression and highlights the potential of targeting the TGF-β, Wnt/β-catenin, and Notch signaling pathways to inhibit EMT and reduce tumor growth in HCC. Future studies and clinical trials are necessary to validate these therapeutic strategies and develop effective treatments for HCC.
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Affiliation(s)
- Yelda Yüregir
- Molecular Biology and Genetics Department, İhsan Doğramacı Bilkent University, Ankara, Turkey
| | - Demet Kaçaroğlu
- Faculty of Medicine, Medical Biology Department, Lokman Hekim University, Ankara, Turkey
| | - Seher Yaylacı
- Faculty of Medicine, Medical Biology Department, Lokman Hekim University, Ankara, Turkey.
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Ferrell LD, Kakar S, Terracciano LM, Wee A. Tumours and Tumour-Like Lesions. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:842-946. [DOI: 10.1016/b978-0-7020-8228-3.00013-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Chen CC, Huang HW, Chen BR, Wong CH. Quantitative mass spectrometric analysis of hepatocellular carcinoma biomarker alpha-fetoprotein. RSC Chem Biol 2023; 4:1073-1081. [PMID: 38033722 PMCID: PMC10685801 DOI: 10.1039/d3cb00069a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 08/22/2023] [Indexed: 12/02/2023] Open
Abstract
Serum alpha-fetoprotein (AFP) has been used as a marker for the diagnosis of hepatocellular carcinoma (HCC) and its core fucosylation is associated with the early stage of HCC. However, current methods for the detection of AFP with core fucose are not highly accurate for early diagnosis. In this study, we established an enzyme-assisted mass spectrometric method for the quantitative analysis of AFP/core fucose with high specificity and sensitivity. We employed endoglycosidase treatment of AFP to improve the biomarker analysis. The accuracy and precision are within the US FDA-suggested value, and a good linearity (r2 = 0.9930) and a detection limit of 15.6 ng mL-1 can be achieved.
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Affiliation(s)
- Chen-Chun Chen
- Department of Chemistry, National Taiwan University Taipei Taiwan
- Genomic Research Center, Academia Sinica Taipei Taiwan
| | - Han-Wen Huang
- Genomic Research Center, Academia Sinica Taipei Taiwan
| | - Bo-Rui Chen
- Genomic Research Center, Academia Sinica Taipei Taiwan
| | - Chi-Huey Wong
- Genomic Research Center, Academia Sinica Taipei Taiwan
- Department of Chemistry, The Scripps Research Institute 10550 N. Torrey Pines Rd. La Jolla CA 92037 USA
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Kohansal-Nodehi M, Swiatek-de Lange M, Kroeniger K, Rolny V, Tabarés G, Piratvisuth T, Tanwandee T, Thongsawat S, Sukeepaisarnjaroen W, Esteban JI, Bes M, Köhler B, Chan HLY, Busskamp H. Discovery of a haptoglobin glycopeptides biomarker panel for early diagnosis of hepatocellular carcinoma. Front Oncol 2023; 13:1213898. [PMID: 37920152 PMCID: PMC10619681 DOI: 10.3389/fonc.2023.1213898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 09/20/2023] [Indexed: 11/04/2023] Open
Abstract
Background There is a need for new serum biomarkers for early detection of hepatocellular carcinoma (HCC). Haptoglobin (Hp) N-glycosylation is altered in HCC, but the diagnostic value of site-specific Hp glycobiomarkers is rarely reported. We aimed to determine the site-specific glycosylation profile of Hp for early-stage HCC diagnosis. Method Hp glycosylation was analyzed in the plasma of patients with liver diseases (n=57; controls), early-stage HCC (n=50) and late-stage HCC (n=32). Hp phenotype was determined by immunoblotting. Hp was immunoisolated and digested into peptides. N-glycopeptides were identified and quantified using liquid chromatography-mass spectrometry. Cohort samples were compared using Wilcoxon rank-sum (Mann-Whitney U) tests. Diagnostic performance was assessed using receiver operating characteristic (ROC) curves and area under curve (AUC). Results Significantly higher fucosylation, branching and sialylation of Hp glycans, and expression of high-mannose glycans, was observed as disease progressed from cirrhosis to early- and late-stage HCC. Several glycopeptides demonstrated high values for early diagnosis of HCC, with an AUC of 93% (n=1), >80% (n=3), >75% (n=13) and >70% (n=11), compared with alpha-fetoprotein (AFP; AUC of 79%). The diagnostic performance of the identified biomarkers was only slightly affected by Hp phenotype. Conclusion We identified a panel of Hp glycopeptides that are significantly differentially regulated in early- and late-stage HCC. Some glycobiomarkers exceeded the diagnostic value of AFP (the most commonly used biomarker for HCC diagnosis). Our findings provide evidence that glycobiomarkers can be effective in the diagnosis of early HCC - individually, as a panel of glycopeptides or combined with conventional serological biomarkers.
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Affiliation(s)
| | | | | | - Vinzent Rolny
- Roche Diagnostics GmbH, Research and Development Core Lab, Penzberg, Germany
| | - Glòria Tabarés
- Roche Diagnostics GmbH, Research and Development Core Lab, Penzberg, Germany
| | - Teerha Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Prince of Songkla University, Hat Yai, Thailand
| | - Tawesak Tanwandee
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Satawat Thongsawat
- Department of Internal Medicine, Maharaj Nakorn Chiang Mai Hospital, Chiang Mai University, Chiang Mai, Thailand
| | | | | | - Marta Bes
- Transfusion Safety Laboratory, Banc de Sang i Teixits (BST), Barcelona, Spain
| | - Bruno Köhler
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
- Liver Cancer Center Heidelberg, Heidelberg, Germany
| | - Henry Lik-Yuen Chan
- Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Holger Busskamp
- Roche Diagnostics GmbH, Research and Development Core Lab, Penzberg, Germany
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Sun L, Yao HJ, Li JC, Zhao BQ, Wang YA, Zhang YG. Activated Carbon nanoparticles Loaded with Metformin for Effective Against Hepatocellular Cancer Stem Cells. Int J Nanomedicine 2023; 18:2891-2910. [PMID: 37283712 PMCID: PMC10239765 DOI: 10.2147/ijn.s382519] [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] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 04/16/2023] [Indexed: 06/08/2023] Open
Abstract
Introduction Hepatocellular cancer stem cells (CSCs) play crucial roles in hepatocellular cancer initiation, development, relapse, and metastasis. Therefore, eradication of this cell population is a primary objective in hepatocellular cancer therapy. We prepared a nanodrug delivery system with activated carbon nanoparticles (ACNP) as carriers and metformin (MET) as drug (ACNP-MET), which was able to selectively eliminate hepatocellular CSCs and thereby increase the effects of MET on hepatocellular cancers. Methods ACNP were prepared by ball milling and deposition in distilled water. Suspension of ACNP and MET was mixed and the best ratio of ACNP and MET was determined based on the isothermal adsorption formula. Hepatocellular CSCs were identified as CD133+ cells and cultured in serum-free medium. We investigated the effects of ACNP-MET on hepatocellular CSCs, including the inhibitory effects, the targeting efficiency, self-renewal capacity, and the sphere-forming capacity of hepatocellular CSCs. Next, we evaluated the therapeutic efficacy of ACNP-MET by using in vivo relapsed tumor models of hepatocellular CSCs. Results The ACNP have a similar size, a regular spherical shape and a smooth surface. The optimal ratio for adsorption was MET: ACNP=1:4. ACNP-MET could target and inhibit the proliferation of CD133+ population and decrease mammosphere formation and renewal of CD133+ population in vitro and in vivo. Conclusion These results not only suggest that nanodrug delivery system increased the effects of MET, but also shed light on the mechanisms of the therapeutic effects of MET and ACNP-MET on hepatocellular cancers. ACNP, as a good nano-carrier, could strengthen the effect of MET by carrying drugs to the micro-environment of hepatocellular CSCs.
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Affiliation(s)
- Lan Sun
- Key Laboratory of Nanopharmacology and Nanotoxicology, Beijing Institute of Pharmacology and Toxicology, Beijing, People’s Republic of China
| | - Hong-Juan Yao
- Key Laboratory of Antibiotic Bioengineering of National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology (IMB), Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, People’s Republic of China
| | - Jing-Cao Li
- Key Laboratory of Nanopharmacology and Nanotoxicology, Beijing Institute of Pharmacology and Toxicology, Beijing, People’s Republic of China
| | - Bao-Quan Zhao
- Key Laboratory of Nanopharmacology and Nanotoxicology, Beijing Institute of Pharmacology and Toxicology, Beijing, People’s Republic of China
| | - Yong-An Wang
- Key Laboratory of Nanopharmacology and Nanotoxicology, Beijing Institute of Pharmacology and Toxicology, Beijing, People’s Republic of China
| | - Ying-Ge Zhang
- Key Laboratory of Nanopharmacology and Nanotoxicology, Beijing Institute of Pharmacology and Toxicology, Beijing, People’s Republic of China
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Hashemi M, Sabouni E, Rahmanian P, Entezari M, Mojtabavi M, Raei B, Zandieh MA, Behroozaghdam M, Mirzaei S, Hushmandi K, Nabavi N, Salimimoghadam S, Ren J, Rashidi M, Raesi R, Taheriazam A, Alexiou A, Papadakis M, Tan SC. Deciphering STAT3 signaling potential in hepatocellular carcinoma: tumorigenesis, treatment resistance, and pharmacological significance. Cell Mol Biol Lett 2023; 28:33. [PMID: 37085753 PMCID: PMC10122325 DOI: 10.1186/s11658-023-00438-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 03/15/2023] [Indexed: 04/23/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is considered one of the greatest challenges to human life and is the most common form of liver cancer. Treatment of HCC depends on chemotherapy, radiotherapy, surgery, and immunotherapy, all of which have their own drawbacks, and patients may develop resistance to these therapies due to the aggressive behavior of HCC cells. New and effective therapies for HCC can be developed by targeting molecular signaling pathways. The expression of signal transducer and activator of transcription 3 (STAT3) in human cancer cells changes, and during cancer progression, the expression tends to increase. After induction of STAT3 signaling by growth factors and cytokines, STAT3 is phosphorylated and translocated to the nucleus to regulate cancer progression. The concept of the current review revolves around the expression and phosphorylation status of STAT3 in HCC, and studies show that the expression of STAT3 is high during the progression of HCC. This review addresses the function of STAT3 as an oncogenic factor in HCC, as STAT3 is able to prevent apoptosis and thus promote the progression of HCC. Moreover, STAT3 regulates both survival- and death-inducing autophagy in HCC and promotes cancer metastasis by inducing the epithelial-mesenchymal transition (EMT). In addition, upregulation of STAT3 is associated with the occurrence of chemoresistance and radioresistance in HCC. Specifically, non-protein-coding transcripts regulate STAT3 signaling in HCC, and their inhibition by antitumor agents may affect tumor progression. In this review, all these topics are discussed in detail to provide further insight into the role of STAT3 in tumorigenesis, treatment resistance, and pharmacological regulation of HCC.
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Affiliation(s)
- Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Eisa Sabouni
- Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Parham Rahmanian
- Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | - Behnaz Raei
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad Arad Zandieh
- Division of Epidemiology, Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Mitra Behroozaghdam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Kiavash Hushmandi
- Division of Epidemiology, Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Noushin Nabavi
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H3Z6, Canada
| | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Jun Ren
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan University, Shanghai, 200032, China
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
- The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Rasoul Raesi
- Department of Health Services Management, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Medical-Surgical Nursing, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
- Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Athanasios Alexiou
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, Australia
- AFNP Med Austria, Vienna, Austria
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten-Herdecke, University of Witten-Herdecke, Heusnerstrasse 40, 42283, Wuppertal, Germany.
| | - Shing Cheng Tan
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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Wang M, Singal AG, Parikh N, Kono Y, Marrero J, Mehta A. A Biomarker Panel Based upon AFP, Fucosylated Kininogen and PEG-Precipitated IgG Is Highly Accurate for the Early Detection Hepatocellular Carcinoma in Patients with Cirrhosis in Phase II and Phase III Biomarker Evaluation. Cancers (Basel) 2022; 14:5970. [PMID: 36497452 PMCID: PMC9740205 DOI: 10.3390/cancers14235970] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 11/07/2022] [Accepted: 11/23/2022] [Indexed: 12/12/2022] Open
Abstract
We have previously identified alterations in glycosylation on serum proteins from patients with HCC and developed plate-based assays using lectins to detect the change in glycosylation. However, heterophilic antibodies, which increase with non-malignant liver disease, compromised these assays. To address this, we developed a method of polyethylene glycol (PEG) precipitation that removed the contaminating IgG and IgM but allowed for the lectin detection of the relevant glycoprotein. We found that this PEG-precipitated material itself could differentiate between cirrhosis and HCC. In the analysis of three training cohorts and one validation cohort, consisting of 571 patients, PEG-IgG had AUC values that ranged from 0.713 to 0.810. In the validation cohort, which contained samples from patients at a time of 1-6 months prior to HCC detection or 7+ months prior to detection, the AUC of this marker remained consistent (0.813 and 0.846, respectively). When this marker was incorporated into a biomarker algorithm that also consisted of AFP and fucosylated kininogen, the AUROC increased to 0.816-0.883 in the training cohort and was 0.909 in the external validation cohort. Biomarker performance was also examined though the analysis of partial ROC curves, at false positive values less than 10% (90-ROC), ≤20% (80-ROC) or ≤30% (70-ROC), which highlighted the algorithm's improvement over the individual markers at clinically relevant specificity values.
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Affiliation(s)
- Mengjun Wang
- Basic Science Building Room 310, Department of Cell and Molecular Pharmacology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA
| | - Amit G. Singal
- Division of Digestive and Liver Diseases, University of Texas Southwestern, 5959 Harry Hines Blvd POB I Suite 420B, Dallas, TX 75201, USA
| | - Neehar Parikh
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yuko Kono
- Division of Gastroenterology, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Jorge Marrero
- Division of Gastroenterology, University of Pennsylvania, 3400 Civic Center Boulevard South Pavilion, 4th Floor, Philadelphia, PA 19104, USA
| | - Anand Mehta
- Basic Science Building Room 310, Department of Cell and Molecular Pharmacology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA
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Jeon D, Song GW, Lee HC, Shim JH. Treatment patterns for hepatocellular carcinoma in patients with Child-Pugh class B and their impact on survival: A Korean nationwide registry study. Liver Int 2022; 42:2830-2842. [PMID: 36287103 DOI: 10.1111/liv.15464] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 09/25/2022] [Accepted: 10/20/2022] [Indexed: 02/13/2023]
Abstract
BACKGROUND AND AIMS There are no established practice guidelines for treating hepatocellular carcinoma (HCC) in patients with Child-Turcotte-Pugh (CTP) class B liver function. To evaluate the impact of various initial treatment modalities on these patients, we conducted a nationwide registry study in Korea. MATERIALS AND METHODS Treatment patterns and overall survival (OS) of patients with HCC and CTP class B according to initial treatment modalities in each Barcelona Clinic Liver Cancer (BCLC) stage were analysed using data from the Korean Primary Liver Cancer Registry between 2008 and 2016. Initial treatment modalities were categorized as standard, alternative treatment and supportive care only, referring to the 2018 BCLC guidelines, irrespective of liver function. RESULTS Of the 2318 newly diagnosed Korean patients with HCC and CTP class B, 29.7%, 60.3% and 15.6% of patients in BCLC stages A, B and C, respectively, underwent standard treatment. Adjusted OS hazard ratios of alternative treatment referring to standard treatment were 1.55 (95% confidence interval [CI], 1.25-1.94; p < .001) in BCLC-A, 0.82 (95% CI, 0.43-1.56; p = .550) for curative alternative treatment, 1.89 (95% CI, 0.97-3.68; p = .059) for non-curative alternative treatment in BCLC-B, 0.40 (95% CI, 0.28-0.56; p < .001) for curative alternative treatment, 0.84 (95% CI, 0.69-1.02; p = .076) for non-curative alternative treatment for BCLC-C. CONCLUSION Regardless of BCLC stages, chemoembolization was conducted the most among patients with CTP class B. Treatment in line with the BCLC treatment algorithm resulted in favourable OS outcomes, except for those with BCLC stage C, as systemic therapy showed poor OS.
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Affiliation(s)
- Dongsub Jeon
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- The Korean Liver Cancer Study Group, Seoul, Republic of Korea
| | - Gi-Won Song
- Department of Surgery, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Han Chu Lee
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- The Korean Liver Cancer Study Group, Seoul, Republic of Korea
| | - Ju Hyun Shim
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- The Korean Liver Cancer Study Group, Seoul, Republic of Korea
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Phosphorylated Proteins from Serum: A Promising Potential Diagnostic Biomarker of Cancer. Int J Mol Sci 2022; 23:ijms232012359. [PMID: 36293212 PMCID: PMC9604268 DOI: 10.3390/ijms232012359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 10/07/2022] [Accepted: 10/07/2022] [Indexed: 11/16/2022] Open
Abstract
Cancer is a fatal disease worldwide. Each year ten million people are diagnosed around the world, and more than half of patients eventually die from it in many countries. A majority of cancer remains asymptomatic in the earlier stages, with specific symptoms appearing in the advanced stages when the chances of adequate treatment are low. Cancer screening is generally executed by different imaging techniques like ultrasonography (USG), mammography, CT-scan, and magnetic resonance imaging (MRI). Imaging techniques, however, fail to distinguish between cancerous and non-cancerous cells for early diagnosis. To confirm the imaging result, solid and liquid biopsies are done which have certain limitations such as invasive (in case of solid biopsy) or missed early diagnosis due to extremely low concentrations of circulating tumor DNA (in case of liquid biopsy). Therefore, it is essential to detect certain biomarkers by a noninvasive approach. One approach is a proteomic or glycoproteomic study which mostly identifies proteins and glycoproteins present in tissues and serum. Some of these studies are approved by the Food and Drug Administration (FDA). Another non-expensive and comparatively easier method to detect glycoprotein biomarkers is by ELISA, which uses lectins of diverse specificities. Several of the FDA approved proteins used as cancer biomarkers do not show optimal sensitivities for precise diagnosis of the diseases. In this regard, expression of phosphoproteins is associated with a more specific stage of a particular disease with high sensitivity and specificity. In this review, we discuss the expression of different serum phosphoproteins in various cancers. These phosphoproteins are detected either by phosphoprotein enrichment by immunoprecipitation using phosphospecific antibody and metal oxide affinity chromatography followed by LC-MS/MS or by 2D gel electrophoresis followed by MALDI-ToF/MS analysis. The updated knowledge on phosphorylated proteins in clinical samples from various cancer patients would help to develop these serum phophoproteins as potential diagnostic/prognostic biomarkers of cancer.
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12
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Bianca C, Sidhartha E, Tiribelli C, El-Khobar KE, Sukowati CHC. Role of hepatitis B virus in development of hepatocellular carcinoma: Focus on covalently closed circular DNA. World J Hepatol 2022; 14:866-884. [PMID: 35721287 PMCID: PMC9157711 DOI: 10.4254/wjh.v14.i5.866] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/31/2022] [Accepted: 04/25/2022] [Indexed: 02/06/2023] Open
Abstract
Chronic infection with hepatitis B virus (HBV) remains a major global health problem, especially in developing countries. It may lead to prolonged liver damage, fibrosis, cirrhosis, and hepatocellular carcinoma. Persistent chronic HBV infection is related to host immune response and the stability of the covalently closed circular DNA (cccDNA) in human hepatocytes. In addition to being essential for viral transcription and replication, cccDNA is also suspected to play a role in persistent HBV infections or hepatitis relapses since cccDNA is very stable in non-dividing human hepatocytes. Understanding the pathogenicity and oncogenicity of HBV components would be essential in the development of new diagnostic tools and treatment strategies. This review summarizes the role and molecular mechanisms of HBV cccDNA in hepatocyte transformation and hepatocarcinogenesis and current efforts to its detection and targeting.
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Affiliation(s)
- Claryssa Bianca
- Department of Biomedicine, Indonesia International Institute for Life Sciences, Jakarta 13210, Indonesia
| | - Elizabeth Sidhartha
- Department of Biomedicine, Indonesia International Institute for Life Sciences, Jakarta 13210, Indonesia
| | - Claudio Tiribelli
- Centro Studi Fegato, Fondazione Italiana Fegato ONLUS, Trieste 34149, Italy
| | - Korri Elvanita El-Khobar
- Eijkman Center for Molecular Biology, National Research and Innovation Agency (BRIN), Jakarta 10340, Indonesia
| | - Caecilia H C Sukowati
- Centro Studi Fegato, Fondazione Italiana Fegato ONLUS, Trieste 34149, Italy
- Eijkman Center for Molecular Biology, National Research and Innovation Agency (BRIN), Jakarta 10340, Indonesia
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13
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Parafibromin Is Highly Expressed in Hepatocellular Carcinoma and Its Expression Correlates with Poor Prognosis. J Clin Med 2022; 11:jcm11071773. [PMID: 35407381 PMCID: PMC9000084 DOI: 10.3390/jcm11071773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/19/2022] [Accepted: 03/21/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Much progress has been made regarding the understanding of hepatocarcinogenesis, yet the long-term survival rate of HCC patients remains poor. Recent efforts have shown parafibromin has a pathologic role in many human cancers, but little is known about the effects of parafibromin in HCC. This study aimed to investigate the pattern of parafibromin expression and its clinicopathologic significance in human HCC. Immunohistochemical analysis of HCC and matched non-tumor liver tissues from 50 HCC patients showed that the nuclear expression of parafibromin was higher in HCC tissues (50/50 cases) than in non-tumor liver tissues (17/50 cases). Moreover, elevated parafibromin expression was found to be significantly correlated with the presence of microvascular invasion (p = 0.017), hepatitis virus infection-induced occurrence (p = 0.005), and poorer tumor differentiation (Edmondson-Steiner grade; p = 0.000). Kaplan-Meier analysis showed that HCC patients with elevated parafibromin expression had poorer recurrence-free (p = 0.014, log-rank test = 6.079) and overall survival (p = 0.036, log-rank test = 4.414). These findings indicate parafibromin may be related to the pathogenesis of HCC and a potential prognostic marker for HCC patients after hepatectomy.
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14
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Boulahtouf Z, Virzì A, Baumert TF, Verrier ER, Lupberger J. Signaling Induced by Chronic Viral Hepatitis: Dependence and Consequences. Int J Mol Sci 2022; 23:ijms23052787. [PMID: 35269929 PMCID: PMC8911453 DOI: 10.3390/ijms23052787] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 02/27/2022] [Accepted: 03/01/2022] [Indexed: 12/12/2022] Open
Abstract
Chronic viral hepatitis is a main cause of liver disease and hepatocellular carcinoma. There are striking similarities in the pathological impact of hepatitis B, C, and D, although these diseases are caused by very different viruses. Paired with the conventional study of protein-host interactions, the rapid technological development of -omics and bioinformatics has allowed highlighting the important role of signaling networks in viral pathogenesis. In this review, we provide an integrated look on the three major viruses associated with chronic viral hepatitis in patients, summarizing similarities and differences in virus-induced cellular signaling relevant to the viral life cycles and liver disease progression.
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Affiliation(s)
- Zakaria Boulahtouf
- Institut de Recherche sur les Maladies Virales et Hepatiques UMR_S1110, Université de Strasbourg, Inserm, F-67000 Strasbourg, France; (Z.B.); (A.V.); (T.F.B.); (E.R.V.)
| | - Alessia Virzì
- Institut de Recherche sur les Maladies Virales et Hepatiques UMR_S1110, Université de Strasbourg, Inserm, F-67000 Strasbourg, France; (Z.B.); (A.V.); (T.F.B.); (E.R.V.)
| | - Thomas F. Baumert
- Institut de Recherche sur les Maladies Virales et Hepatiques UMR_S1110, Université de Strasbourg, Inserm, F-67000 Strasbourg, France; (Z.B.); (A.V.); (T.F.B.); (E.R.V.)
- Service d’Hépato-Gastroentérologie, Hôpitaux Universitaires de Strasbourg, F-67000 Strasbourg, France
- Institut Universitaire de France (IUF), F-75005 Paris, France
| | - Eloi R. Verrier
- Institut de Recherche sur les Maladies Virales et Hepatiques UMR_S1110, Université de Strasbourg, Inserm, F-67000 Strasbourg, France; (Z.B.); (A.V.); (T.F.B.); (E.R.V.)
| | - Joachim Lupberger
- Institut de Recherche sur les Maladies Virales et Hepatiques UMR_S1110, Université de Strasbourg, Inserm, F-67000 Strasbourg, France; (Z.B.); (A.V.); (T.F.B.); (E.R.V.)
- Correspondence:
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15
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Dubey AK, Kumar Gupta V, Kujawska M, Orive G, Kim NY, Li CZ, Kumar Mishra Y, Kaushik A. Exploring nano-enabled CRISPR-Cas-powered strategies for efficient diagnostics and treatment of infectious diseases. JOURNAL OF NANOSTRUCTURE IN CHEMISTRY 2022; 12:833-864. [PMID: 35194511 PMCID: PMC8853211 DOI: 10.1007/s40097-022-00472-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 01/23/2022] [Indexed: 05/02/2023]
Abstract
Biomedical researchers have subsequently been inspired the development of new approaches for precisely changing an organism's genomic DNA in order to investigate customized diagnostics and therapeutics utilizing genetic engineering techniques. Clustered Regulatory Interspaced Short Palindromic Repeats (CRISPR) is one such technique that has emerged as a safe, targeted, and effective pharmaceutical treatment against a wide range of disease-causing organisms, including bacteria, fungi, parasites, and viruses, as well as genetic abnormalities. The recent discovery of very flexible engineered nucleic acid binding proteins has changed the scientific area of genome editing in a revolutionary way. Since current genetic engineering technique relies on viral vectors, issues about immunogenicity, insertional oncogenesis, retention, and targeted delivery remain unanswered. The use of nanotechnology has the potential to improve the safety and efficacy of CRISPR/Cas9 component distribution by employing tailored polymeric nanoparticles. The combination of two (CRISPR/Cas9 and nanotechnology) offers the potential to open new therapeutic paths. Considering the benefits, demand, and constraints, the goal of this research is to acquire more about the biology of CRISPR technology, as well as aspects of selective and effective diagnostics and therapies for infectious illnesses and other metabolic disorders. This review advocated combining nanomedicine (nanomedicine) with a CRISPR/Cas enabled sensing system to perform early-stage diagnostics and selective therapy of specific infectious disorders. Such a Nano-CRISPR-powered nanomedicine and sensing system would allow for successful infectious illness control, even on a personal level. This comprehensive study also discusses the current obstacles and potential of the predicted technology. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s40097-022-00472-7.
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Affiliation(s)
- Ankit Kumar Dubey
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, 600036, Chennai, Tamil Nadu India
| | - Vijai Kumar Gupta
- Biorefining and Advanced Materials Research Center, Scotland’s Rural College (SRUC), Kings Buildings, West Mains Road, Edinburgh, EH9 3JG UK
| | - Małgorzata Kujawska
- Department of Toxicology, Poznan University of Medical Sciences, Dojazd 30, 60-631 Poznań, Poland
| | - Gorka Orive
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain
- CIBER Bioengineering, Biomaterials and Nanomedicine (CIBERBBN), Institute of Health Carlos III, Madrid, Spain
- Bioaraba Health Research Institute, Nanobiocel Research Group, Vitoria-Gasteiz, Spain
- University Institute for Regenerative Medicine and Oral Implantology, UIRMI (UPV/EHU-Fundación Eduardo Anitua), Vitoria-Gasteiz, Spain
- Singapore Eye Research Institute, Singapore, Singapore
| | - Nam-Young Kim
- Department of Electronics Engineering, RFIC Bio Centre, NDAC Centre, RFIC Bio Centre, NDAC Centre, Kwangwoon University, 20 Kwangwoon-ro, Nowon-gu, Seoul, 01897 South Korea
| | - Chen-zhong Li
- Center for Cellular and Molecular Diagnostics, Tulane University School of Medicine, 1430 Tulane Ave., New Orleans, LA 70112 USA
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, 1430 Tulane Ave., New Orleans, LA 70112 USA
| | - Yogendra Kumar Mishra
- Mads Clausen Institute, NanoSYD, University of Southern Denmark, Alison 2, 6400 Sønderborg, Denmark
| | - Ajeet Kaushik
- NanoBioTech Laboratory, Health System Engineering, Department of Natural Sciences, Florida Polytechnic University, Lakeland, FL-33805 USA
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Chen YJ, Shen CJ, Yu SH, Lin CL, Shih HM. Increased risk of hepatocellular carcinoma in patients with traumatic liver injury: Real-world data from a nationwide population-based study. Medicine (Baltimore) 2022; 101:e28837. [PMID: 35147128 PMCID: PMC8830875 DOI: 10.1097/md.0000000000028837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 01/27/2022] [Indexed: 01/04/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common cancer globally, and liver is one of the most commonly injured organs after blunt abdominal trauma. The traumatic liver injury-HCC risk relationship remains unclear.We extracted data of patients with traumatic liver injury between 2000 and 2013 from Taiwan National Health Insurance Research Database (n = 15,966) and those of age-, gender-, occupation-, and index year-matched individuals without traumatic liver injury from the general population (n = 63,864). Cox proportional hazard models were employed to determine the hazard ratios (HRs) and 95% confidence intervals (CIs) for HCC occurrence in the traumatic liver injury cohort compared with that in the comparison cohort.Patients with traumatic liver injury had an increased HCC risk (adjusted HR 2.13, 95% CI 1.59-2.85); this increased risk was more pronounced within 1 year after injury (adjusted HR 8.84, 95% CI 4.29-18.2). After >1 year of injury, HCC risk remained 1.53-fold higher in patients with traumatic liver injury than in those without traumatic liver injury (95% CI 1.08-2.15).People with traumatic liver injury demonstrate a high HCC risk, particularly within the first year of the injury.
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Affiliation(s)
- Yen-Ju Chen
- College of Medicine, China Medical University, Taichung, Taiwan
- Department of Emergency Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chih-Jung Shen
- College of Medicine, China Medical University, Taichung, Taiwan
- Department of Emergency Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Shao-Hua Yu
- College of Medicine, China Medical University, Taichung, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Cheng-Li Lin
- Management Office for Health Data, Clinical Trial Center, China Medical University Hospital, Taichung, Taiwan
| | - Hong-Mo Shih
- College of Medicine, China Medical University, Taichung, Taiwan
- Department of Emergency Medicine, China Medical University Hospital, Taichung, Taiwan
- Department of Public Health, China Medical University, Taichung, Taiwan
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17
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Gomez-Quiroz LE, Roman S. Influence of genetic and environmental risk factors in the development of hepatocellular carcinoma in Mexico. Ann Hepatol 2022; 27 Suppl 1:100649. [PMID: 34902602 DOI: 10.1016/j.aohep.2021.100649] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 11/20/2021] [Accepted: 11/24/2021] [Indexed: 02/06/2023]
Abstract
The latest studies on the epidemiology of diverse types of cancers have located in the scene the relevance of liver tumors, particularly hepatocellular carcinoma (HCC). HCC is a life-threatening malignancy triggered by chronic exposure to hepatitis B and C viruses, excessive alcohol intake, hepatic lipid droplet accumulation, and aflatoxins that lead to persistent liver damage. The occurrence of such etiological risk factors deeply marks the variability in the incidence of HCC worldwide reflected by geography, ethnicity, age, and lifestyle factors influenced by cultural aspects. New perspectives on the primary risk factors and their potential gene-environment interactions (GxE) have been well-addressed in some cancers; however, it continues to be a partially characterized issue in liver malignancies. In this review, the epidemiology of the risk factors for HCC are described enhancing the GxE interactions identified in Mexico, which could mark the risk of this liver malignancy among the population and the measures needed to revert them. Updated healthcare policies focusing on preventive care should be tailored based on the genetic and environmental risk factors, which may influence the effect of the etiological agents of HCC. Robust regional investigations related to epidemiological, clinical, and basic studies are warranted to understand this health problem complying with the rules of ethnic, genetic, environmental, and social diversity.
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Affiliation(s)
- Luis E Gomez-Quiroz
- Área de Medicina Experimental y Traslacional, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico
| | - Sonia Roman
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, "Fray Antonio Alcalde," Guadalajara, Jalisco, Mexico; Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico.
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18
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OUP accepted manuscript. Carcinogenesis 2022; 43:671-681. [DOI: 10.1093/carcin/bgac030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 03/15/2022] [Accepted: 03/28/2022] [Indexed: 11/14/2022] Open
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19
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Chen X, Xia Z, Wan Y, Huang P. Identification of hub genes and candidate drugs in hepatocellular carcinoma by integrated bioinformatics analysis. Medicine (Baltimore) 2021; 100:e27117. [PMID: 34596112 PMCID: PMC8483840 DOI: 10.1097/md.0000000000027117] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 08/14/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the third cancer-related cause of death in the world. Until now, the involved mechanisms during the development of HCC are largely unknown. This study aims to explore the driven genes and potential drugs in HCC. METHODS Three mRNA expression datasets were used to analyze the differentially expressed genes (DEGs) in HCC. The bioinformatics approaches include identification of DEGs and hub genes, Gene Ontology terms analysis and Kyoto encyclopedia of genes and genomes enrichment analysis, construction of protein-protein interaction network. The expression levels of hub genes were validated based on The Cancer Genome Atlas, Gene Expression Profiling Interactive Analysis, and the Human Protein Atlas. Moreover, overall survival and disease-free survival analysis of HCC patients were further conducted by Kaplan-Meier plotter and Gene Expression Profiling Interactive Analysis. DGIdb database was performed to search the candidate drugs for HCC. RESULTS A total of 197 DEGs were identified. The protein-protein interaction network was constructed using Search Tool for the Retrieval of Interacting Genes software, 10 genes were selected by Cytoscape plugin cytoHubba and served as hub genes. These 10 genes were all closely related to the survival of HCC patients. DGIdb database predicted 29 small molecules as the possible drugs for treating HCC. CONCLUSION Our study provides some new insights into HCC pathogenesis and treatments. The candidate drugs may improve the efficiency of HCC therapy in the future.
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Affiliation(s)
- Xiaolong Chen
- National Key Clinical Department, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhixiong Xia
- Department of Pathology, The Center Hospital of Wuhan, Hubei, China
| | - Yafeng Wan
- Department of Hepatobiliary Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Ping Huang
- National Key Clinical Department, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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20
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Shriki A, Lanton T, Sonnenblick A, Levkovitch-Siany O, Eidelshtein D, Abramovitch R, Rosenberg N, Pappo O, Elgavish S, Nevo Y, Safadi R, Peled A, Rose-John S, Galun E, Axelrod JH. Multiple Roles of IL6 in Hepatic Injury, Steatosis, and Senescence Aggregate to Suppress Tumorigenesis. Cancer Res 2021; 81:4766-4777. [PMID: 34117031 DOI: 10.1158/0008-5472.can-21-0321] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 05/05/2021] [Accepted: 06/10/2021] [Indexed: 11/16/2022]
Abstract
Hepatocellular carcinoma (HCC) typically develops on a background of chronic hepatitis for which the proinflammatory cytokine IL6 is conventionally considered a crucial driving factor. Paradoxically, IL6 also acts as a hepatoprotective factor in chronic liver injury. Here we used the multidrug-resistant gene 2 knockout (Mdr2-/-) mouse model to elucidate potential roles of IL6 in chronic hepatitis-associated liver cancer. Long-term analysis of three separate IL6/Stat3 signaling-deficient Mdr2-/- strains revealed aggravated liver injury with increased dysplastic nodule formation and significantly accelerated tumorigenesis in all strains. Tumorigenesis in the IL6/Stat3-perturbed models was strongly associated with enhanced macrophage accumulation and hepatosteatosis, phenotypes of nonalcoholic steatohepatitis (NASH), as well as with significant reductions in senescence and the senescence-associated secretory phenotype (SASP) accompanied by increased hepatocyte proliferation. These findings reveal a crucial suppressive role for IL6/Stat3 signaling in chronic hepatitis-associated hepatocarcinogenesis by impeding protumorigenic NASH-associated phenotypes and by reinforcing the antitumorigenic effects of the SASP. SIGNIFICANCE: These findings describe a context-dependent role of IL6 signaling in hepatocarcinogenesis and predict that increased IL6-neutralizing sgp130 levels in some patients with NASH may herald early HCC development.See related commentary by Huynh and Ernst, p. 4671.
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Affiliation(s)
- Anat Shriki
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Tali Lanton
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Amir Sonnenblick
- Oncology Division, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Orr Levkovitch-Siany
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Dana Eidelshtein
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Rinat Abramovitch
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
- The Wohl Institute for Translational Medicine, Human Biology Research Center, Hadassah University Medical Center, Jerusalem, Israel
| | - Nofar Rosenberg
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Orit Pappo
- Department of Pathology, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Sharona Elgavish
- Bioinformatics Unit, The Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Hadassah Medical School, Ein Karem, Jerusalem, Israel
| | - Yuval Nevo
- Bioinformatics Unit, The Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Hadassah Medical School, Ein Karem, Jerusalem, Israel
| | - Rifaat Safadi
- Liver Unit, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Amnon Peled
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Stefan Rose-John
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
| | - Eithan Galun
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
| | - Jonathan H Axelrod
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
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21
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Xu X, Lei Y, Chen L, Zhou H, Liu H, Jiang J, Yang Y, Wu B. Phosphorylation of NF-κBp65 drives inflammation-mediated hepatocellular carcinogenesis and is a novel therapeutic target. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:253. [PMID: 34380537 PMCID: PMC8359590 DOI: 10.1186/s13046-021-02062-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 08/06/2021] [Indexed: 01/09/2023]
Abstract
BACKGROUND Nuclear factor-κB (NF-κB) plays a vital role in hepatocellular carcinoma (HCC). β-arrestin1 (ARRB1) has been proved to enhance the activity of NF-κBp65, and our previous study indicated that ARRB1 promotes hepatocellular carcinogenesis and development of HCC. However, it remains unknown whether p65 is involved in hepatocellular carcinogenesis through the ARRB1-mediated pathway. METHODS The levels of NF-κBp65 and NF-κBp65 phosphorylation (p-p65) were assessed in including normal liver, primary HCC and paired paracancerous tissues. Liver-specific p65 knockout mice were used to examine the role of p65 and p-p65 in hepatocarcinogenesis. The mechanism of NF-κBp65 and p-p65 in hepatocarcinogenesis via ARRB1 was also studied both in vitro and in vivo. RESULTS Phosphorylation of NF-κBp65 was markedly upregulated in inflammation-related HCC patients and was significantly increased in mouse hepatic inflammation models, which were induced by tetrachloromethane (CCl4), diethylnitrosamine (DEN), TNF-α, as well as DEN-induced HCC. Hepatocyte-specific p65-deficient mice markedly decreased in the HCC incidence and size of tumours by the repressing of the proliferation of malignant cells in a DEN-induced HCC model. Furthermore, ARRB1 directly bounds p65 to promote the phosphorylation of NF-κBp65 at ser536, resulted in cell malignant proliferation through GSK3β/mTOR signalling. CONCLUSION The data demonstrated that phosphorylation of NF-κBp65 drives hepatocellular carcinogenesis in response to inflammation-mediated ARRB1, and that inhibition of the phosphorylation of NF-κBp65 restrains the hepatocellular carcinogenesis. The results indicate that phosphorylation of NF-κBp65 is a novel therapeutic target for HCC.
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Affiliation(s)
- Xuan Xu
- Department of Gastroenterology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630, Guangdong Province, China
| | - Yiming Lei
- Department of Gastroenterology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630, Guangdong Province, China
| | - Lingjun Chen
- Department of Gastroenterology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630, Guangdong Province, China
| | - Haoxiong Zhou
- Department of Gastroenterology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630, Guangdong Province, China
| | - Huiling Liu
- Department of Gastroenterology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630, Guangdong Province, China
| | - Jie Jiang
- Department of Gastroenterology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630, Guangdong Province, China
| | - Yidong Yang
- Department of Gastroenterology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong Province, China. .,Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630, Guangdong Province, China.
| | - Bin Wu
- Department of Gastroenterology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong Province, China. .,Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630, Guangdong Province, China.
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Montella L, Sarno F, Ambrosino A, Facchini S, D’Antò M, Laterza MM, Fasano M, Quarata E, Ranucci RAN, Altucci L, Berretta M, Facchini G. The Role of Immunotherapy in a Tolerogenic Environment: Current and Future Perspectives for Hepatocellular Carcinoma. Cells 2021; 10:1909. [PMID: 34440678 PMCID: PMC8393830 DOI: 10.3390/cells10081909] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 07/22/2021] [Accepted: 07/23/2021] [Indexed: 12/11/2022] Open
Abstract
In contrast to several tumors whose prognoses are radically affected by novel immunotherapeutic approaches and/or targeted therapies, the outcomes of advanced hepatocellular carcinoma (HCC) remain poor. The underlying cirrhosis that is frequently associated with it complicates medical treatment and often determines survival. The landscape of HCC treatment had included sorafenib as the only drug available for ten years, until 2018, when lenvatinib was approved for treatment. The second-line systemic treatments available for hepatocellular carcinoma include regorafenib, cabozantinib, ramucirumab, and, more recently, immune checkpoint inhibitors. However, the median survival remains below 15 months. The results obtained in clinics should be interpreted whilst considering the peculiar role of the liver as an immune organ. A healthy liver microenvironment ordinarily experiences stimulation by gut-derived antigens. This setup elucidates the response to chronic inflammation and the altered balance between tolerance and immune response in HCC development. This paper provides an overview of the mechanisms involved in HCC pathogenesis, with a special focus on the immune implications, along with current and future clinical perspectives.
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Affiliation(s)
- Liliana Montella
- ASL NA2 NORD, Oncology Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (M.M.L.); (E.Q.)
| | - Federica Sarno
- Precision Medicine Department, “Luigi Vanvitelli” University of Campania, 80138 Naples, Italy; (F.S.); (L.A.)
| | - Annamaria Ambrosino
- ASL NA2 NORD, Internal Medicine Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (A.A.); (M.D.); (R.A.N.R.)
| | - Sergio Facchini
- Department of Precision Medicine, Division of Medical Oncology, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (S.F.); (M.F.)
| | - Maria D’Antò
- ASL NA2 NORD, Internal Medicine Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (A.A.); (M.D.); (R.A.N.R.)
| | - Maria Maddalena Laterza
- ASL NA2 NORD, Oncology Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (M.M.L.); (E.Q.)
| | - Morena Fasano
- Department of Precision Medicine, Division of Medical Oncology, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (S.F.); (M.F.)
| | - Ermelinda Quarata
- ASL NA2 NORD, Oncology Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (M.M.L.); (E.Q.)
| | - Raffaele Angelo Nicola Ranucci
- ASL NA2 NORD, Internal Medicine Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (A.A.); (M.D.); (R.A.N.R.)
| | - Lucia Altucci
- Precision Medicine Department, “Luigi Vanvitelli” University of Campania, 80138 Naples, Italy; (F.S.); (L.A.)
| | - Massimiliano Berretta
- Department of Clinical and Experimental Medicine, University of Messina, 98121 Messina, Italy;
| | - Gaetano Facchini
- ASL NA2 NORD, Oncology Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (M.M.L.); (E.Q.)
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23
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El-Far YM, Khodir AE, Noor AO, Almasri DM, Bagalagel AA, Diri RM, Kutbi HI, Al-Gayyar MMH. Selective cytotoxic activity and protective effects of sodium ascorbate against hepatocellular carcinoma through its effect on oxidative stress and apoptosis in vivo and in vitro. Redox Rep 2021; 25:17-25. [PMID: 32172678 PMCID: PMC7144217 DOI: 10.1080/13510002.2020.1739870] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Objectives: Hepatocellular carcinoma (HCC) is characterized by elevated in oxidative stress and inflammatory cytokines, which enhance destructive effects of the tumor. Therefore, we conducted this study to investigate the protective effects of sodium ascorbate against thioacetamide-induced HCC in rats through studying its effect on the apoptotic pathway in rats. In addition, in vitro activity of sodium ascorbate was investigated on HepG2 and compared with cisplatin. Methods: HCC was experimentally induced by injecting rats with 200 mg/kg thioacetamide intraperitoneally twice weekly for 16 weeks. Part of HCC rats was concomitantly treated with 100 mg/kg sodium ascorbate intraperitoneally during the 16-week period. Hepatic tissues were used for the determination of NFκB, Nrf2, TNF-α, caspase-3, caspase-8 and caspase-9. Results: Sodium ascorbate significantly attenuated HCC-induced reduction in the expression of NrF2 associated with a reduction in concentrations of hydrogen peroxide and superoxide anion. In addition, sodium ascorbate blocked HCC-induced increase in the expression of NFκB and TNF-α. Sodium ascorbate slightly increased the activity of caspase-3, -8 and -9 in vitro but inhibited their activities in vivo. Conclusion: In spite of the antioxidant and anti-inflammatory activity of sodium ascorbate, it produced selective cytotoxic activity via direct activation of the apoptotic pathway in cancer cells without affecting the apoptotic pathway in normal hepatic cells.
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Affiliation(s)
- Yousra M El-Far
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Ahmed E Khodir
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa City, Mansoura, Dakhliya, Egypt
| | - Ahmad O Noor
- Deparment of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Deina M Almasri
- Deparment of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Alaa A Bagalagel
- Deparment of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Reem M Diri
- Deparment of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Hussam I Kutbi
- Deparment of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammed M H Al-Gayyar
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.,Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
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24
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Dzobo K. The Role of Viruses in Carcinogenesis and Molecular Targeting: From Infection to Being a Component of the Tumor Microenvironment. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2021; 25:358-371. [PMID: 34037476 DOI: 10.1089/omi.2021.0052] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
About a tenth of all cancers are caused by viruses or associated with viral infection. Recent global events including the coronavirus disease-2019 (COVID-19) pandemic means that human encounter with viruses is increased. Cancer development in individuals with viral infection can take many years after infection, demonstrating that the involvement of viruses in cancer development is a long and complex process. This complexity emanates from individual genetic heterogeneity and the many steps involved in cancer development owing to viruses. The process of tumorigenesis is driven by the complex interaction between several viral factors and host factors leading to the creation of a tumor microenvironment (TME) that is ideal and promotes tumor formation. Viruses associated with human cancers ensure their survival and proliferation through activation of several cellular processes including inflammation, migration, and invasion, resistance to apoptosis and growth suppressors. In addition, most human oncoviruses evade immune detection and can activate signaling cascades including the PI3K-Akt-mTOR, Notch and Wnt pathways associated with enhanced proliferation and angiogenesis. This expert review examines and synthesizes the multiple biological factors related to oncoviruses, and the signaling cascades activated by these viruses contributing to viral oncogenesis. In particular, I examine and review the Epstein-Barr virus, human papillomaviruses, and Kaposi's sarcoma herpes virus in a context of cancer pathogenesis. I conclude with a future outlook on therapeutic targeting of the viruses and their associated oncogenic pathways within the TME. These anticancer strategies can be in the form of, but not limited to, antibodies and inhibitors.
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Affiliation(s)
- Kevin Dzobo
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa.,Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
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25
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Huang FY, Wong DKH, Seto WK, Mak LY, Cheung TT, Yuen MF. Tumor suppressive role of mitochondrial sirtuin 4 in induction of G2/M cell cycle arrest and apoptosis in hepatitis B virus-related hepatocellular carcinoma. Cell Death Discov 2021; 7:88. [PMID: 33931611 PMCID: PMC8087836 DOI: 10.1038/s41420-021-00470-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 03/06/2021] [Accepted: 04/03/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is developed from uncontrolled cell growth after the malignant transformation of hepatocytes. The hepatitis B virus (HBV) X protein (HBx) has shown to induce cell cycle progression and hepatocarcinogenesis. A sub-fraction of HBx is localized in the mitochondria. Sirtuin 4 (SIRT4), a mitochondrial protein, has been demonstrated to play a tumor-suppressive role in many cancers, including HCC. However, little is known about the association between mitochondrial HBx and SIRT4 during hepatocarcinogenesis. We aimed to investigate the clinical significance and functional role of SIRT4 in HBV-related HCC. SIRT4 expression was significantly lower in the HCC tissues collected from 30 patients with HBV-related HCC than in normal liver tissues from control patients (p < 0.0001). TCGA data analysis indicated that SIRT4 expression was also lower in patients with HBV infection than in those without, and SIRT4 levels were positively associated with better patient survival. Similarly, HCC cell lines had lower SIRT4 expression than normal liver cell lines (all p < 0.01). Among the HCC cell lines, those harbored HBV had a lower SIRT4 expression than those without HBV (p < 0.0001). In vitro experiments revealed that stable HBx transfection suppressed SIRT4 expression in both HepG2 and Huh7 cells (both p < 0.001). Ectopic SIRT4 overexpression alone could induce cellular senescence through arresting cell-cycle progression at G2/M, and inducing cell apoptosis in HCC cells. Mechanistically, SIRT4 upregulated cell-cycle governing genes p16 and p21 protein expression, suppressed CyclinB1/Cdc2 and Cdc25c which normally induce cell-cycle progression, and suppressed survivin to induce apoptosis. Our findings demonstrate the interaction between HBV and SIRT4 in the context of HCC. SIRT4 involves in G2/M DNA damage checkpoint control and genomic stability in hepatocarcinogenesis, which could be targeted for future anticancer strategies.
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Affiliation(s)
- Fung-Yu Huang
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Danny Ka-Ho Wong
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, China
| | - Wai-Kay Seto
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, China
| | - Lung-Yi Mak
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, China
| | - Tan-To Cheung
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, China.,Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China. .,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, China.
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26
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Chen HA, Li CC, Lin YJ, Wang TF, Chen MC, Su YH, Yeh YL, Padma VV, Liao PH, Huang CY. Hsa-miR-107 regulates chemosensitivity and inhibits tumor growth in hepatocellular carcinoma cells. Aging (Albany NY) 2021; 13:12046-12057. [PMID: 33901009 PMCID: PMC8109096 DOI: 10.18632/aging.202908] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 03/25/2021] [Indexed: 01/19/2023]
Abstract
Hepatocellular carcinoma is a common type of liver cancer. Resistance to chemotherapeutic agents is a major problem in cancer therapy. MicroRNAs have been reported in cancer development and tumor growth; however, the relationship between chemoresistance and hepatocellular carcinoma needs to be fully investigated. Here, we treated hepatocellular carcinoma cell line (HA22T) with a histone deacetylase inhibitor to establish hepatocellular carcinoma-resistant cells (HDACi-R) and investigated the molecular mechanisms of chemoresistance in HCC cells. Although histone deacetylase inhibitor could not enhance cell death in HDACi-R but upregulation of miR-107 decreased cell viability both in parental cells and resistance cells, decreased the expression of cofilin-1, enhanced ROS-induced cell apoptosis, and dose-dependently sensitized HDACi-R to HDACi. Further, miR-107 upregulation resulted in tumor cell disorganization in both HA22T and HDACi-R in a mice xenograft model. Our findings demonstrated that miR-107 downregulation leads to hepatocellular carcinoma cell resistance in HDACi via a cofilin-1-dependent molecular mechanism and ROS accumulation.
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Affiliation(s)
- Hsin-An Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City 250, Taiwan.,Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei City 250, Taiwan.,Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, Taiwan.,TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei City 250, Taiwan
| | - Chi-Cheng Li
- Center of Stem Cell & Precision Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan
| | - Yu-Jung Lin
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan
| | - Tso-Fu Wang
- Department of Hematology and Oncology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan
| | - Ming-Cheng Chen
- Division of Colorectal Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung 407, Taiwan
| | - Yen-Hao Su
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City 250, Taiwan.,Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei City 250, Taiwan.,Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, Taiwan.,TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei City 250, Taiwan
| | - Yu-Lan Yeh
- Department of Pathology, Changhua Christian Hospital, Changhua 500, Taiwan.,Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli 356, Taiwan
| | - V Vijaya Padma
- Department of Biotechnology, Bharathiar University, Coimbatore 641046, India
| | - Po-Hsiang Liao
- Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, Taiwan
| | - Chih-Yang Huang
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan.,Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien 970, Taiwan.,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan.,Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan.,Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung 413, Taiwan
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27
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Chihab H, Badre W, Tahiri M, Jadid FZ, Zaidane I, Elfihry R, Marchio A, Pineau P, Ezzikouri S, Benjelloun S. IFNL4 rs12979860 polymorphism influences HBV DNA viral loads but not the outcome of HBV infection in Moroccan patients. Microbes Infect 2021; 23:104802. [PMID: 33607264 DOI: 10.1016/j.micinf.2021.104802] [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: 06/22/2020] [Revised: 01/20/2021] [Accepted: 02/08/2021] [Indexed: 12/18/2022]
Abstract
OBJECTIVES The interferon (IFN) is known to bridge innate and adaptive immune responses, and to play a critical role particularly against hepatitis B virus (HBV) infection. Defects in IFN signals may result, therefore, in attenuated responses against HBV. Accordingly, polymorphisms in genes coding for immune response effectors may affect the clinical outcome of HBV infection. We analyzed the putative association between IFNL4 rs12979860 polymorphism and the outcome of HBV infection in Moroccan patients. METHODS In this study, 237 chronic HBV (CHB) patients and 129 spontaneously resolved HBV (SRB) individuals were enrolled and genotyped using a predesigned Taqman allelic discrimination assay. RESULTS Our data show a significant increase of HBV DNA loads in patients with IFNL4 rs12979860 CC genotype compared to patients with CT and TT genotypes (p = 0.0008). However, there was no consistent association between IFNL4 rs12979860 polymorphism and the outcome of HBV infection. CONCLUSIONS Although IFNL4 rs12979860 polymorphism seems to modulate circulating HBV DNA levels, it is disconnected from chronic disease progression. This observation suggests that the role of rs12979860 in liver disease is restricted to viral control and inactive in the deleterious immune pathology that affects liver tissue. Taken together, our data suggest that rs12979860 CC genotypes could be useful as a predictor of success or failure of IFN-based therapy in chronic HBV-infected patients.
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Affiliation(s)
- Hajar Chihab
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Wafaa Badre
- Faculté de Médecine de Casablanca, CHU Ibn Rochd, Casablanca, Morocco
| | - Mohamed Tahiri
- Faculté de Médecine de Casablanca, CHU Ibn Rochd, Casablanca, Morocco
| | - Fatima-Zahra Jadid
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Imane Zaidane
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Raouia Elfihry
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Agnès Marchio
- Unité "Organisation Nucléaire et Oncogenèse", INSERM U993, Institut Pasteur, Paris, France
| | - Pascal Pineau
- Unité "Organisation Nucléaire et Oncogenèse", INSERM U993, Institut Pasteur, Paris, France
| | - Sayeh Ezzikouri
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Soumaya Benjelloun
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco.
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28
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The Dark Side of the Force: When the Immune System Is the Fuel of Tumor Onset. Int J Mol Sci 2021; 22:ijms22031224. [PMID: 33513730 PMCID: PMC7865698 DOI: 10.3390/ijms22031224] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/19/2021] [Accepted: 01/22/2021] [Indexed: 12/26/2022] Open
Abstract
Nowadays, it is well accepted that inflammation is a critical player in cancer, being, in most cases, the main character of the process. Different types of tumor arise from sites of infection or chronic inflammation. This non-resolving inflammation is responsible for tumor development at different levels: it promotes tumor initiation, as well as tumor progression, stimulating both tumor growth and metastasis. Environmental factors, lifestyle and infections are the three main triggers of chronic immune activation that promote or increase the risk of many different cancers. In this review, we focus our attention on tumor onset; in particular, we summarize the knowledge about the cause and the mechanisms behind the inflammation-driven cancer development.
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29
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Bastian K, Scott E, Elliott DJ, Munkley J. FUT8 Alpha-(1,6)-Fucosyltransferase in Cancer. Int J Mol Sci 2021; 22:E455. [PMID: 33466384 PMCID: PMC7795606 DOI: 10.3390/ijms22010455] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 12/21/2020] [Accepted: 12/24/2020] [Indexed: 12/15/2022] Open
Abstract
Aberrant glycosylation is a universal feature of cancer cells that can impact all steps in tumour progression from malignant transformation to metastasis and immune evasion. One key change in tumour glycosylation is altered core fucosylation. Core fucosylation is driven by fucosyltransferase 8 (FUT8), which catalyses the addition of α1,6-fucose to the innermost GlcNAc residue of N-glycans. FUT8 is frequently upregulated in cancer, and plays a critical role in immune evasion, antibody-dependent cellular cytotoxicity (ADCC), and the regulation of TGF-β, EGF, α3β1 integrin and E-Cadherin. Here, we summarise the role of FUT8 in various cancers (including lung, liver, colorectal, ovarian, prostate, breast, melanoma, thyroid, and pancreatic), discuss the potential mechanisms involved, and outline opportunities to exploit FUT8 as a critical factor in cancer therapeutics in the future.
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Affiliation(s)
- Kayla Bastian
- Institute of Biosciences, Newcastle University, Newcastle Upon Tyne NE1 3BZ, UK; (E.S.); (D.J.E.); (J.M.)
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30
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Wan L, Guo L, Hu Y, Huang H, Zhang M, Xu K, De G, Zheng F, Wu Z, Hu C, Wen Z. Comparing the diagnostic value of serum oligosaccharide chain (G-test) and alpha-fetoprotein for hepatitis B virus-related liver cancer. Clin Biochem 2020; 89:44-50. [PMID: 33309517 DOI: 10.1016/j.clinbiochem.2020.12.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 11/19/2020] [Accepted: 12/07/2020] [Indexed: 02/08/2023]
Abstract
OBJECTIVES The study compared the diagnostic efficiency of serum oligosaccharide chain (G-test) and alpha-fetoprotein (AFP) for hepatitis B-related hepatocellular carcinoma (HCC). METHODS Serum samples from 100 patients (divided into five groups of 20 each, namely the hepatitis, liver cirrhosis, liver cancer, health, and interference groups) who were admitted to the Second Affiliated Hospital of Nanchang University from October 2019 to January 2020 were collected, and the levels of G-test and AFP were determined. The sensitivity and specificity of the two indicators were compared, and the receiver operating characteristic curve of the subjects was drawn to evaluate the diagnostic values of G-test and AFP for HCC. RESULTS The diagnostic ability of G-test (area under the curve [AUC]: 0.88 ± 0.05) was better than that of AFP (AUC: 0.76 ± 0.05). When G-test and AFP were combined for detection, the AUC was larger than that of either indicator. The G-test was superior to AFP in the differential diagnosis of early HCC and cirrhosis. A combination of the two indicators (AUC: 0.769 ± 0.05) significantly improved the diagnostic rate for early HCC, indicating that G-test and AFP complemented each other. CONCLUSION G-test was better than AFP for screening HCC in patients with chronic hepatitis B and cirrhosis. The combination of the two further improved the diagnostic rate of hepatitis B-related liver cancer. The G-test improves the screening rate of early HCC in patients with cirrhosis. Therefore, these markers are of great clinical significance and can improve the sensitivity of HCC detection and reduce missed diagnosis rates.
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Affiliation(s)
- Lijun Wan
- Department of Gastroenterology and Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Li Guo
- Department of Gastroenterology and Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Youwen Hu
- Department of Gastroenterology and Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Hongyan Huang
- Department of Gastroenterology and Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Moran Zhang
- Department of Gastroenterology and Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Kedong Xu
- Department of Gastroenterology and Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Gejirifu De
- Department of Gastroenterology and Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Fengfei Zheng
- Department of Gastroenterology and Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zhengqiang Wu
- Department of Gastroenterology and Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Chungen Hu
- Department of Gastroenterology and Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zhili Wen
- Department of Gastroenterology and Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
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31
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Sokkar HH, Abo Dena AS, Mahana NA, Badr A. Artichoke extracts in cancer therapy: do the extraction conditions affect the anticancer activity? FUTURE JOURNAL OF PHARMACEUTICAL SCIENCES 2020. [DOI: 10.1186/s43094-020-00088-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Artichoke is an edible plant that is grown in the Mediterranean region and is known for its antimicrobial, antifungal, antibacterial, antioxidant and anticancer activities. Different artichoke extraction methods can impressively affect the nature as well as the yield of the extracted components.
Main body
The different methods of artichoke extraction and the influence of the extraction conditions on the extraction efficiency are summarized herein. In addition, cancer causalities and hallmarks together with the molecular mechanisms of artichoke active molecules in cancer treatment are also discussed. Moreover, a short background is given on the common types of cancer that can be treated with artichoke extracts as well as their pathogenesis. A brief discussion of the previous works devoted to the application of artichoke extracts in the treatment of these cancers is also given.
Conclusion
This review article covers the extraction methods, composition, utilization and applications of artichoke extracts in the treatment of different cancers.
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32
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Lim HK, Jeffrey GP, Ramm GA, Soekmadji C. Pathogenesis of Viral Hepatitis-Induced Chronic Liver Disease: Role of Extracellular Vesicles. Front Cell Infect Microbiol 2020; 10:587628. [PMID: 33240824 PMCID: PMC7683521 DOI: 10.3389/fcimb.2020.587628] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 10/13/2020] [Indexed: 12/11/2022] Open
Abstract
Extracellular vesicles are encapsulated lipid nanoparticles secreted by a variety of cell types in living organisms. They are known to carry proteins, metabolites, nucleic acids, and lipids as their cargoes and are important mediators of intercellular communication. The role of extracellular vesicles in chronic liver disease has been reported. Chronic liver disease such as viral hepatitis accounts for a significant mortality and morbidity burden worldwide. Hepatic fibrosis has been commonly associated with the chronic form of viral hepatitis, which results in end-stage liver disease, including cirrhosis, liver failure, and carcinoma in some patients. In this review, we discuss the potential role of extracellular vesicles in mediating communication between infectious agents (hepatitis B and C viruses) and host cells, and how these complex cell-cell interactions may facilitate the development of chronic liver disease. We will further discuss how understanding their biological mechanism of action might be beneficial for developing therapeutic strategies to treat chronic liver disease.
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Affiliation(s)
- Hong Kiat Lim
- Hepatic Fibrosis Group, Department of Cellular and Molecular Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Gary P Jeffrey
- Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia.,Sir Charles Gairdner Hospital, Nedlands, Hepatology Department and Liver Transplant Service, Perth, WA, Australia
| | - Grant A Ramm
- Hepatic Fibrosis Group, Department of Cellular and Molecular Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Carolina Soekmadji
- Hepatic Fibrosis Group, Department of Cellular and Molecular Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
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D'souza S, Lau KCK, Coffin CS, Patel TR. Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma. World J Gastroenterol 2020; 26:5759-5783. [PMID: 33132633 PMCID: PMC7579760 DOI: 10.3748/wjg.v26.i38.5759] [Citation(s) in RCA: 146] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/03/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic infection with viral hepatitis affects half a billion individuals worldwide and can lead to cirrhosis, cancer, and liver failure. Liver cancer is the third leading cause of cancer-associated mortality, of which hepatocellular carcinoma (HCC) represents 90% of all primary liver cancers. Solid tumors like HCC are complex and have heterogeneous tumor genomic profiles contributing to complexity in diagnosis and management. Chronic infection with hepatitis B virus (HBV), hepatitis delta virus (HDV), and hepatitis C virus (HCV) are the greatest etiological risk factors for HCC. Due to the significant role of chronic viral infection in HCC development, it is important to investigate direct (viral associated) and indirect (immune-associated) mechanisms involved in the pathogenesis of HCC. Common mechanisms used by HBV, HCV, and HDV that drive hepatocarcinogenesis include persistent liver inflammation with an impaired antiviral immune response, immune and viral protein-mediated oxidative stress, and deregulation of cellular signaling pathways by viral proteins. DNA integration to promote genome instability is a feature of HBV infection, and metabolic reprogramming leading to steatosis is driven by HCV infection. The current review aims to provide a brief overview of HBV, HCV and HDV molecular biology, and highlight specific viral-associated oncogenic mechanisms and common molecular pathways deregulated in HCC, and current as well as emerging treatments for HCC.
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Affiliation(s)
- Simmone D'souza
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
| | - Keith CK Lau
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
| | - Carla S Coffin
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
| | - Trushar R Patel
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
- Department of Chemistry and Biochemistry, Alberta RNA Research and Training Institute, University of Lethbridge, Lethbridge T1K3M4, AB, Canada
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Systematic review of outcomes and meta-analysis of risk factors for prognosis after liver resection for hepatocellular carcinoma without cirrhosis. Asian J Surg 2020; 44:36-45. [PMID: 32988708 DOI: 10.1016/j.asjsur.2020.08.019] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 07/28/2020] [Accepted: 08/09/2020] [Indexed: 02/07/2023] Open
Abstract
Long-term overall survival (OS) after liver resection for non-cirrhotic hepatocellular carcinoma (NCHCC) has been reported recently. The aim of this study was to review outcomes systematically and analyze risk factors for survival after surgical resection for HCC without cirrhosis. A literature search was performed of the PubMed and Embase databases for papers published between January 1995 and October 2012, which focused on hepatic resection for HCC without underlying cirrhosis. Cochrane systematic review methodology was used for this review. Outcomes were OS, operative mortality and disease-free survival (DFS). Pooled hazard ratios (HR) were calculated using the random effects model for parameters considered as potential prognostic factors. Totally, 26 retrospective case series were eligible for inclusion. The 1-, 3- and 5-year OS rate after surgical resection of NCHCC ranged from 62% to 100%, 46.3%-78.0%, and 30%-64%, respectively. The corresponding DFS rates ranged from 48.7% to 84%, 31.0%-66.0%, and 24.0%-58.0%, respectively. Five variables were related to poor survival: multiple tumors (HR 1.68, 95%CI 1.25-2.11); larger tumor size (HR 2.66, 95%CI 1.69-3.63); non-clear resection margin (R0 resection) (HR 3.52, 95%CI 1.63-5.42); poor tumor stage (HR 2.61, 95%CI 1.64-3.58); and invasion of the lymphatic vessels (HR 4.85, 95%CI 2.67-7.02). In sum, hepatic resection provides excellent OS rates for patients with NCHCC, and results have tended to improve recently. Risk factors for poor prognosis comprise multiple tumors, lager tumor size, non-R0 resection and invasion of the lymphatic vessels.
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Liu Y, Wang X, Yang Y. Hepatic Hippo signaling inhibits development of hepatocellular carcinoma. Clin Mol Hepatol 2020; 26:742-750. [PMID: 32981290 PMCID: PMC7641559 DOI: 10.3350/cmh.2020.0178] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Accepted: 09/10/2020] [Indexed: 12/21/2022] Open
Abstract
Primary liver cancer is one of the most common cancer worldwide. Hepatocellular carcinoma (HCC) in particular, is the second leading cause of cancer deaths in the world. The Hippo signaling pathway has emerged as a major oncosuppressive pathway that plays critical roles inhibiting hepatocyte proliferation, survival, and HCC formation. A key component of the Hippo pathway is the inhibition of yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) transcription factors by the Hippo kinase cascade. Aberrant activation of YAP or TAZ has been found in several human cancers including HCC. It is also well established that YAP/TAZ activation in hepatocytes causes HCC in mouse models, indicating that YAP/TAZ are potential therapeutic targets for human liver cancer. In this review, we summarize the recent findings regarding the multifarious roles of Hippo/YAP/TAZ in HCC development, and focus on their cell autonomous roles in controlling hepatocyte proliferation, differentiation, survival and metabolism as well as their non-cell autonomous in shaping the tumor microenvironment.
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Affiliation(s)
- Yuchen Liu
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
| | - Xiaohui Wang
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
| | - Yingzi Yang
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA.,Harvard Stem Cell Institute, Boston, MA, USA.,Program in Gastrointestinal Malignancies, Dana-Farber/Harvard Cancer Center, Boston, MA, USA
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36
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Nakayama J, Gong Z. Transgenic zebrafish for modeling hepatocellular carcinoma. MedComm (Beijing) 2020; 1:140-156. [PMID: 34766114 PMCID: PMC8491243 DOI: 10.1002/mco2.29] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 08/05/2020] [Accepted: 08/05/2020] [Indexed: 12/14/2022] Open
Abstract
Liver cancer is the third leading cause of cancer‐related deaths throughout the world, and more than 0.6 million people die from liver cancer annually. Therefore, novel therapeutic strategies to eliminate malignant cells from liver cancer patients are urgently needed. Recent advances in high‐throughput genomic technologies have identified de novo candidates for oncogenes and pharmacological targets. However, testing and understanding the mechanism of oncogenic transformation as well as probing the kinetics and therapeutic responses of spontaneous tumors in an intact microenvironment require in vivo examination using genetically modified animal models. The zebrafish (Danio rerio) has attracted increasing attention as a new model for studying cancer biology since the organs in the model are strikingly similar to human organs and the model can be genetically modified in a short time and at a low cost. This review summarizes the current knowledge of epidemiological data and genetic alterations in hepatocellular carcinoma (HCC), zebrafish models of HCC, and potential therapeutic strategies for targeting HCC based on knowledge from the models.
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Affiliation(s)
- Joji Nakayama
- Department of Biological Sciences National University of Singapore Singapore
| | - Zhiyuan Gong
- Department of Biological Sciences National University of Singapore Singapore
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Zhou C, Chen Z, Peng C, Chen C, Li H. Long Noncoding RNA TRIM52-AS1 Sponges miR-514a-5p to Facilitate Hepatocellular Carcinoma Progression Through Increasing MRPS18A. Cancer Biother Radiopharm 2020; 36:211-219. [PMID: 32391716 DOI: 10.1089/cbr.2019.3271] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Background: Hepatocellular carcinoma (HCC) is associated with high morbidity and mortality and has become the most frequently diagnosed liver cancer globally. Long noncoding RNAs have been widely studied because they exert essential functions in human diseases. Aim of the Study: The aim of the study is to explore the role and molecular regulatory mechanism of TRIM52-AS1 in HCC. Materials and Methods: Real-time quantitative polymerase chain reaction examined TRIM52-AS1, miR-514a-5p, and mitochondrial ribosomal protein S18a (MRPS18A) expression in HCC cells. Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, JC-1, transwell, and Western blot assays uncovered the function of TRIM52-AS1 in HCC. RNA immunoprecipitation (RIP), RNA pull down, and luciferase reporter assays validated the association among TRIM52-AS1, miR-514a-5p, and MRPS18A. Nuclear-cytoplasmic fractionation assay revealed the subcellular location of TRIM52-AS1 in HCC cells. Results: TRIM52-AS1 was revealed to be upregulated in HCC tissue samples according to GEPIA database. Consistent results were recognized in HCC cell lines. Subsequently, loss-of-function assays confirmed that TRIM52-AS1 ablation depressed cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition process in vitro and inhibited tumor growth in vivo. Furthermore, the authors validated TRIM52-AS1 bound with miR-514a-5p in HCC. TRIM52-AS1 inversely regulated miR-514a-5p expression. Afterward, MRPS18A was identified to be a downstream target of miR-514a-5p. Ultimately, rescue assays manifested that MRPS18A upregulation could neutralize the attenuated effects resulting from TRIM52-AS1 deficiency. Conclusions: All in all, TRIM52-AS1 sponged miR-514a-5p to facilitate HCC progression through increasing MRPS18A expression. The findings highlight TRIM52-AS1 as a novel therapeutic target for HCC.
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Affiliation(s)
- Chunhui Zhou
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, China
| | - Zhen Chen
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, China
| | - Changli Peng
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, China
| | - Changyong Chen
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, China
| | - Haiping Li
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, China
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Zhou B, Chen TW, Jiang YB, Wei XB, Lu CD, Li JJ, Xie D, Cheng SQ. Scinderin suppresses cell proliferation and predicts the poor prognosis of hepatocellular carcinoma. Oncol Lett 2020; 19:2011-2020. [PMID: 32194697 DOI: 10.3892/ol.2020.11262] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 11/26/2019] [Indexed: 12/20/2022] Open
Abstract
Hepatocellular carcinoma (HCC) remains an intractable disease despite numerous advancements made in the available treatments over recent decades. Therefore, investigation of the underlying pathogenesis of HCC is urgently required. Our previous microarray result showed that SCIN was generally downregulated in 23 paired tumor/normal tissues. Reverse transcription-quantitative PCR, western blotting and immunohistochemistry were performed in the present study in order to detect the expression of scinderin (SCIN). Lentivirus-mediated gene delivery was used in order to produce SCIN-manipulated cell lines. MTT and crystal violet assays were performed in order to investigate cell growth, and fluorescence-activated cell sorting analysis was used in order to determine cell cycle distribution. SCIN was downregulated in HCC samples, and low SCIN expression predicted the poor prognosis of patients with HCC. Notably, SCIN may have the potential to serve as an independent risk factor for overall survival (3-year overall survival rate of 28.6 and 10.3% in high SCIN expression and low SCIN expression groups, respectively) and disease-free survival (3-year recurrence rate of 71.4 and 84.6% in high SCIN expression and low SCIN expression groups, respectively) in HCC. SCIN inhibited HCC cell proliferation both in vitro and in subcutaneous tumor formation assay. Furthermore, SCIN decreased the levels of phosphorylated STAT3, thereby downregulating cyclin A1 levels in HCC cells. The results of the present study demonstrate the tumor suppressive role of SCIN in HCC, providing a candidate strategy to treat this disease.
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Affiliation(s)
- Bin Zhou
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, P.R. China
| | - Tian-Wei Chen
- Laboratory of Molecular Oncology, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, P.R. China
| | - Ya-Bo Jiang
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, P.R. China
| | - Xu-Biao Wei
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, P.R. China
| | - Chong-De Lu
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, P.R. China
| | - Jing-Jing Li
- Laboratory of Molecular Oncology, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, P.R. China
| | - Dong Xie
- Laboratory of Molecular Oncology, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, P.R. China
| | - Shu-Qun Cheng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, P.R. China
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Chen S, Li J, Tan X, Xu Q, Mo Y, Qin H, Zhou L, Ma L, Wei Z. Clinical role of combining alpha-fetoprotein and lens culinaris agglutinin-reactive fraction of alpha-fetoprotein for hepatocellular carcinoma: Evidence from literature and an original study. J Clin Lab Anal 2020; 34:e23262. [PMID: 32167614 PMCID: PMC7370718 DOI: 10.1002/jcla.23262] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Revised: 01/18/2020] [Accepted: 01/28/2020] [Indexed: 12/21/2022] Open
Abstract
Background To evaluate the clinical diagnostic efficacy of the combination of alpha‐fetoprotein (AFP) and lens culinaris agglutinin‐reactive fraction of AFP/total AFP (AFP‐L3%) for detecting hepatocellular carcinoma (HCC). Methods A comprehensive and systemic literature search was executed in Web of Science, PubMed, and the Cochrane Library websites. Then, the related articles were reviewed and the quality of included studies was evaluated with the QUADAS tool. Further, serum samples were collected from 49 HCC patients, 52 cirrhosis patients, 47 hepatitis patients, and 48 healthy controls and these samples were tested for AFP and AFP‐L3% levels. Results A total of 16 eligible articles were included in our meta‐analysis. The overall sensitivity (SEN) of AFP + AFP‐L3% was higher than that of AFP or AFP‐L3 alone; the overall specificity (SPE) of AFP + AFP‐L3% was lower than that of AFP or AFP‐L3 alone. In the original study, the related statistics were, respectively, SEN = 0.592 and SPE = 0.918 for AFP; SEN = 0.367 and SPE = 1.000 for AFP‐L3%; and SEN = 0.592 and SPE = 0.918 for the combination. Conclusion The results of meta‐analysis indicate there is a beneficial effect of using the unity of AFP and AFP‐L3% for HCC diagnosing. However, in the original study, just for the results of sensitivity and specificity, there is no significant difference between AFP alone and AFP + AFP‐L3%.
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Affiliation(s)
- Siyuan Chen
- Department of Nuclear Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Junhong Li
- Department of Nuclear Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xiaodan Tan
- Department of Nuclear Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Qi Xu
- Department of Nuclear Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yuncong Mo
- Department of Nuclear Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Hongyan Qin
- Department of Nuclear Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Lili Zhou
- Department of Nuclear Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Lingxiu Ma
- Department of Nuclear Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zhixiao Wei
- Department of Nuclear Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
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40
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Comparison of clinical manifestations and outcomes of noncirrhotic and cirrhotic hepatocellular carcinoma patients with chronic hepatitis B. Eur J Gastroenterol Hepatol 2020; 32:66-73. [PMID: 31268949 DOI: 10.1097/meg.0000000000001478] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
AIM The differences of the clinical features and survival outcomes between cirrhotic and noncirrhotic hepatocellular carcinoma (HCC) patients with hepatitis B virus (HBV) infection remain to be determined. We evaluated clinical characteristics and survival outcomes of noncirrhotic HBV-associated HCC patients compared with cirrhotic patients. PATIENTS AND METHODS Between January 2005 and December 2015, 1345 patients were diagnosed to have HCC at our hospital. Of these, 860 HBV-associated HCC patients with (cirrhotic group, n = 519, 60.3%) or without cirrhosis (noncirrhotic group, n = 341, 39.7%) were retrospectively analyzed. Propensity score matching (PSM) was used to adjust for differences between the two groups. RESULTS The noncirrhotic group had lower Child-Turcotte-Pugh (CTP) classes and greater tumor sizes and were less likely to have portal vein thrombosis than the cirrhotic group. Age and sex were not significantly different between the two groups. Cumulative overall survival (OS) rates at 2, 4, 6, and 8 years after treatment were significantly higher in the noncirrhotic group (67.2, 57.1, 43.2, and 38.3 vs. 58.3, 41.3, 33.2, and 27.8%, respectively, P < 0.001). However, no significant intergroup difference in OS rates was observed after PSM (P = 0.680). Significant predictive factors of OS were CTP class, tumor size, tumor number, and curative-intended treatment for the noncirrhotic group, and serum alanine aminotransferase, CTP class, tumor size, tumor number, and curative-intended treatment for the cirrhotic group. CONCLUSION After PSM, cumulative OS rates were similar between HBV-related HCC patients with and without cirrhosis, and they were clearly dependent on CTP class, regardless of the presence of cirrhosis itself both in cirrhotic and noncirrhotic patients.
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Siregar GA, Irwansyah D. Comparison of Platelet to Lymphocyte Ratio between Degrees of the Barcelona Clinic Liver Cancer on Hepatocellular Carcinoma Patients at Haji Adam Malik General Hospital. Open Access Maced J Med Sci 2019; 7:3451-3454. [PMID: 32002072 PMCID: PMC6980812 DOI: 10.3889/oamjms.2019.444] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 09/15/2019] [Accepted: 09/16/2019] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND: Hepatocellular carcinoma (HCC) is the fifth most common malignancy. The Barcelona Clinical Liver Cancer System (BCLC), guides the treatment of patients with HCC. Platelet to lymphocyte ratio (PLR) is an inflammatory marker used as a prognostic factor disease of HCC. An increase in PLR indicates higher host’s inflammatory response and is associated with aggressive HCC behaviour, according to BCLC. AIM: This study aims to determine the PLRs between among the degrees of BCLC (The Barcelona Clinic Liver Cancer) in HCC patients at Haji Adam Malik General Hospital in Medan during 2015-2016. METHODS: This retrospective study involved 166 patients with HCC who were then classified by the BCLC guidelines. PLRs among the patient’s degrees of BCLC were compared using Kruskal Wallis test. RESULTS: A total of 166 HCC patients, 129 (77.7%) were men and 37 (22.3%) were women. The PLR value has a median value of 17841with the lowest value of 1776 and the highest value of 223684. There were differences in PLR levels with various BCLC stages in patients with HCC at Haji Adam Malik Hospital during 2015-2016 (p = 0.026). CONCLUSION: There were differences in PLR levels with various BCLC stages in patients with HCC at Haji Adam Malik Hospital during 2015-2016.
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Affiliation(s)
- Gontar Alamsyah Siregar
- Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Dedi Irwansyah
- Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
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Anti-Tumor Effects of Vitamin B2, B6 and B9 in Promonocytic Lymphoma Cells. Int J Mol Sci 2019; 20:ijms20153763. [PMID: 31374832 PMCID: PMC6696026 DOI: 10.3390/ijms20153763] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 07/27/2019] [Accepted: 07/30/2019] [Indexed: 12/16/2022] Open
Abstract
Chronic inflammation can lead to tumour initiation and progression. Vitamin B complex has the ability to regulate the immune response and, therefore, inflammation but many of the mechanistic and molecular processes involved in this regulation are still not fully understood. This study sought to determine some of these processes by studying the effects of vitamin B2 (riboflavin) B6 (pyridoxine) and B9 (folic acid) on un-differentiated pro-monocytic lymphoma cells in regard to their ability to alter the proliferation, migration, apoptosis, cytokines and expression levels of programmed death ligand 1. We show that vitamin B2, B6 and B9, on pro-monocytic lymphoma cells exerted an anti-tumorigenic effect. This data could form the basis for future studies in using vitamin B supplementation to reduce cancer cell growth in vivo.
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Hyun CS, Ko O, Lee S, McMenamin J. Long term outcome of a community-based hepatitis B awareness campaign: eight-year follow-up on linkage to care (LTC) in HBV infected individuals. BMC Infect Dis 2019; 19:638. [PMID: 31319805 PMCID: PMC6637477 DOI: 10.1186/s12879-019-4283-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Accepted: 07/11/2019] [Indexed: 01/05/2023] Open
Abstract
Background Chronic hepatitis B (CHB) is a major cause of liver-related morbidity and mortality. High HBV prevalence in immigrants and ethnic minorities and numerous barriers to healthcare access are associated with serious health disparities in the United States. Reportedly, self-awareness of HBV infection is low, suggesting a greater need for effective screening and education. Further, low levels of linkage to care (LTC) (completion of a first doctor’s visit after the diagnosis of chronic HBV infection) may be responsible for the lack of engagement over the continuum of care and for needed services. Methods Demographics and survey data were obtained from 97 Korean American adults chronically infected with HBV, initially identified through a series of community screening events in northern New Jersey between Dec. 2009 and June 2015. Eight year follow-up on these HBV-infected individuals was obtained to determine their access to care, and thus the efficacy of a campaign to improve LTC. The participants’ self-awareness of HBV infection and other factors for LTC were also evaluated. Results Of a total of 97 HBV-infected participants (age range 30 to 79), 74 were aware of their infections at screening. The remaining 23 had been unaware of their infections until screening. Eight years after the campaign, some 66 of these 97 individuals accessed care (LTC rate 68%). Health insurance status, presence or absence of symptoms and level of knowledge of CHB were among the most significant factors in LTC. Conclusion A community-based hepatitis B screening and education campaign can be instrumental in prompting HBV infected individuals to access care, as demonstrated in the cumulative increase in LTC in our cohort. Despite many years of awareness of HBV infection, many are not accessing care owing to a lack of health insurance, suggesting a pressing need for advocacy and health education to improve access to affordable coverage in the Asian American population. Community efforts and strategies similar to the ones employed in the current study may serve as a model to improve the engagement of HBV-infected individuals in high risk immigrant populations.
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Affiliation(s)
- Chul S Hyun
- Center for Viral Hepatitis, 35 Van Nostrand Avenue, Englewood, NJ, 07631, USA.
| | - Okhyun Ko
- KCS Public Health and Research Center, 2 W. 32nd St. Suite 604, New York, NY, 10001, USA
| | - Seulgi Lee
- Asian Health Services, Holy Name Medical Center, 718, Teaneck, NJ, 07666, USA
| | - Joseph McMenamin
- McMenamin Law Offices, PPLC, 10617 Falconbridge Drive, Richmond, VA, 23238, USA
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Abstract
Liver diseases that are caused by the hepatitis B virus (HBV) and hepatitis C virus (HCV), including cirrhosis and hepatocellular carcinoma (HCC), have become increasingly important in patients infected with the human immunodeficiency virus (HIV) as their life expectancy is getting longer with successful anti-HIV therapy. Due to their shared transmission routes, dual infection by HIV and HBV or HIV and HCV, and triple infection by all three viruses are fairly common and affect millions of people worldwide. Whereas the immunodeficiency caused by HIV enhances the likelihood of HBV and HCV persistence, hepatotoxicity associated with anti-HIV therapy can worsen the liver diseases associated with HBV or HCV persistence. Evidence suggests HIV infection increases the risk of HBV- or HCV-associated HCC risk although the precise mechanisms of enhanced hepatocarcinogenesis remain to be fully elucidated. Recent success in curing HCV infection, and the availability of therapeutic options effective in long-term suppression of both HIV and HBV replication, bring hope, fortunately, to those who are coinfected but also highlight the need for judicious selection of antiviral therapies.
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Groopman JD. Environmental health in the biology century: Transitions from population to personalized prevention. Exp Biol Med (Maywood) 2019; 244:728-733. [PMID: 30895818 PMCID: PMC6567587 DOI: 10.1177/1535370219837903] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
IMPACT STATEMENT There is a rapidly occurring, dynamic change, in the causes of morbidity and mortality in different populations across the globe. More people today are being diagnosed and treated for chronic diseases such as cancer, cardiovascular disease, and diabetes than ever before. Environmental exposures across the lifespan have a profound impact on the outcomes of these chronic diseases. Further, there are more people living today who have survived their therapy from these diagnoses and who are now differentially susceptible to environmental exposures. Collectively, this poses both the challenge and opportunity to the experimental biology and medicine community to build new models that reflect this changing human situation. The extraordinary advances in our understanding of the biology of disease provide extraordinary insights for both therapeutic and prevention strategies. Multidisciplinary teams including biological, physical, engineering and social and behavioral scientists will be needed to address this problem over the next several decades.
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Affiliation(s)
- John D Groopman
- Sidney Kimmel Comprehensive Cancer Center, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
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Hyun S, Lee S, Ventura WR, McMenamin J. Knowledge, Awareness, and Prevention of Hepatitis B Virus Infection Among Korean American Parents. J Immigr Minor Health 2019. [PMID: 28639095 PMCID: PMC6061079 DOI: 10.1007/s10903-017-0609-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hepatitis B (HB) affects 240 million people around the world, and children and young adults make up a large proportion of the infected population. Approximately 1 million people die from HB each year. Despite the seriousness of HB and its complications, many are poorly linked to clinical care. A lack of health literacy may be a critical barrier hindering access to HB care for adults as well as children in these populations. We, therefore, performed a survey to assess the level of knowledge of HB among Korean American parents. The survey was conducted on 521 Korean American adults who attended community-based HB awareness campaigns held at various locations throughout the metropolitan New York area between January 2015 and November 2016. Of these, 296 parents, who had children between ages 1 and 30, were identified. All participants were asked a series of questions regarding various aspects of HB and were evaluated on the basis of their awareness on each subject. A separate questionnaire was also employed to obtain demographic characteristics of the participants. The study revealed a significant deficit of knowledge of HB in most aspects the survey evaluated. Although the majority of the participants knew that HB is a liver disease, and many of them had been screened for HB, they had a poor understanding of vaccination, screening, their own HB status, modes of HBV transmission, and the consequences and treatment of HB. The participants also had a low level of awareness of their own children’s HB status. This study demonstrates a low level of knowledge of HB among Korean American parents electing to attend a hepatitis education program. In addition, many parents are not aware of their children’s screening and immune (or non-immune) status. The lack of health literacy may contribute to poor health access in HB care, not only in adults but also in children. This suggests an urgent need for education on HB in Korean American parents as well as in young children.
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Affiliation(s)
| | - Seulgi Lee
- Holy Name Medical Center, Teaneck, NJ USA
| | | | - Joseph McMenamin
- Virginia Commonwealth University School of Medicine, Richmond, VA USA
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Living donor liver transplantation in hepatocellular carcinoma: A single-center experiences. JOURNAL OF SURGERY AND MEDICINE 2019. [DOI: 10.28982/josam.557019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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Wan Y, Li M, Huang P. LINC01296 promotes proliferation, migration, and invasion of HCC cells by targeting miR-122-5P and modulating EMT activity. Onco Targets Ther 2019; 12:2193-2203. [PMID: 30988624 PMCID: PMC6441465 DOI: 10.2147/ott.s197338] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Introduction Long noncoding RNAs (lncRNAs) play an important role in the origination and progression of hepatocellular carcinoma (HCC). However, the biological function of the long intergenic non-protein-coding RNA, LINC01296, in HCC remains unknown. Methods Here, we observed an increase in the expression levels of LINC01296 in HCC tissues and cell lines using reverse transcription quantitative PCR; these data were consistent with that obtained from The Cancer Genome Atlas database. Results A higher expression level was correlated with higher alpha fetoprotein levels, a larger tumor size, an advanced TNM stage, and a poorer overall survival rate. Upregulation of LINC01296 promoted the proliferation, migration, and invasion of HCC cells. Improvement of cell migration and invasion attributable to the overexpression of LINC01296 was related to an increase in epithelial–mesenchymal transition (EMT). Mechanistically, miR-122-5P can bind to LINC01296 and decrease its oncogenic effect. Conclusion Collectively, the results of this study revealed that LINC01296 is a tumor promoter that can promote the migration and invasion of HCC cells through EMT, while miR-122-5P is involved in the underlying mechanisms.
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Affiliation(s)
- Yafeng Wan
- National Key Clinical Department, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing 400000, People's Republic of China,
| | - Molin Li
- National Key Clinical Department, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing 400000, People's Republic of China,
| | - Ping Huang
- National Key Clinical Department, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing 400000, People's Republic of China,
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Ouyang G, Liu J, Wang P, Ren Y, Yi P, Zhou Q, Chen J, Xiang B, Zhang Y, Zhang Z, Li L. Multiple factors affect the regeneration of liver. ACTA ACUST UNITED AC 2019; 64:791-798. [PMID: 30672999 DOI: 10.1590/1806-9282.64.09.791] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 01/20/2018] [Indexed: 11/21/2022]
Abstract
OBJECTIVE To study factors affecting the liver regeneration after hepatectomy. METHODS With 3D reconstitution technology, liver regeneration ability of 117 patients was analysed, and relative factors were studied. RESULTS There was no statistically difference between the volume of simulated liver resection and the actual liver resection. All livers had different degrees of regeneration after surgery. Age, gender and blood indicators had no impact on liver regeneration, while surgery time, intraoperative blood loss, blood flow blocking time and different ways of liver resection had a significant impact on liver regeneration; In addition, the patients' own pathological status, including, hepatitis and liver fibrosis all had a significant impact on liver regeneration. CONCLUSION 3D reconstitution model is a good model to calculate liver volume. Age, gender, blood indicators and biochemistry indicators have no impact on liver regeneration, but surgery indicators and patients' own pathological status have influence on liver regeneration.
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Affiliation(s)
- Gaoxiong Ouyang
- . Department of Hepatobiliary Surgery, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Jianyong Liu
- . Department of Hepatobiliary Surgery, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Peng Wang
- . Department of Radiology, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Yuan Ren
- . Department of Hepatobiliary Surgery, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Ping Yi
- . Department of Hepatobiliary Surgery, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Quan Zhou
- . Department of Hepatobiliary Surgery, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Jun Chen
- . Department of Pathology, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Bangde Xiang
- . Department of Hepatobiliary Surgery, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Yumei Zhang
- . Department of Hepatobiliary Surgery, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Zhiming Zhang
- . Department of Hepatobiliary Surgery, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Lequn Li
- . Department of Hepatobiliary Surgery, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi, China
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Analysis of Hepatocellular Carcinoma Tissue for Biomarker Discovery. MOLECULAR AND TRANSLATIONAL MEDICINE 2019. [DOI: 10.1007/978-3-030-21540-8_5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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