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Guo B, Gu J, Zhuang T, Zhang J, Fan C, Li Y, Zhao M, Chen R, Wang R, Kong Y, Xu S, Gao W, Liang L, Yu H, Han T. MicroRNA-126: From biology to therapeutics. Biomed Pharmacother 2025; 185:117953. [PMID: 40036996 DOI: 10.1016/j.biopha.2025.117953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 02/22/2025] [Accepted: 02/27/2025] [Indexed: 03/06/2025] Open
Abstract
MicroRNA-126 (miR-126) has emerged as one of the most extensively studied microRNAs in the context of human diseases, particularly in vascular disorders and cancer. Its high degree of conservation across vertebrates underscores its evolutionary significance and essential functional roles. Extensive research has been devoted to elucidating the molecular mechanisms through which miR-126 modulates key physiological and pathological processes, including angiogenesis, immune response, inflammation, tumor growth, and metastasis. Furthermore, miR-126 plays a causal role in the pathogenesis of various diseases, serving as potential biomarkers for disease prediction, diagnosis, prognosis and drug response, as well as a promising therapeutic target. In this review, we synthesize findings from 283 articles, focusing on the roles of miR-126 in critical biological processes such as cell development, survival, cycle regulation, proliferation, migration, invasion, communication, and metabolism. Additionally, miR-126 represents a promising candidate for miRNA-based therapeutic strategies. A comprehensive understanding and evaluation of miR-126 are crucial for advancing its clinical applications and therapeutic potential.
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Affiliation(s)
- Bei Guo
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Jia Gu
- Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Tongtian Zhuang
- Department of Dermatology, Air Force Hospital of Northern Theater Command, Shenyang, China
| | - Jingbin Zhang
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Chunyang Fan
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Yiyao Li
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Mengdi Zhao
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Ruoran Chen
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Rui Wang
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Yuan Kong
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Shuang Xu
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Wei Gao
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Linlang Liang
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Hao Yu
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China.
| | - Tao Han
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.
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El-Hammady AM, Marei YM, Mohammed RR, Rahman SMAE, Marei YM, Sarhan RS. PLASMA EXPRESSION LEVELS OF MICRORNA-21 MIGHT HELP IN THE DETECTION OF HCV PATIENTS COMPLICATED BY HEPATOCELLULAR CARCINOMA. ARQUIVOS DE GASTROENTEROLOGIA 2024; 61:e24025. [PMID: 39776121 DOI: 10.1590/s0004-2803.24612024-025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Accepted: 07/29/2024] [Indexed: 01/11/2025]
Abstract
OBJECTIVE To investigate the ability of the estimated plasma gene-expression levels of microRNA (miR)-21 and 126 to define patients suspected to have hepatocellular carcinoma (HCC) among patients with complicated hepatitis-C virus (HCV) infection. METHODS Patients with uncomplicated (U-HCV) or complicated HCV underwent clinical and ultrasonographic (US) evaluations and assessment for the computerized hepatorenal index, hepatic steatosis index and fibrosis indices. Blood samples were obtained for estimation of serum levels of alpha-fetoprotein (AFP) and tumor necrosis factor-α (TNF-α), and plasma expression levels of miR-21 and miR-126 using the quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). RESULTS Serum levels of AFP and TNF-α were significantly higher in samples of HCV-HCC patients than controls and other HCV patients. Plasma levels of miR-21 were the highest, while miR-126 levels were the lowest in samples of HCV-HCC patients with significant differences in comparison to samples of controls and other HCV patients. The ROC curve analysis defined high plasma miR-21 levels as specific predictor for HCV infection, and could identify samples of complicated HCV, and samples of HCV-HCC patients, while estimated plasma levels of miR-126 could be applied to screen for HCV and its related complications. CONCLUSION Deregulated plasma expression levels of miR-21 and miR-126 might distinguish cases of HCV complicated by HCC and define cases of HCV-LC, even those that showed low Fib-4 scores.
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Affiliation(s)
- Amr M El-Hammady
- Department of Internal Medicine, Faculty of Medicine, Benha University, Benha, Egypt
| | - Yasmin M Marei
- Department of Medical Biochemistry, Faculty of Medicine, Benha University, Benha, Egypt
| | - Raafat R Mohammed
- Assistant Consultant of Medical Biochemistry, Hospital Lab, Clinical Pathology Department, Benha University, Benha, Egypt
| | | | - Yomna M Marei
- Department of Internal Medicine, Faculty of Medicine, Benha University, Benha, Egypt
| | - Rizk S Sarhan
- Department of Internal Medicine, Faculty of Medicine, Benha University, Benha, Egypt
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Mirandari A, Parker H, Ashton-Key M, Stevens B, Walewska R, Stamatopoulos K, Bryant D, Oscier DG, Gibson J, Strefford JC. The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2024; 5:877-901. [PMID: 39280243 PMCID: PMC11390296 DOI: 10.37349/etat.2024.00253] [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: 02/27/2024] [Accepted: 05/08/2024] [Indexed: 09/18/2024] Open
Abstract
Splenic marginal zone lymphoma (SMZL) is a rare, predominantly indolent B-cell lymphoma constituting fewer than 2% of lymphoid neoplasms. However, around 30% of patients have a shorter survival despite currently available treatments and the prognosis is especially poor for the 5-15% of cases that transform to a large cell lymphoma. Mounting evidence suggests that the molecular pathogenesis of SMZL is critically shaped by microenvironmental triggering and cell-intrinsic aberrations. Immunogenetic investigations have revealed biases in the immunoglobulin gene repertoire, indicating a role of antigen selection. Furthermore, cytogenetic studies have identified recurrent chromosomal abnormalities such as deletion of the long arm of chromosome 7, though specific disease-associated genes remain elusive. Our knowledge of SMZL's mutational landscape, based on a limited number of cases, has identified recurring mutations in KLF2, NOTCH2, and TP53, as well as genes clustering within vital B-cell differentiation pathways. These mutations can be clustered within patient subgroups with different patterns of chromosomal lesions, immunogenetic features, transcriptional signatures, immune microenvironments, and clinical outcomes. Regarding SMZL epigenetics, initial DNA methylation profiling has unveiled epigenetically distinct patient subgroups, including one characterized by elevated expression of Polycomb repressor complex 2 (PRC2) components. Furthermore, it has also demonstrated that patients with evidence of high historical cell division, inferred from methylation data, exhibit inferior treatment-free survival. This review provides an overview of our current understanding of SMZL's molecular basis and its implications for patient outcomes. Additionally, it addresses existing knowledge gaps, proposes future research directions, and discusses how a comprehensive molecular understanding of the disease will lead to improved management and treatment choices for patients.
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Affiliation(s)
- Amatta Mirandari
- Cancer Sciences, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, UK
| | - Helen Parker
- Cancer Sciences, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, UK
| | - Margaret Ashton-Key
- Cancer Sciences, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, UK
- Department of Pathology, University Hospital Southampton NHS Foundation Trust, SO16 6YD Southampton, UK
| | - Benjamin Stevens
- Cancer Sciences, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, UK
| | - Renata Walewska
- Department of Molecular Pathology, University Hospitals Dorset, SO16 6YD Bournemouth, UK
| | - Kostas Stamatopoulos
- Institute of Applied Biosciences, Centre for Research and Technology Hellas, 57001 Thessaloniki, Greece
| | - Dean Bryant
- Cancer Sciences, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, UK
| | - David G Oscier
- Department of Molecular Pathology, University Hospitals Dorset, SO16 6YD Bournemouth, UK
| | - Jane Gibson
- Cancer Sciences, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, UK
| | - Jonathan C Strefford
- Cancer Sciences, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, UK
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Zahid S, Malik A, Waqar S, Zahid F, Tariq N, Khawaja AI, Safir W, Gulzar F, Iqbal J, Ali Q. Countenance and implication of Β-sitosterol, Β-amyrin and epiafzelechin in nickel exposed Rat: in-silico and in-vivo approach. Sci Rep 2023; 13:21351. [PMID: 38049552 PMCID: PMC10695965 DOI: 10.1038/s41598-023-48772-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 11/30/2023] [Indexed: 12/06/2023] Open
Abstract
The detrimental impact of reactive oxygen species on D.N.A. repair processes is one of the contributing factors to colon cancer. The idea that oxidative stress may be a significant etiological element for carcinogenesis is currently receiving more and more support. The goal of the current study is to evaluate the anti-inflammatory and anticancer activity of three powerful phytocompounds-sitosterol, amyrin, and epiafzelechin-alone and in various therapeutic combinations against colon cancer to identify the critical mechanisms that mitigate nickel's carcinogenic effect. To evaluate the ligand-protein interaction of four selected components against Vascular endothelial growth factor (VEGF), Matrix metalloproteinase-9 (MMP9) inhibitor and Interleukin-10 (IL-10) molecular docking approach was applied using PyRx bioinformatics tool. For in vivo analysis, hundred albino rats were included, divided into ten groups, each containing ten rats of weight 160-200 g. All the groups were injected with 1 ml/kg nickel intraperitoneally per week for three months, excluding the negative control group. Three of the ten groups were treated with β-sitosterol (100 mg/kg b wt), β-amyrin (100 mg/kg b wt), and epiafzelechin (200 mg/kg b wt), respectively, for one month. The later four groups were fed with combinatorial treatments of the three phyto compounds for one month. The last group was administered with commercial drug Nalgin (500 mg/kg b wt). The biochemical parameters Creatinine, Protein carbonyl, 8-hydroxydeoxyguanosine (8-OHdG), VEGF, MMP-9 Inhibitor, and IL-10 were estimated using ELISA kits and Glutathione (G.S.H.), Superoxide dismutase (S.O.D.), Catalase (C.A.T.) and Nitric Oxide (NO) were analyzed manually. The correlation was analyzed through Pearson's correlation matrix. All the parameters were significantly raised in the positive control group, indicating significant inflammation. At the same time, the levels of the foresaid biomarkers were decreased in the serum in all the other groups treated with the three phytocompounds in different dose patterns. However, the best recovery was observed in the group where the three active compounds were administered concomitantly. The correlation matrix indicated a significant positive correlation of IL-10 vs VEGF (r = 0.749**, p = 0.009), MMP-9 inhibitor vs SOD (r = 0.748**, p = 0.0 21). The study concluded that the three phytocompounds β-sitosterol, β-amyrin, and epiafzelechin are important anticancer agents which can target the cancerous biomarkers and might be used as a better therapeutic approach against colon cancer soon.
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Affiliation(s)
- Sara Zahid
- Institute of Molecular Biology and Biotechnology (IMBB), The University of Lahore, Lahore, Pakistan
| | - Arif Malik
- Institute of Molecular Biology and Biotechnology (IMBB), The University of Lahore, Lahore, Pakistan.
| | - Suleyman Waqar
- Institute of Molecular Biology and Biotechnology (IMBB), The University of Lahore, Lahore, Pakistan
| | - Fatima Zahid
- Ibadat International University (IIUI), Islamabad, Pakistan
| | - Nusrat Tariq
- M. Islam Medical and Dental College, Gujranwala, Pakistan
| | - Ali Imran Khawaja
- Institute of Molecular Biology and Biotechnology (IMBB), The University of Lahore, Lahore, Pakistan
| | - Waqas Safir
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Sciences and Technology, Xinjiang University, Urumqi, 830046, Xinjiang, China
| | - Faisal Gulzar
- Faculty of Pharmacy, The University of Lahore, Lahore, Pakistan
| | - Javeid Iqbal
- School of Pharmacy, Minhaj University Lahore, Lahore, Pakistan
| | - Qurban Ali
- Department of Plant Breeding and Genetics, Faculty of Agricultural Sciences, University of the Punjab, Lahore, Pakistan.
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Zhang W, Du F, Wang L, Bai T, Zhou X, Mei H. Hepatitis Virus-associated Non-hodgkin Lymphoma: Pathogenesis and Treatment Strategies. J Clin Transl Hepatol 2023; 11:1256-1266. [PMID: 37577221 PMCID: PMC10412707 DOI: 10.14218/jcth.2022.00079s] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 01/21/2023] [Accepted: 03/22/2023] [Indexed: 07/03/2023] Open
Abstract
Over the last decade, epidemiological studies have discovered a link between hepatitis C virus (HCV) and hepatitis B virus (HBV) infection and non-Hodgkin lymphoma (NHL). The regression of HCV-associated NHL after HCV eradication is the most compelling proof supporting HCV infection's role in lymphoproliferative diseases. HBV infection was found to significantly enhance the incidence of NHL, according to the epidemiological data. The exact mechanism of HCV leading to NHL has not been fully clarified, and there are mainly the following possible mechanisms: (1) Indirect mechanisms: stimulation of B lymphocytes by extracellular HCV and cytokines; (2) Direct mechanisms: oncogenic effects mediated by intracellular HCV proteins; (3) hit-and-run mechanism: permanent genetic B lymphocytes damage by the transitional entry of HCV. The specific role of HBV in the occurrence of NHL is still unclear, and the research on its mechanism is less extensively explored than HCV, and there are mainly the following possible mechanisms: (1) Indirect mechanisms: stimulation of B lymphocytes by extracellular HBV; (2) Direct mechanisms: oncogenic effects mediated by intracellular HBV DNA. In fact, it is reasonable to consider direct-acting antivirals (DAAs) as first-line therapy for indolent HCV-associated B-NHL patients who do not require immediate chemotherapy. Chemotherapy for NHL is affected by HBV infection and replication. At the same time, chemotherapy can also activate HBV replication. Following recent guidelines, all patients with HBsAg positive/HBV DNA≥2,000 IU/mL should be treated for HBV. The data on epidemiology, interventional studies, and molecular mechanisms of HCV and HBV-associated B-NHL are systematically summarized in this review.
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Affiliation(s)
- Wenjing Zhang
- Department of Hematology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Fan Du
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Li Wang
- Department of Hematology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Tao Bai
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiang Zhou
- Department of Internal Medicine II, Würzburg University Hospital, University of Würzburg, Würzburg, Germany
| | - Heng Mei
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Cacoub P, Comarmond C, Vieira M, Régnier P, Saadoun D. HCV-related lymphoproliferative disorders in the direct-acting antiviral era: From mixed cryoglobulinaemia to B-cell lymphoma. J Hepatol 2022; 76:174-185. [PMID: 34600000 DOI: 10.1016/j.jhep.2021.09.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 08/31/2021] [Accepted: 09/14/2021] [Indexed: 02/06/2023]
Abstract
HCV has been shown to induce many B-cell lymphoproliferative disorders. B lymphocytes specialise in producing immunoglobulins and, during chronic HCV infection, they can cause manifestations ranging from polyclonal hypergammaglobulinaemia without clinical repercussions, through mixed cryoglobulinaemic vasculitis to B-cell non-Hodgkin lymphoma. This spectrum is supported by substantial epidemiological, pathophysiological and therapeutic data. Many, although not all, of the pathogenic pathways leading from one extreme to another have been decrypted. Chronic viral antigen stimulation of B lymphocytes has a central role until the final steps before overt malignancy. This has direct implications for treatment strategies, which always include the use of direct-acting antivirals sometimes alongside immunosuppressants. The role of direct-acting antivirals has been well established in patients with cryoglobulinaemia vasculitis. However, their positive impact on B-cell non-Hodgkin lymphoma needs to be confirmed in larger studies with longer follow-up.
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Affiliation(s)
- Patrice Cacoub
- AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France; Centre de Référence des Maladies Auto-Immunes Systémiques Rares, Centre de Référence des Maladies Auto-Inflammatoires et de l'Amylose inflammatoire, F-75013, Paris, France; Institut National de la Santé et de la Recherche Médicale, INSERM, UMR_S 959, F-75013, Paris, France; CNRS, FRE3632, F-75005, Paris, France; Sorbonne Université, UPMC Univ Paris 06, Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75005, Paris, France.
| | - Cloé Comarmond
- AP-HP, Lariboisière Hospital, Department of Internal Medicine and Clinical Immunology, Paris, France
| | - Matheus Vieira
- AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France; Centre de Référence des Maladies Auto-Immunes Systémiques Rares, Centre de Référence des Maladies Auto-Inflammatoires et de l'Amylose inflammatoire, F-75013, Paris, France; Institut National de la Santé et de la Recherche Médicale, INSERM, UMR_S 959, F-75013, Paris, France; CNRS, FRE3632, F-75005, Paris, France; Sorbonne Université, UPMC Univ Paris 06, Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75005, Paris, France
| | - Paul Régnier
- AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France; Centre de Référence des Maladies Auto-Immunes Systémiques Rares, Centre de Référence des Maladies Auto-Inflammatoires et de l'Amylose inflammatoire, F-75013, Paris, France; Institut National de la Santé et de la Recherche Médicale, INSERM, UMR_S 959, F-75013, Paris, France; CNRS, FRE3632, F-75005, Paris, France; Sorbonne Université, UPMC Univ Paris 06, Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75005, Paris, France
| | - David Saadoun
- AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France; Centre de Référence des Maladies Auto-Immunes Systémiques Rares, Centre de Référence des Maladies Auto-Inflammatoires et de l'Amylose inflammatoire, F-75013, Paris, France; Institut National de la Santé et de la Recherche Médicale, INSERM, UMR_S 959, F-75013, Paris, France; CNRS, FRE3632, F-75005, Paris, France; Sorbonne Université, UPMC Univ Paris 06, Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75005, Paris, France
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Sun L, Xu A, Li M, Xia X, Li P, Han R, Fei G, Zhou S, Wang R. Effect of Methylation Status of lncRNA-MALAT1 and MicroRNA-146a on Pulmonary Function and Expression Level of COX2 in Patients With Chronic Obstructive Pulmonary Disease. Front Cell Dev Biol 2021; 9:667624. [PMID: 34604205 PMCID: PMC8479795 DOI: 10.3389/fcell.2021.667624] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 04/19/2021] [Indexed: 12/25/2022] Open
Abstract
This study aimed to investigate the role of methylation of MALAT1 and miR-146a in the pathogenesis of chronic obstructive pulmonary disease (COPD). COPD patients were grouped according to their methylation status of MALAT1 and miR-146a promoters, and we found that forced vital capacity, volume that has been exhaled at the end of the first second of forced expiration, and diffusion capacity for carbon monoxide were the highest in the MALAT1 HYPO + miR-146a HYPER group and lowest in the MALAT1 HYPER + miR-146a HYPO group, and COPD patients with hypermethylated MALAT1 showed lower expression of MALAT1 than that in the COPD patients with hypomethylated MALAT1. Meanwhile, miR-146a was the most significantly upregulated in the MALAT1 HYPER + miR-146a HYPO group and the most significantly downregulated in the MALAT1 HYPO + miR-146a HYPER group. Both prostaglandin E1 and cyclooxygenase 2 (COX2) expression were the highest in the MALAT1 HYPO + miR-146a HYPER group and the lowest in the MALAT1 HYPER + miR-146a HYPO group. In conclusion, our results established a MALAT1/miR-146a/COX2 signaling axis. The overexpression of MALAT1 could increase the expression of COX2 by inhibiting the expression of miR-146a, thus affecting the pulmonary function of COPD patients.
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Affiliation(s)
- Li Sun
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Aiqun Xu
- Department of General Medicine, Hefei Second People's Hospital, Hefei, China
| | - Min Li
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xingyuan Xia
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Pulin Li
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Rui Han
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Guanghe Fei
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Sijing Zhou
- Hefei Third Clinical College of Anhui Medical University, Hefei, China.,Hefei Prevention and Treatment Center for Occupational Diseases, Hefei, China
| | - Ran Wang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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Alderuccio JP, Lossos IS. NOTCH signaling in the pathogenesis of splenic marginal zone lymphoma-opportunities for therapy. Leuk Lymphoma 2021; 63:279-290. [PMID: 34586000 DOI: 10.1080/10428194.2021.1984452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
NOTCH signaling is a highly conserved pathway mediated by four receptors (NOTCH 1-4) playing critical functions in proliferation, differentiation, and cell death. Under physiologic circumstances, NOTCH2 is a key regulator in marginal zone differentiation and development. Over the last decade, growing data demonstrated frequent NOTCH2 mutations in splenic marginal zone lymphoma (SMZL) underscoring its critical role in the pathogenesis of this disease. Moreover, NOTCH2 specificity across studies supports the rationale to assess its value as a diagnosis biomarker in a disease without pathognomonic features. These data make NOTCH signaling an appealing target for drug discovery in SMZL; however, prior efforts attempting to manipulate this pathway failed to demonstrate meaningful clinical benefit, or their safety profile prevented further development. In this review, we discuss the current knowledge of NOTCH implications in the pathogenesis and as a potential druggable target in SMZL.
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Affiliation(s)
- Juan Pablo Alderuccio
- Division of Hematology, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Izidore S Lossos
- Division of Hematology, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Molecular and Cellular Pharmacology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
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Impact of DAA-Based Regimens on HCV-Related Extra-Hepatic Damage: A Narrative Review. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1323:115-147. [PMID: 33326112 DOI: 10.1007/5584_2020_604] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Two-third of patients with chronic hepatitis C show extrahepatic manifestations due to HCV infection of B lymphocytes, such as mixed cryoglobulinemia and non-Hodgkin B-cell lymphoma, or develop a chronic inflammatory status that may favor the development of adverse cardiovascular events, kidney diseases or metabolic abnormalities.DAAs treatments induce HCV eradication in 95% of treated patients, which also improves the clinical course of extrahepatic manifestations, but with some limitations. After HCV eradication a good compensation of T2DM has been observed, but doubts persist about the possibility of obtaining a stable reduction in fasting glucose and HbA1c levels.Chronic HCV infection is associated with low total and LDL cholesterol serum levels, which however increase significantly after HCV elimination, possibly due to the disruption of HCV/lipid metabolism interaction. Despite this adverse effect, HCV eradication exerts a favorable action on cardiovascular system, possibly by eliminating numerous other harmful effects exerted by HCV on this system.DAA treatment is also indicated for the treatment of patients with mixed cryoglobulinemia syndrome, since HCV eradication results in symptom reduction and, in particular, is effective in cryoglobulinemic vasculitis. Furthermore, HCV eradication exerts a favorable action on HCV-related lymphoproliferative disorders, with frequent remission or reduction of clinical manifestations.There is also evidence that HCV clearance may improve impaired renal functions, but same conflicting data persist on the effect of some DAAs on eGFR.
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The Multifaceted Role and Utility of MicroRNAs in Indolent B-Cell Non-Hodgkin Lymphomas. Biomedicines 2021; 9:biomedicines9040333. [PMID: 33806113 PMCID: PMC8064455 DOI: 10.3390/biomedicines9040333] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/14/2021] [Accepted: 03/18/2021] [Indexed: 02/07/2023] Open
Abstract
Normal B-cell development is a tightly regulated complex procedure, the deregulation of which can lead to lymphomagenesis. One common group of blood cancers is the B-cell non-Hodgkin lymphomas (NHLs), which can be categorized according to the proliferation and spread rate of cancer cells into indolent and aggressive ones. The most frequent indolent B-cell NHLs are follicular lymphoma and marginal zone lymphoma. MicroRNAs (miRNAs) are small non-coding RNAs that can greatly influence protein expression. Based on the multiple interactions among miRNAs and their targets, complex networks of gene expression regulation emerge, which normally are essential for proper B-cell development. Multiple miRNAs have been associated with B-cell lymphomas, as the deregulation of these complex networks can lead to such pathological states. The aim of the present review is to summarize the existing information regarding the multifaceted role of miRNAs in indolent B-cell NHLs, affecting the main B-cell subpopulations. We attempt to provide insight into their biological function, the complex miRNA-mRNA interactions, and their biomarker utility in these malignancies. Lastly, we address the limitations that hinder the investigation of the role of miRNAs in these lymphomas and discuss ways that these problems could be overcome in the future.
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The Relevance of MicroRNAs in the Pathogenesis and Prognosis of HCV-Disease: The Emergent Role of miR-17-92 in Cryoglobulinemic Vasculitis. Viruses 2020; 12:v12121364. [PMID: 33260407 PMCID: PMC7761224 DOI: 10.3390/v12121364] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 11/18/2020] [Accepted: 11/27/2020] [Indexed: 12/26/2022] Open
Abstract
Hepatitis C virus (HCV) is a major public health problem. HCV is a hepatotropic and lymphotropic virus that leads to hepatocellular carcinoma (HCC) and lymphoproliferative disorders such as cryoglobulinemic vasculitis (CV) and non-Hodgkin's lymphoma (NHL). The molecular mechanisms by which HCV induces these diseases are not fully understood. MicroRNAs (miRNAs) are small non-coding molecules that negatively regulate post-transcriptional gene expression by decreasing their target gene expression. We will attempt to summarize the current knowledge on the role of miRNAs in the HCV life cycle, HCV-related HCC, and lymphoproliferative disorders, focusing on both the functional effects of their deregulation as well as on their putative role as biomarkers, based on association analyses. We will also provide original new data regarding the miR 17-92 cluster in chronically infected HCV patients with and without lymphoproliferative disorders who underwent antiviral therapy. All of the cluster members were significantly upregulated in CV patients compared to patients without CV and significantly decreased in those who achieved vasculitis clinical remission after viral eradication. To conclude, miRNAs play an important role in HCV infection and related oncogenic processes, but their molecular pathways are not completely clear. In some cases, they may be potential therapeutic targets or non-invasive biomarkers of tumor progression.
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12
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Huang CF, Lai HC, Chen CY, Tseng KC, Kuo HT, Hung CH, Wang JH, Chen JJ, Lee PL, Chien RN, Yang CC, Lo GH, Tai CM, Lin CW, Kao JH, Liu CJ, Liu CH, Yan SL, Bair MJ, Lin CY, Su WW, Chu CH, Chen CJ, Tung SY, Lo CC, Cheng PN, Chiu YC, Wang CC, Cheng JS, Tsai WL, Lin HC, Huang YH, Yeh ML, Huang JF, Dai CY, Chuang WL, Tsai PC, Peng CY, Yu ML. Extrahepatic Malignancy Among Patients With Chronic Hepatitis C After Antiviral Therapy: A Real-World Nationwide Study on Taiwanese Chronic Hepatitis C Cohort (T-COACH). Am J Gastroenterol 2020; 115:1226-1235. [PMID: 32221162 DOI: 10.14309/ajg.0000000000000606] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Chronic hepatitis C virus (HCV) infection is associated with nonhepatocellular carcinoma malignancies. We aimed to evaluate whether achieving a sustained virological response (SVR, defined as HCV RNA seronegativity throughout posttreatment 24-week follow-up) could reduce the risk of non-hepatocellular carcinoma malignancy in a real-world nationwide Taiwanese Chronic Hepatitis C Cohort (T-COACH). METHODS A total of 10,714 patients with chronic hepatitis C who had received interferon-based therapy (8,186 SVR and 2,528 non-SVR) enrolled in T-COACH and were linked to the National Cancer Registry database for the development of 12 extrahepatic malignancies, including those with potential associations with HCV and with the top-ranking incidence in Taiwan, over a median follow-up period was 3.79 years (range, 0-16.44 years). RESULTS During the 44,354 person-years of follow-up, 324 (3.02%) patients developed extrahepatic malignancies, without a difference between patients with and without SVR (annual incidence: 0.69% vs 0.87%, respectively). Compared with patients with SVR, patients without SVR had a significantly higher risk of gastric cancer (0.10% vs 0.03% per person-year, P = 0.004) and non-Hodgkin lymphoma (NHL) (0.08% vs 0.03% per person-year, respectively, P = 0.03). When considering death as a competing risk, non-SVR was independently associated with gastric cancer (hazard ratio [HR]/95% confidence intervals [CIs]: 3.29/1.37-7.93, P = 0.008). When patients were stratified by age, the effect of SVR in reducing gastric cancer (HR/CI: 0.30/0.11-0.83) and NHL (HR/CI: 0.28/0.09-0.85) was noted only in patients aged <65 years but not those aged >65 years. DISCUSSION HCV eradication reduced the risk of gastric cancer and NHL, in particular among younger patients, indicating that patients with chronic hepatitis C should be treated as early as possible.
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Affiliation(s)
- Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hsueh-Chou Lai
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, School of Medicine, China Medical University, Taichung, Taiwan
| | - Chi-Yi Chen
- Department of Internal Medicine, Chiayi Christian Hospital, Chiayi, Taiwan
| | - Kuo-Chih Tseng
- Department of Gastroenterology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, Taiwan
| | - Hsing-Tao Kuo
- Division of Hepato-gastroenterology, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, ChiaYi Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jyh-Jou Chen
- Division of Gastroenterology and Hepatology, Chi-Mei Medical Center, Liouying, Tainan
| | - Pei-Lun Lee
- Division of Gastroenterology and Hepatology, Chi-Mei Medical Center, Liouying, Tainan
| | - Rong-Nan Chien
- Division of Hepatology, Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chi-Chieh Yang
- Division of Gastroenterology, Department of Internal Medicine, Show Chwan Memorial Hospital, Changhua, Taiwan
| | - Gin-Ho Lo
- Division of Gastroenterology and Hepatology, Department of Medicine, E-Da Hospital, School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Chi-Ming Tai
- Division of Gastroenterology and Hepatology, Department of Medicine, E-Da Hospital, School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Chih-Wen Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, E-Da Hospital, School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Jia-Horng Kao
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, the National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, the National Taiwan University Hospital, Taipei, Taiwan
| | - Chen-Hua Liu
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, the National Taiwan University Hospital, Taipei, Taiwan
| | - Sheng-Lei Yan
- Division of Gastroenterology, Department of Internal Medicine, Chang Bing Show-Chwan Memorial Hospital, Changhua City, Taiwan
| | - Ming-Jong Bair
- Division of Gastroenterology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taitung City, Taiwan
| | - Chun-Yen Lin
- Division of Hepatology, Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Wei-Wen Su
- Division of Gastroenterology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Cheng-Hsin Chu
- Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan
| | - Chih-Jen Chen
- Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan
| | - Shui-Yi Tung
- Division of Hepatogastroenterology, Department of Internal Medicine, ChiaYi Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Ching-Chu Lo
- Department of Internal Medicine, St. Martin De Porres Hospital, Daya, Chiayi, Taiwan
| | - Pin-Nan Cheng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yen-Cheng Chiu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chia-Chi Wang
- Division of Gastroenterology, Department of Internal Medicine, Taipei Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, New Taipei City, Taiwan
| | - Jin-Shiung Cheng
- Division of Gastroenterology and Hepatology, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Wei-Lun Tsai
- Division of Gastroenterology and Hepatology, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Han-Chieh Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Pei-Chien Tsai
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Cheng-Yuan Peng
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, School of Medicine, China Medical University, Taichung, Taiwan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
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13
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Peveling-Oberhag J, Bankov K, Dultz G, Ballo O, Lohmeyer J, Brunnberg U, Marcu V, Walter D, Zeuzem S, Hansmann ML, Welzel TM, Vermehren J. miRNA-26b downregulation in peripheral blood mononuclear cells of patients with hepatitis C associated lymphomas is restored by successful interferon-free antiviral therapy. Antivir Ther 2020; 24:437-442. [PMID: 31180334 DOI: 10.3851/imp3322] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/28/2019] [Indexed: 10/26/2022]
Abstract
BACKGROUND Patients with chronic HCV infection are at increased risk of developing B-cell non-Hodgkin lymphoma (B-NHL). Regression of HCV-associated B-NHL (HCV-NHL) can be achieved through HCV eradication using interferon (IFN). However, only about two-thirds of patients with sustained virological response (SVR) also had a consecutive lymphoma response. miRNA-26b is associated with HCV-NHL response to antiviral therapy. Recent data suggest that IFN-free direct-acting antiviral (DAA) regimens also have anti-lymphoma activity in this patient population. METHODS We report four patients with HCV-NHL who were treated with different IFN-free DAA regimens as oncological monotherapy in our centre between 2015 and 2016. We analysed the virological and lymphoproliferative disease response. Moreover, we analysed miRNA-26b expression in peripheral blood mononuclear cells at different time points during antiviral therapy for all included patients as well as for a total of 10 controls with (n=5) and without (n=5) chronic HCV infection. RESULTS All patients had marginal zone lymphoma subtype and received different DAA regimens for 12-24 weeks. All four patients achieved SVR, but only three patients also had lymphoma response (one complete response, two partial responses). One patient showed progression to a high-grade lymphoma subtype after SVR. miRNA-26b expression was generally decreased in patients with HCV-NHL. Moreover, miRNA-26b expression was restored in those HCV-NHL patients with lymphoma response after 6 months (P=0.009). CONCLUSIONS We have demonstrated that IFN-free DAA treatment of HCV can improve or even cure NHL. miRNA-26b-levels could be a potentially useful biomarker to predict lymphoma response in HCV-NHL patients.
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Affiliation(s)
- Jan Peveling-Oberhag
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany.,Department of Internal Medicine 1, Robert-Bosch-Hospital, Stuttgart, Germany.,Senckenberg Institute for Pathology, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Katrin Bankov
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany.,Senckenberg Institute for Pathology, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Georg Dultz
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Olivier Ballo
- Department of Internal Medicine 2, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Julian Lohmeyer
- Department of Internal Medicine 2, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Uta Brunnberg
- Department of Internal Medicine 2, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Vasile Marcu
- Department of Internal Medicine 2, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Dirk Walter
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Stefan Zeuzem
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Martin-Leo Hansmann
- Senckenberg Institute for Pathology, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Tania M Welzel
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Johannes Vermehren
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany
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14
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Kooshkaki O, Rezaei Z, Rahmati M, Vahedi P, Derakhshani A, Brunetti O, Baghbanzadeh A, Mansoori B, Silvestris N, Baradaran B. MiR-144: A New Possible Therapeutic Target and Diagnostic/Prognostic Tool in Cancers. Int J Mol Sci 2020; 21:ijms21072578. [PMID: 32276343 PMCID: PMC7177921 DOI: 10.3390/ijms21072578] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 04/02/2020] [Accepted: 04/04/2020] [Indexed: 12/14/2022] Open
Abstract
MicroRNAs (miRNAs) are small and non-coding RNAs that display aberrant expression in the tissue and plasma of cancer patients when tested in comparison to healthy individuals. In past decades, research data proposed that miRNAs could be diagnostic and prognostic biomarkers in cancer patients. It has been confirmed that miRNAs can act either as oncogenes by silencing tumor inhibitors or as tumor suppressors by targeting oncoproteins. MiR-144s are located in the chromosomal region 17q11.2, which is subject to significant damage in many types of cancers. In this review, we assess the involvement of miR-144s in several cancer types by illustrating the possible target genes that are related to each cancer, and we also briefly describe the clinical applications of miR-144s as a diagnostic and prognostic tool in cancers.
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Affiliation(s)
- Omid Kooshkaki
- Student Research Committee, Birjand University of Medical Sciences, Birjand 9717853577, Iran;
- Department of Immunology, Birjand University of Medical Sciences, Birjand 9717853577, Iran
| | - Zohre Rezaei
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand 9717853577, Iran;
- Department of Biology, University of Sistan and Baluchestan, Zahedan 9816745845, Iran
| | - Meysam Rahmati
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz 5166/15731, Iran;
| | - Parviz Vahedi
- Department of Anatomical Sciences, Maragheh University of Medical Sciences, Maragheh 5165665931, Iran;
| | - Afshin Derakhshani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran; (A.D.); (A.B.)
| | - Oronzo Brunetti
- Medical Oncology Unit—IRCCS Istituto Tumori “Giovanni Paolo II” of Bari, 70124 Bari, Italy;
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran; (A.D.); (A.B.)
| | - Behzad Mansoori
- Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark;
| | - Nicola Silvestris
- Medical Oncology Unit—IRCCS Istituto Tumori “Giovanni Paolo II” of Bari, 70124 Bari, Italy;
- Department of Biomedical Sciences and Human Oncology DIMO—University of Bari, 70124 Bari, Italy
- Correspondence: (N.S.); (B.B.); Tel.: +39-0805555419 (N.S.); +98-413-3371440 (B.B.)
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran; (A.D.); (A.B.)
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran
- Correspondence: (N.S.); (B.B.); Tel.: +39-0805555419 (N.S.); +98-413-3371440 (B.B.)
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15
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Ghetti M, Vannini I, Storlazzi CT, Martinelli G, Simonetti G. Linear and circular PVT1 in hematological malignancies and immune response: two faces of the same coin. Mol Cancer 2020; 19:69. [PMID: 32228602 PMCID: PMC7104523 DOI: 10.1186/s12943-020-01187-5] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 03/18/2020] [Indexed: 12/19/2022] Open
Abstract
Non coding RNAs (ncRNAs) have emerged as regulators of human carcinogenesis by affecting the expression of key tumor suppressor genes and oncogenes. They are divided into short and long ncRNAs, according to their length. Circular RNAs (circRNAs) are included in the second group and were recently discovered as being originated by back-splicing, joining either single or multiple exons, or exons with retained introns. The human Plasmacytoma Variant Translocation 1 (PVT1) gene maps on the long arm of chromosome 8 (8q24) and encodes for 52 ncRNAs variants, including 26 linear and 26 circular isoforms, and 6 microRNAs. PVT1 genomic locus is 54 Kb downstream to MYC and several interactions have been described among these two genes, including a feedback regulatory mechanism. MYC-independent functions of PVT1/circPVT1 have been also reported, especially in the regulation of immune responses. We here review and discuss the role of both PVT1 and circPVT1 in the hematopoietic system. No information is currently available concerning their transforming ability in hematopoietic cells. However, present literature supports their cooperation with a more aggressive and/or undifferentiated cell phenotype, thus contributing to cancer progression. PVT1/circPVT1 upregulation through genomic amplification or rearrangements and/or increased transcription, provides a proliferative advantage to malignant cells in acute myeloid leukemia, acute promyelocytic leukemia, Burkitt lymphoma, multiple myeloma (linear PVT1) and acute lymphoblastic leukemia (circPVT1). In addition, PVT1 and circPVT1 regulate immune responses: the overexpression of the linear form in myeloid derived suppressor cells induced immune tolerance in preclinical tumor models and circPVT1 showed immunosuppressive properties in myeloid and lymphoid cell subsets. Overall, these recent data on PVT1 and circPVT1 functions in hematological malignancies and immune responses reflect two faces of the same coin: involvement in cancer progression by promoting a more aggressive phenotype of malignant cells and negative regulation of the immune system as a novel potential therapy-resistance mechanism.
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Affiliation(s)
- Martina Ghetti
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy
| | - Ivan Vannini
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy.
| | | | - Giovanni Martinelli
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy
| | - Giorgia Simonetti
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy
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16
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Defrancesco I, Zerbi C, Rattotti S, Merli M, Bruno R, Paulli M, Arcaini L. HCV infection and non-Hodgkin lymphomas: an evolving story. Clin Exp Med 2020; 20:321-328. [PMID: 32052244 DOI: 10.1007/s10238-020-00615-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Accepted: 02/07/2020] [Indexed: 12/11/2022]
Abstract
Hepatitis C virus infection represents a global health problem with 3% of population infected worldwide. Several epidemiological studies have shown an increased risk of B cell non-Hodgkin lymphomas in HCV-infected subjects with a wide geographic variability. The observation that HCV eradication by antiviral treatment is associated with successful lymphoma response provided the most convincing evidence for the causal role of HCV in lymphoma's development. According to the most accepted model, HCV-driven chronic antigenic stimulation may represent the major stimulus for lymphoma growth. Several evidences have led to recommend antiviral therapy (in the past interferon-based, now the new direct-acting antiviral agents) in the setting of asymptomatic indolent B cell lymphomas not requiring an immediate systemic treatment. The favourable profile of direct-acting antiviral agents supports the HCV eradication also in the setting of HCV-positive diffuse large B cell lymphoma; however, further studies are needed to assess the appropriate timing of these drugs in the treatment of aggressive lymphomas. Multidisciplinary management involving expert hepatologists is highly warranted.
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Affiliation(s)
| | - Caterina Zerbi
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Sara Rattotti
- Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Viale Golgi 19, 27100, Pavia, Italy
| | - Michele Merli
- Division of Hematology, University Hospital Ospedale di Circolo e Fondazione Macchi-Azienda Socio-Sanitaria Territoriale Sette Laghi, University of Insubria, Varese, Italy
| | - Raffaele Bruno
- Division of Infectious Diseases Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.,Department of Medical, Surgical, Diagnostic and Paediatric Science, University of Pavia, Pavia, Italy
| | - Marco Paulli
- Department of Molecular Medicine, University of Pavia, Pavia, Italy.,Anatomic Pathology Section, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Luca Arcaini
- Department of Molecular Medicine, University of Pavia, Pavia, Italy. .,Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Viale Golgi 19, 27100, Pavia, Italy.
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17
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Marrone A, Ciotti M, Rinaldi L, Adinolfi LE, Ghany M. Hepatitis B and C virus infection and risk of haematological malignancies. J Viral Hepat 2020; 27:4-12. [PMID: 31325404 DOI: 10.1111/jvh.13183] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 05/23/2019] [Accepted: 06/20/2019] [Indexed: 12/13/2022]
Abstract
Hepatitis B virus (HBV) and hepatitis C virus (HCV) are classified as oncogenic human viruses. Chronic HBV and HCV infections are associated with higher risk of haematological malignancy development. Direct and indirect oncogenic mechanisms have been demonstrated for both HBV and HCV in several studies. HCV and overt/occult HBV infections in patients with oncohaematological disease constitute an impediment and a threat during immunosuppressive chemotherapy treatment. We review the HBV and HCV oncogenic mechanisms and the impact and the safety of antiviral treatment in patients with haematological malignancies.
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Affiliation(s)
- Aldo Marrone
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Marco Ciotti
- Laboratory of Clinical Microbiology and Virology, Polyclinic Tor Vergata Foundation, Rome, Italy
| | - Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Luigi Elio Adinolfi
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Marc Ghany
- Liver Diseases Branch, Division of Digestive Diseases and Nutrition, National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, Maryland, USA
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18
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Okay M, Aslan T, Özdemir E, Üner A, Sağlam A, Güngör E, Uysal A, Alayvaz Aslan N, Yıldızhan E, Ağıt A, Dal MS, Korkmaz S, Namdaroğlu S, Sivgin S, Akgün Çağlıyan G, Demircioğlu S, Barışta İ, Özhamam E, Vural F, Eser B, Özet G, Yıldırım R, Doğu MH, Berber İ, Erkurt MA, Malkan ÜY, Altuntaş F, Büyükaşık Y. Splenic Marginal Zone Lymphoma in Turkey: Association with Hepatitis B Instead of Hepatitis C Virus as an Etiologic and Possible Prognostic Factor - A Multicenter Cohort Study. Turk J Haematol 2019; 37:84-90. [PMID: 31630512 PMCID: PMC7236417 DOI: 10.4274/tjh.galenos.2019.2019.0177] [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] [Indexed: 02/06/2023] Open
Abstract
Objective: Chronic antigenic stimulation is frequently blamed in the pathogenesis of extranodal marginal zone lymphomas including splenic marginal zone lymphoma (SMZL). Chronic hepatitis C is frequently observed in SMZL patients in some geographical regions. However, these reports are largely from North America and Europe, and data from other countries are insufficient. In this multicenter study we aimed to identify the clinical characteristics of SMZL patients in Turkey, including viral hepatitis status and treatment details. Materials and Methods: Data were gathered from participating centers from different regions of Turkey using IBM SPSS Statistics 23 for Windows. Hepatitis B virus surface antigen (HBsAg), anti-HBs antibody, anti-HB core antigen antibody (anti-HBcAg), HB viral load, anti-hepatitis C virus (HCV) antibody, HCV viral load results were analyzed. Results: One hundred and four patients were reported. Hepatitis C virus positivity was observed in only one patient. However, hepatitis B virus surface antigen (HBsAg) positivity was observed in 11.2% and HBsAg and/or anti-HB core antigen antibody (anti-HBcAg) positivities were seen in 34.2% of the patients. The median age was 60 years (range=35-87). Median follow-up duration was 21.2 months (range=00.2-212; 23.2 months for surviving patients). Median overall survival was not reached. Estimated 3-year and 10-year survival rates were 84.8% and 68.9%, respectively. Older age, no splenectomy during follow-up, platelet count of <90x103/μL, lower albumin, higher lactate dehydrogenase, higher β2-microglobulin, and HBsAg positivity were associated with increased risk of death. Only albumin remained significant in multivariable analysis. Conclusion: These results indicate that hepatitis B virus may be a possible risk factor for SMZL in our population. It may also be an indirect prognostic factor.
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Affiliation(s)
- Müfide Okay
- Hacettepe University Faculty of Medicine, Department of Internal Medicine, Division of Hematology, Ankara, Turkey
| | - Tuncay Aslan
- Hacettepe University Faculty of Medicine, Department of Internal Medicine, Division of Hematology, Ankara, Turkey
| | - Evren Özdemir
- Medicana International Ankara Hospital, Clinic of Medical Oncology, Ankara, Turkey
| | - Ayşegül Üner
- Hacettepe University Faculty of Medicine, Department of Pathology, Ankara, Turkey
| | - Arzu Sağlam
- Hacettepe University Faculty of Medicine, Department of Pathology, Ankara, Turkey
| | - Elif Güngör
- Trakya University Faculty of Medicine, Department of Internal Medicine, Edirne, Turkey
| | - Ayşe Uysal
- University of Health Sciences, Trabzon Kanuni Training and Research Hospital, Division of Hematology, Trabzon, Turkey
| | - Nevin Alayvaz Aslan
- Ondokuz Mayıs University Faculty of Medicine, Department of Hematology, Samsun, Turkey
| | - Esra Yıldızhan
- Erciyes University Faculty of Medicine, Department of Hematology, Kayseri, Turkey
| | - Abdullah Ağıt
- Ankara Numune Training and Research Hospital, Division of Hematology, Ankara, Turkey
| | - Mehmet Sinan Dal
- University of Health Sciences, Ankara Oncology Training and Research Hospital, Clinic of Hematology and BMT Unit, Ankara, Turkey
| | - Serdal Korkmaz
- Kayseri Training and Research Hospital, Division of Hematology, Kayseri, Turkey
| | | | | | | | - Sinan Demircioğlu
- Yüzüncü Yıl University Faculty of Medicine, Department of Hematology, Van, Turkey
| | - İbrahim Barışta
- Hacettepe University Faculty of Medicine, Department of Medical Oncology, Ankara, Turkey
| | - Esra Özhamam
- Ankara Numune Training and Research Hospital, Division of Pathology, Ankara, Turkey
| | - Filiz Vural
- Ege University Faculty of Medicine, Department of Internal Medicine, Division of Hematology, İzmir, Turkey
| | - Bülent Eser
- Erciyes University Faculty of Medicine, Department of Hematology, Kayseri, Turkey
| | - Gülsüm Özet
- Ankara Numune Training and Research Hospital, Division of Hematology, Ankara, Turkey
| | - Rahşan Yıldırım
- Atatürk University Faculty of Medicine, Department of Hematology, Erzurum, Turkey
| | - Mehmet Hilmi Doğu
- İstanbul Training and Research Hospital, Clinic Hematology, İstanbul, Turkey
| | - İlhami Berber
- Malatya Training and Research Hospital, Division of Hematology, Malatya, Turkey
| | - Mehmet Ali Erkurt
- İnönü University Faculty of Medicine, Department of Internal Medicine, Division of Hematology, Malatya, Turkey
| | - Ümit Yavuz Malkan
- University of Health Sciences, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Clinic of Hematology, Ankara, Turkey
| | - Fevzi Altuntaş
- University of Health Sciences, Ankara Oncology Training and Research Hospital, Clinic of Hematology and BMT Unit, Ankara, Turkey,Yıldırım Beyazıt University Faculty of Medicine, Department of Internal Medicine, Division of Hematology, Ankara, Turkey
| | - Yahya Büyükaşık
- Hacettepe University Faculty of Medicine, Department of Internal Medicine, Division of Hematology, Ankara, Turkey
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19
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Birkett N, Al-Zoughool M, Bird M, Baan RA, Zielinski J, Krewski D. Overview of biological mechanisms of human carcinogens. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART B, CRITICAL REVIEWS 2019; 22:288-359. [PMID: 31631808 DOI: 10.1080/10937404.2019.1643539] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
This review summarizes the carcinogenic mechanisms for 109 Group 1 human carcinogens identified as causes of human cancer through Volume 106 of the IARC Monographs. The International Agency for Research on Cancer (IARC) evaluates human, experimental and mechanistic evidence on agents suspected of inducing cancer in humans, using a well-established weight of evidence approach. The monographs provide detailed mechanistic information about all carcinogens. Carcinogens with closely similar mechanisms of action (e.g. agents emitting alpha particles) were combined into groups for the review. A narrative synopsis of the mechanistic profiles for the 86 carcinogens or carcinogen groups is presented, based primarily on information in the IARC monographs, supplemented with a non-systematic review. Most carcinogens included a genotoxic mechanism.
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Affiliation(s)
- Nicholas Birkett
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
- McLaughlin Centre for Population Health Risk Assessment, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Mustafa Al-Zoughool
- Department of Community and Environmental Health, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Michael Bird
- McLaughlin Centre for Population Health Risk Assessment, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Robert A Baan
- International Agency for Research on Cancer, Lyon, France
| | - Jan Zielinski
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
- McLaughlin Centre for Population Health Risk Assessment, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Daniel Krewski
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
- McLaughlin Centre for Population Health Risk Assessment, Faculty of Medicine, University of Ottawa, Ottawa, Canada
- Risk Sciences International, Ottawa, Canada
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20
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Heterogeneity and coexistence of oncogenic mechanisms involved in HCV-associated B-cell lymphomas. Crit Rev Oncol Hematol 2019; 138:156-171. [PMID: 31092372 DOI: 10.1016/j.critrevonc.2019.04.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 04/02/2019] [Accepted: 04/03/2019] [Indexed: 12/15/2022] Open
Abstract
The association of HCV-infection with B-lymphomas is supported by the regression of most indolent/low-grade lymphomas following anti-viral therapy. Studies on direct and indirect oncogenic mechanisms have elucidated the pathogenesis of HCV-associated B-lymphoma subtypes. These include B-lymphocyte proliferation and sustained clonal expansion by HCV-envelope protein stimulation of B-cell receptors, and prolonged HCV-infected B-cell growth by overexpression of an anti-apoptotic BCL-2 oncogene caused by the increased frequency of t(14;18) chromosomal translocations in follicular lymphomas. HCV has been implicated in lymphomagenesis by a "hit-and-run" mechanism, inducing enhanced mutation rate in immunoglobulins and anti-oncogenes favoring immune escape, due to permanent genetic damage by double-strand DNA-breaks. More direct oncogenic mechanisms have been identified in cytokines and chemokines in relation to NS3 and Core expression, particularly in diffuse large B-cell lymphoma. By reviewing genetic alterations and disrupted signaling pathways, we intend to highlight how mutually non-contrasting mechanisms cooperate with environmental factors toward progression of HCV-lymphoma.
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21
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Couronné L, Bachy E, Roulland S, Nadel B, Davi F, Armand M, Canioni D, Michot JM, Visco C, Arcaini L, Besson C, Hermine O. From hepatitis C virus infection to B-cell lymphoma. Ann Oncol 2019; 29:92-100. [PMID: 29045541 DOI: 10.1093/annonc/mdx635] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
In addition to liver disorders, hepatitis C virus (HCV) is also associated with extrahepatic immune manifestations and B-cell non-Hodgkin lymphoma (NHL), especially marginal zone lymphoma, de novo or transformed diffuse large B-cell lymphoma and to a lesser extent, follicular lymphoma. Epidemiological data and clinical observations argue for an association between HCV and lymphoproliferative disorders. The causative role of HCV in NHL has been further supported by the response to antiviral therapy. Pathophysiological processes at stake leading from HCV infection to overt lymphoma still need to be further elucidated. Based on reported biological studies, several mechanisms of transformation seem however to emerge. A strong body of evidence supports the hypothesis of an indirect transformation mechanism by which sustained antigenic stimulation leads from oligoclonal to monoclonal expansion and sometimes to frank lymphoma, mostly of marginal zone subtype. By infecting lymphocytes, HCV could play a direct role in cellular transformation, particularly in de novo large B-cell lymphoma. Finally, HCV is associated with follicular lymphoma in a subset of patients. In this setting, it may be hypothesized that inflammatory cytokines stimulate proliferation and transformation of IgH-BCL2 clones that are increased during chronic HCV infection. Unraveling the pathogenesis of HCV-related B-cell lymphoproliferation is of prime importance to optimize therapeutic strategies, especially with the recent development of new direct-acting antiviral drugs.
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Affiliation(s)
- L Couronné
- Department of Hematology, Assistance Publique-Hôpitaux de Paris (APHP), Necker Hospital, Paris, France.,INSERM UMR 1163, CNRS ERL 8254, Imagine Institute, Paris, France.,Paris Descartes-Sorbonne Paris Cité University, Paris, France
| | - E Bachy
- Cancer Research Center of Lyon, INSERM U1052, CNRS UMR 5286, Lyon, France.,Department of Hematology, Lyon Sud Hospital, Lyon, France
| | - S Roulland
- Center of Immunology of Marseille-Luminy, Aix Marseille University, Marseille, France
| | - B Nadel
- Center of Immunology of Marseille-Luminy, Aix Marseille University, Marseille, France
| | - F Davi
- INSERM U1104, Marseille, France.,CNRS UMR 7280, Marseille, France.,Department of Hematology, Pitié-Salpêtrière Hospital, Pierre et Marie Curie University, Paris, France
| | - M Armand
- INSERM U1104, Marseille, France.,CNRS UMR 7280, Marseille, France.,Department of Hematology, Pitié-Salpêtrière Hospital, Pierre et Marie Curie University, Paris, France
| | - D Canioni
- Department of Pathology, Necker Hospital, AP-HP, Paris Descartes-Sorbonne Paris Cité University, Paris, France
| | - J M Michot
- Department of Hematology and Drug Development, Gustave Roussy Institute, Villejuif; France
| | - C Visco
- Department of Cell Therapy and Hematology, San Bortolo Hospital, Vicenza, Italy
| | - L Arcaini
- Department of Molecular Medicine, University of Pavia, Pavia, Italy.,Departement of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - C Besson
- Department of Hematology and Oncology, Hospital of Versailles, Le Chesnay, France.,University of Versailles Saint Quentin en Yvelines, Paris-Saclay University, Communauté Paris-Saclay, Paris, France.,INSERM U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Le Kremlin-Bicêtre, France
| | - O Hermine
- Department of Hematology, Assistance Publique-Hôpitaux de Paris (APHP), Necker Hospital, Paris, France.,INSERM UMR 1163, CNRS ERL 8254, Imagine Institute, Paris, France.,Paris Descartes-Sorbonne Paris Cité University, Paris, France
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22
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Ying X, Zhang W, Fang M, Zhang W, Wang C, Han L. miR-345-5p regulates proliferation, cell cycle, and apoptosis of acute myeloid leukemia cells by targeting AKT2. J Cell Biochem 2019; 120:1620-1629. [PMID: 30278103 DOI: 10.1002/jcb.27461] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 07/18/2018] [Indexed: 01/24/2023]
Abstract
Acute myeloid leukemia (AML) is a malignant clonal hematopoietic disease, which is caused by hematopoietic stem cell abnormalities. Epigenetic regulation, especially of microRNAs (miRNAs), mostly results from external or environmental effects and is critical to AML. In this study, for the first time, we report that decreased expression of miR-345-5p facilitates the proliferation of leukemia cells in AML. Further study demonstrated that AKT1/2 was the target of miR-345-5p and was responsible for the dysregulation of leukemia cell proliferation and apoptosis. Inhibition of AKT1/2 ameliorated this malignant effect, which provides new insight into AML diagnosis, treatment, prognosis, and next-step translational investigations.
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Affiliation(s)
- Xiaoyang Ying
- Department of Clinical Hematology, Affiliated No. 2 Hospital School of Medicine, Xi'an Jiaotong University, China.,Department of Hematology, Affiliated Zhongshan Hospital of Dalian University, China
| | - Wanggang Zhang
- Department of Clinical Hematology, Affiliated No. 2 Hospital School of Medicine, Xi'an Jiaotong University, China
| | - Meiyun Fang
- Department of Hematology, Affiliated Zhongshan Hospital of Dalian University, China
| | - Weijun Zhang
- Department of Laboratory, Affiliated Zhongshan Hospital of Dalian University, China
| | - Chenchen Wang
- Department of Hematology, Affiliated Zhongshan Hospital of Dalian University, China
| | - Li Han
- Department of Hematology, Affiliated Zhongshan Hospital of Dalian University, China
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23
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Cacoub P, Comarmond C. Considering hepatitis C virus infection as a systemic disease. Semin Dial 2018; 32:99-107. [PMID: 30549107 DOI: 10.1111/sdi.12758] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatitis C virus (HCV) infection has been demonstrated to result in several adverse hepatic outcomes and has been associated with a number of important extrahepatic manifestations. The scope of extrahepatic clinical possibilities includes systemic diseases such as vasculitis and lymphoproliferative disorders, cardiovascular disease, myalgia, arthritis, and sicca syndrome. These end-organ effects of HCV may dominate the clinical course beyond the hepatic complications and significantly worsen the long-term prognosis of infected patients. Until several years ago, the standard of care for the treatment of HCV infection had been interferon-alpha-based regimens, which not only had limited effectiveness in achieving a cure but were often poorly tolerated, especially in patients with kidney disease. In those HCV-infected patients with significant systemic manifestations, the interferon-based regimens were problematic given their association with a wide variety of toxicities. The development of highly effective direct-acting antiviral agents to treat HCV infection presented an opportunity to improve the HCV care cascade with the eradication of HCV in most infected patients and by reducing the burden of both hepatic and extrahepatic complications.
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Affiliation(s)
- Patrice Cacoub
- UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Sorbonne Universités, UPMC Univ Paris 06, Paris, France.,INSERM, UMR_S 959, Paris, France.,CNRS, FRE3632, Paris, France.,Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
| | - Cloé Comarmond
- UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Sorbonne Universités, UPMC Univ Paris 06, Paris, France.,INSERM, UMR_S 959, Paris, France.,CNRS, FRE3632, Paris, France.,Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
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24
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Chen X, Wang CC, Yin J, You ZH. Novel Human miRNA-Disease Association Inference Based on Random Forest. MOLECULAR THERAPY. NUCLEIC ACIDS 2018; 13:568-579. [PMID: 30439645 PMCID: PMC6234518 DOI: 10.1016/j.omtn.2018.10.005] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 07/30/2018] [Accepted: 10/05/2018] [Indexed: 01/23/2023]
Abstract
Since the first microRNA (miRNA) was discovered, a lot of studies have confirmed the associations between miRNAs and human complex diseases. Besides, obtaining and taking advantage of association information between miRNAs and diseases play an increasingly important role in improving the treatment level for complex diseases. However, due to the high cost of traditional experimental methods, many researchers have proposed different computational methods to predict potential associations between miRNAs and diseases. In this work, we developed a computational model of Random Forest for miRNA-disease association (RFMDA) prediction based on machine learning. The training sample set for RFMDA was constructed according to the human microRNA disease database (HMDD) version (v.)2.0, and the feature vectors to represent miRNA-disease samples were defined by integrating miRNA functional similarity, disease semantic similarity, and Gaussian interaction profile kernel similarity. The Random Forest algorithm was first employed to infer miRNA-disease associations. In addition, a filter-based method was implemented to select robust features from the miRNA-disease feature set, which could efficiently distinguish related miRNA-disease pairs from unrelated miRNA-disease pairs. RFMDA achieved areas under the curve (AUCs) of 0.8891, 0.8323, and 0.8818 ± 0.0014 under global leave-one-out cross-validation, local leave-one-out cross-validation, and 5-fold cross-validation, respectively, which were higher than many previous computational models. To further evaluate the accuracy of RFMDA, we carried out three types of case studies for four human complex diseases. As a result, 43 (esophageal neoplasms), 46 (lymphoma), 47 (lung neoplasms), and 48 (breast neoplasms) of the top 50 predicted disease-related miRNAs were verified by experiments in different kinds of case studies. The results of cross-validation and case studies indicated that RFMDA is a reliable model for predicting miRNA-disease associations.
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Affiliation(s)
- Xing Chen
- School of Information and Control Engineering, China University of Mining and Technology, Xuzhou 221116, China.
| | - Chun-Chun Wang
- School of Information and Control Engineering, China University of Mining and Technology, Xuzhou 221116, China
| | - Jun Yin
- School of Information and Control Engineering, China University of Mining and Technology, Xuzhou 221116, China
| | - Zhu-Hong You
- Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Science, Ürümqi 830011, China.
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25
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Zhu Y, Zhou C, He Q. High miR-139-3p expression predicts a better prognosis for hepatocellular carcinoma: a pooled analysis. J Int Med Res 2018; 47:383-390. [PMID: 30394818 PMCID: PMC6384489 DOI: 10.1177/0300060518802727] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Objective To observe the expression and clinical significance of micro RNA (miR)-139-3p in liver cancer tissues, and to explore its relationship with miR-139-3p target genes related to the prognosis of hepatocellular carcinoma (HCC). Methods A total of 362 patients with HCC were included in the study. Liver hepatocellular carcinoma data were obtained directly from The Cancer Genome Atlas data portal .The bioinformatics analysis tool TargetScan was applied to predict miR-139-3p target genes. Results Survival time was significantly higher in patients with high miR-139-3p expression, compared with the low miR-139-3p expression group. Bioinformatics analysis showed that miR-139-3p target genes ISG20L2, RAD54B, KIAA0101, and PIGS were significantly negatively correlated with miR-139-3p expression. Conclusions High miR-139-3p expression in HCC tissues was indicative of good patient prognosis. miR-139-3p target genes ISG20L2, RAD54B, KIAA0101, and PIGS were related to HCC prognosis.
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Affiliation(s)
- Yu Zhu
- Zhaoqing Medical College, Guangdong, China
| | | | - Qixiong He
- Zhaoqing Medical College, Guangdong, China
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26
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Robinson JE, Cutucache CE. Deciphering splenic marginal zone lymphoma pathogenesis: the proposed role of microRNA. Oncotarget 2018; 9:30005-30022. [PMID: 30042829 PMCID: PMC6057449 DOI: 10.18632/oncotarget.25487] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Accepted: 05/09/2018] [Indexed: 12/20/2022] Open
Abstract
Splenic marginal zone lymphoma (SMZL) is a malignancy of mature B-cells that primarily involves the spleen, but can affect peripheral organs as well. Even though SMZL is overall considered an indolent malignancy, the majority of cases will eventually progress to be more aggressive. In recent years, the gene expression profile of SMZL has been characterized in an effort to identify: 1) the etiology of SMZL, 2) biological consequences of SMZL, and 3) putative therapeutic targets. However, due to the vast heterogeneity of the malignancy, no conclusive target(s) have been deciphered. However, the role of miRNA in SMZL, much as it has in chronic lymphocytic leukemia, may serve as a guiding light. As a result, we review the comprehensive expression profiling in SMZL to-date, as well as describe the miRNA (and potential mechanistic roles) that may play a role in SMZL transformation, particularly within the 7q region.
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Affiliation(s)
- Jacob E Robinson
- Deptartment of Biology, University of Nebraska at Omaha, Omaha, NE 68182, USA
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27
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Hassan AM, Osman HA, Mahmoud HS, Hassan MH, Hashim AKA, Ameen HH. Sofosbuvir-daclatasvir improves hepatitis C virus-induced mixed cryoglobulinemia: Upper Egypt experience. Infect Drug Resist 2018; 11:895-901. [PMID: 29983581 PMCID: PMC6027820 DOI: 10.2147/idr.s167093] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND AND AIMS Hepatitis C virus (HCV) infection is associated with extrahepatic manifestations such as cryoglobulinemia and accounts for up to 90% of all cases of mixed cryoglobulinemia (MC). The present study aimed to evaluate the effect of sofosbuvir-daclatasvir therapy on symptomatic HCV-related MC and sustained virologic response (SVR) achievement. PATIENTS AND METHODS This prospective cohort study was carried out on 120 patients with chronic HCV infection, clinically suspected to have MC, but only 63 of whom were positive for cryoglobulins. HCV-MC patients were treated with sofosbuvir 400 mg and daclatasvir 60 mg once daily for 3 months. The serum cryoglobulins levels, complement 3 (C3), complement 4 (C4) (using ELISA assay kits) and rheumatoid factor (RF) (using immunoturbidimetric assay kit), were measured in the included HCV infected patients (to confirm HCV-MC diagnosis), in addition to quantitave HCV-RNA assays, using real time PCR. All these measurements have been done before stating therapy and 12, 24 weeks post-therapy for assessments of immunological recovery, viral load and SVR. RESULTS Significant increase in the serum cryoglobulin levels and RF with significant decrease in C3 and C4 serum levels were detected in only 63 out of 120 included HCV infected patients, upon whom the study has been completed. They showed significant decrease in their mean cryoglobulin levels from 41.47 µg/mL ±12.32 SD to 5.12 µg/mL ±3.59 SD then to 5.09 µg/mL ±3.02 SD, 12 to 24 weeks post-therapy respectively (p<0.001), with significant decline in RF concentrations and rise in C3 and C4 serum levels approaching the normal values. There were improvements in the presenting HCV-MC clinical manifestations in variable degrees, ranging from 5 (71.42%) in patients with glomerulonephritis to 62 (98.4%) in patients with purpura. Eighty-seven percent of the included patients showed complete response (clinical, virological and immunological recovery) and 13% showed partial response (virological and immunological recovery without clinical improvement of cryoglobulinemia associated manifestations). CONCLUSION A combined therapy of sofosbuvir 400 mg and daclatasvir 60 mg once daily for 3 months was associated with a significant decrease in serum cryoglobulin levels and appears as a reasonable treatment option for HCV-associated MC.
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Affiliation(s)
- Amro M Hassan
- Tropical Medicine Department, Faculty of Medicine, Al-Azhar University (Assiut Branch), Assiut, Egypt
| | - Heba A Osman
- Tropical Medicine and Gastroenterology Department, Faculty of Medicine, South Valley University, Qena, Egypt
| | - Hasan S Mahmoud
- Tropical Medicine and Gastroenterology Department, Faculty of Medicine, South Valley University, Qena, Egypt
| | - Mohammed H Hassan
- Department of Medical Biochemistry, Faculty of Medicine, South Valley University, Qena, Egypt,
| | - Abdel-Kader A Hashim
- Department of Internal Medicine, Faculty of Medicine, South Valley University, Qena, Egypt
| | - Hesham H Ameen
- Clinical Pathology Department, Faculty of Medicine Al-Azhar University (Assiut Branch), Assiut, Egypt
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28
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Chen X, Niu YW, Wang GH, Yan GY. HAMDA: Hybrid Approach for MiRNA-Disease Association prediction. J Biomed Inform 2017; 76:50-58. [DOI: 10.1016/j.jbi.2017.10.014] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Revised: 09/27/2017] [Accepted: 10/30/2017] [Indexed: 12/27/2022]
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29
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Solé C, Larrea E, Di Pinto G, Tellaetxe M, Lawrie CH. miRNAs in B-cell lymphoma: Molecular mechanisms and biomarker potential. Cancer Lett 2017; 405:79-89. [DOI: 10.1016/j.canlet.2017.07.020] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Revised: 07/06/2017] [Accepted: 07/14/2017] [Indexed: 12/16/2022]
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30
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Visentini M, Fiorilli M, Casato M. From the pathogenesis to the cure of indolent B-cell lymphoproliferative disorders associated with hepatitis C virus infection: which role for direct-acting antivirals? Expert Rev Hematol 2017; 10:719-727. [PMID: 28675071 DOI: 10.1080/17474086.2017.1349607] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Hepatitis C virus (HCV) causes monoclonal B cell lymphoproliferative disorders ranging from benign, such as in mixed cryoglobulinemia (MC), to indolent or aggressive lymphomas. MC and indolent lymphomas commonly regress when HCV is eradicated with interferon (IFN) therapy; however, sustained virologic response (SVR) to IFN is achieved only in ~50% of patients. The new all oral direct-acting antivirals (DAA), yielding nearly 100% SVR, promise a breakthrough in the treatment of HCV-associated lymphoproliferative disorders, but experience is still scanty. Areas covered: A literature search was performed to summarize current pathogenetic hypotheses in HCV-associated indolent lymphoproliferative disorders and to identify clinical trials focused on the use of antiviral therapy. Hematological outcomes of IFN-based and IFN-free DAA-based regimens were compared. Expert commentary: While MC appears to regress in most patients after DAA therapy, the still very limited experience with indolent lymphomas suggests that hematologic responses might be less than those observed with IFN. Furthermore, anecdotal observations of early progression to aggressive lymphoma after DAA are disquieting. Large studies are needed to determine the values and limits of DAA for treating HCV-associated indolent lymphomas and to identify subgroups at risk of non-response.
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Affiliation(s)
- Marcella Visentini
- a Department of Clinical Medicine , Sapienza University of Rome , Rome , Italy
| | - Massimo Fiorilli
- a Department of Clinical Medicine , Sapienza University of Rome , Rome , Italy
| | - Milvia Casato
- a Department of Clinical Medicine , Sapienza University of Rome , Rome , Italy
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31
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Ragab G, Hussein MA. Vasculitic syndromes in hepatitis C virus: A review. J Adv Res 2017; 8:99-111. [PMID: 28149646 PMCID: PMC5272950 DOI: 10.1016/j.jare.2016.11.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 11/07/2016] [Accepted: 11/07/2016] [Indexed: 12/20/2022] Open
Abstract
Vasculitis is a remarkable presentation of the extrahepatic manifestations of HCV. According to the presence or absence of cryoglobulins it is subdivided into two main types: cryoglobulinemic vasculitis and non cryoglobulinemic vasculitis based on the attribution of vasculitis to serum cryoglobulins as a pathogenic factor. The attribution of cryoglobulinemia to HCV represents a success story in the history of immunology, microbiology, and clinical medicine. HCV can bind to and invade lymphocytes, consequently triggering an immune response through different mechanisms. The epidemiology of the disease is well described and the clinical picture describes cutaneous, pulmonary, musculoskeletal, neurological, renal, endocrine, gastrointestinal, hepatic and cardiovascular manifestations. It may also be associated with sicca symptoms, an increased risk of lymphoma and serious catastrophic events. The pathology is well characterized. A classification criteria of the syndrome that was validated in 2014 is discussed. Management of CV is decided according to the presence and severity of its clinical presentation. It is divided into asymptomatic, mild, moderate, severe and life threatening disease. Recently introduced direct antiviral agents are proving safe and effective in the management of cryoglobulinemic vasculitis, and it is advocated that the two types of vasculitis be given prioritization in the Egyptian mass campaign to eradicate HCV.
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Key Words
- ANCA, antineutrophil cytoplasmic antibody
- APS, antiphospholipid syndrome
- BAL, bronchoalveolar lavage
- CAPS, catastrophic antiphospholipid syndrome
- CRP, C reactive protein
- CTD, connective tissue disease
- Cryoglobulins
- DAA, direct acting antiviral drugs
- Direct acting anti-HCV drugs
- ESR, erythrocyte sedimentation rate
- Extrahepatic manifestations vasculitis
- GIT, gastrointestinal tract
- HSP, Henoch-Schonlein Purpura
- HUS, hemolytic uremic syndrome
- Hepatitis C virus
- IFN α, interferon alpha
- IHD, ischemic heart disease
- MOH, minister of health
- MRI, magnetic resonance imaging
- NHL, non Hodgkin lymphoma
- PAN, polyarteritis nodosa
- PCR, polymerase chain reaction
- PFT, pulmonary function test
- PN, peripheral neuropathy
- RNA, ribonucleic acid
- TIAs, transient ischemic attacks
- TTP, thrombotic thrombocytopenic purpura
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Affiliation(s)
- Gaafar Ragab
- Rheumatology and Clinical Immunology Unit, Department of Internal Medicine, Cairo University, Egypt
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Hepatitis C virus - Associated marginal zone lymphoma. Best Pract Res Clin Haematol 2017; 30:41-49. [PMID: 28288715 DOI: 10.1016/j.beha.2017.02.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Accepted: 02/06/2017] [Indexed: 12/18/2022]
Abstract
The link between hepatitis C virus (HCV) infection and the development of B-cell non-Hodgkin lymphoma is now well established and based on a number of epidemiological studies. It is further supported by the observation of lymphoma regression after HCV eradication by antiviral treatment. The far most frequent entities are marginal zone lymphoma (MZL) and diffuse large B-cell lymphoma (DLBCL). MZL usually emerge on a background of mixed cryoglobulinemia, a low-grade lymphoproliferation, and often transform into DLBCL, thereby following a multistep oncogenesis process. The role of HCV in lymphomagenesis is not yet fully understood but several mechanisms have been proposed including (i) chronic external stimulation through the B-cell receptor and other surface receptors, and (ii) direct transformation by intracellular viral proteins, the former being probably predominant in MZL. Regression of HCV-associated MZL can be achieved with antiviral therapy and the novel generation of direct-acting antiviral agents appears highly effective and safe for the treatment of these lymphoma.
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Cryoglobulin Test and Cryoglobulinemia Hepatitis C-Virus Related. Mediterr J Hematol Infect Dis 2017; 9:e2017007. [PMID: 28101312 PMCID: PMC5224812 DOI: 10.4084/mjhid.2017.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2016] [Accepted: 12/12/2016] [Indexed: 12/14/2022] Open
Abstract
Cryoglobulins are immunoglobulins that precipitate in serum at temperatures below 37°C and resolubilize upon warming. The clinical syndrome of cryoglobulinemia usually includes purpura, weakness, and arthralgia, but the underlying disease may also contribute other symptoms. Blood samples for cryoglobulin are collected, transported, clotted and spun at 37°C, before the precipitate is allowed to form when serum is stored at 4°C in a Wintrobe tube for at least seven days. The most critical and confounding factor affecting the cryoglobulin test is when the preanalytical phase is not fully completed at 37°C. The easiest way to quantify cryoglobulins is the cryocrit estimate. However, this approach has low accuracy and sensitivity. Furthermore, the precipitate should be resolubilized by warming to confirm that it is truly formed of cryoglobulins. The characterization of cryoglobulins requires the precipitate is several times washed, before performing immunofixation, a technique by which cryoglobulins can be classified depending on the characteristics of the detected immunoglobulins. These features imply a pathogenic role of these molecules which are consequently associated with a wide range of symptoms and manifestations. According to the Brouet classification, Cryoglobulins are grouped into three types by the immunochemical properties of immunoglobulins in the cryoprecipitate. The aim of this paper is to review the major aspects of cryoglobulinemia and the laboratory techniques used to detect and characterize cryoglobulins, taking into consideration the presence and consequences of cryoglobulinemia in Hepatitis C Virus (HCV) infection.
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El-Halawani N, Nazir A, Mashali N, Sorour A, Moussa MA. The Diagnostic and Prognostic Impact of Serum miRNA-21 in a Sample of Hepatitis C/None Hepatitis Diffuse Large B Cell Lymphoma Egyptian Patients. ACTA ACUST UNITED AC 2017. [DOI: 10.4236/ajmb.2017.71005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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35
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Hepatitis C virus and non-Hodgkin's lymphomas: A minireview. J Adv Res 2016; 8:131-137. [PMID: 28149648 PMCID: PMC5272953 DOI: 10.1016/j.jare.2016.11.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 11/28/2016] [Accepted: 11/30/2016] [Indexed: 12/14/2022] Open
Abstract
B-cell NHL is strongly associated with HCV that was proved in the last 2 decades. The most common HCV infection related B-NHL subtypes include MZL and DLBCL lymphomas. HCV-positive NHL patients usually present with older age at diagnosis, higher LDH, and more extranodal disease. The standard chemo-immunotherapy tolerance is generally good. Antiviral treatment achieves virological and hematological remission in HCV associated indolent lymphoma. More aggressive lymphoma requires combination of antiviral treatment and chemotherapy. New generation of HCV antiviral drugs is safe and is highly efficacious. Regimens including DAAs appear promising options as they can reduce the HCV-associated NHL incidence by dramatically lowering the HCV chronic carriers.
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36
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Abstract
Chronic hepatitis B infection (CHB) is a known risk factor for malignancy. Unlike hepatocellular carcinoma (HCC), less is known about the risk of non-HCC malignancy. However, epidemiology and pathologic evidence suggests a strong association between non-Hodgkin lymphoma and CHB. Data regarding the risk of other malignancies, such as pancreatic adenocarcinoma and intrahepatic cholangiocarcinoma, are mixed. Surveillance and appropriate treatment of infection and malignancy in these patients is essential. Further study of these associations is needed and may bring new insights in the pathogenesis and treatment of these diseases.
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Affiliation(s)
- Ryan M Kwok
- Gastroenterology Fellowship Program, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA.
| | - Tram T Tran
- Gastroenterology Fellowship Program, Cedars Sinai Medical Center, Geffen School of Medicine at University of California Los Angeles, 8900 Beverly Boulevard, Los Angeles, CA 90048, USA
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37
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Merli M, Carli G, Arcaini L, Visco C. Antiviral therapy of hepatitis C as curative treatment of indolent B-cell lymphoma. World J Gastroenterol 2016; 22:8447-8458. [PMID: 27784957 PMCID: PMC5064026 DOI: 10.3748/wjg.v22.i38.8447] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Revised: 08/02/2016] [Accepted: 08/23/2016] [Indexed: 02/06/2023] Open
Abstract
The association of hepatitis C virus (HCV) and B-cell non-Hodgkin lymphomas (NHL) has been highlighted by several epidemiological and biological insights; however the most convincing evidence is represented by interventional studies demonstrating the capability of antiviral treatment (AT) with interferon (IFN) with or without ribavirin to induce the regression of indolent lymphomas, especially of marginal-zone origin. In the largest published retrospective study (100 patients) the overall response rate (ORR) after first-line IFN-based AT was 77% (44% complete responses) and responses were sustainable (median duration of response 33 mo). These results were confirmed by a recent meta-analysis on 254 patients, demonstrating an ORR of 73%. Moreover this analysis confirmed the highly significant correlation between the achievement of viral eradication sustained virological response (SVR) and hematological responses. Two large prospective studies demonstrated that AT is associated with improved survival and argue in favor of current guidelines’ recommendation of AT as preferential first-line option in asymptomatic patients with HCV-associated indolent NHL. The recently approved direct-acting antiviral agents (DAAs) revolutionized the treatment of HCV infection, leading to SVR approaching 100% in all genotypes. Very preliminary data of IFN-free DAAs therapy in indolent HCV-positive NHL seem to confirm their activity in inducing lymphoma regression.
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38
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Ren JP, Ying RS, Cheng YQ, Wang L, El Gazzar M, Li GY, Ning SB, Moorman JP, Yao ZQ. HCV-induced miR146a controls SOCS1/STAT3 and cytokine expression in monocytes to promote regulatory T-cell development. J Viral Hepat 2016; 23:755-66. [PMID: 27004559 PMCID: PMC5028233 DOI: 10.1111/jvh.12537] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Accepted: 02/19/2016] [Indexed: 02/06/2023]
Abstract
Host innate and adaptive immune responses must be tightly regulated by an intricate balance between positive and negative signals to ensure their appropriate onset and termination while fighting pathogens and avoiding autoimmunity; persistent pathogens may usurp these regulatory machineries to dampen host immune responses for their persistence in vivo. Here, we demonstrate that miR146a is up-regulated in monocytes from hepatitis C virus (HCV)-infected individuals compared to control subjects. Interestingly, miR146a expression in monocytes without HCV infection increased, whereas its level in monocytes with HCV infection decreased, following Toll-like receptor (TLR) stimulation. This miR146a induction by HCV infection and differential response to TLR stimulation were recapitulated in vitro in monocytes co-cultured with hepatocytes with or without HCV infection. Importantly, inhibition of miR146a in monocytes from HCV-infected patients led to a decrease in IL-23, IL-10 and TGF-β expressions through the induction of suppressor of cytokine signalling 1 (SOCS1) and the inhibition of signal transducer and activator transcription 3 (STAT3), and this subsequently resulted in a decrease in regulatory T cells (Tregs) accumulated during HCV infection. These results suggest that miR146a may regulate SOCS1/STAT3 and cytokine signalling in monocytes, directing T-cell differentiation and balancing immune clearance and immune injury during chronic viral infection.
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Affiliation(s)
- J P Ren
- Center for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
| | - R S Ying
- Center for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
- Department of Hepatology, Guangzhou Number 8 People's Hospital, Guangzhou, China
| | - Y Q Cheng
- Center for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
- International Center for Diagnosis and Treatment of Liver Diseases, 302 Hospital, Beijing, China
| | - L Wang
- Center for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
| | - M El Gazzar
- Center for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
| | - G Y Li
- Center for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
| | - S B Ning
- Center for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
| | - J P Moorman
- Center for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
- Hepatitis (HCV/HIV) Program, James H. Quillen VA Medical Center, Johnson City, TN, USA
| | - Z Q Yao
- Center for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
- Hepatitis (HCV/HIV) Program, James H. Quillen VA Medical Center, Johnson City, TN, USA.
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MicroRNA-139-5p regulates proliferation of hematopoietic progenitors and is repressed during BCR-ABL-mediated leukemogenesis. Blood 2016; 128:2117-2129. [PMID: 27605510 DOI: 10.1182/blood-2016-02-702464] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 09/02/2016] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) have emerged as important regulators of the immune system. However, despite this prominence, our understanding of the function of miRNAs in the early hematopoietic stages is incomplete. In this study, we found that miR-139-5p negatively regulated the proliferation of hematopoietic stem cells and progenitor cells and that downregulation of miR-139-5p expression was associated with hematopoietic malignancy, such as chronic myeloid leukemia (CML). Knockdown of miR-139-5p resulted in myeloid-biased differentiation with expansion of myeloid progenitor cells. In contrast, miR-139-5p expression inhibited the proliferation of hematopoietic progenitors and resulted in the remission of a CML-like disease that is induced by breakpoint cluster region-Abelson (BCR-ABL) transformation. We also found that Brg1 is a functional target of miR-139-5p and that Brg1 is involved in BCR-ABL-induced leukemogenesis. Thus, our results identify miR-139-5p as a key regulator of cellular proliferation during early hematopoiesis and suggest that it is a potent antileukemic molecule.
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40
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Spina V, Rossi D. NF-κB deregulation in splenic marginal zone lymphoma. Semin Cancer Biol 2016; 39:61-7. [PMID: 27503810 DOI: 10.1016/j.semcancer.2016.08.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 08/03/2016] [Accepted: 08/04/2016] [Indexed: 11/29/2022]
Abstract
Splenic marginal zone lymphoma is a rare mature B-cell malignancy involving the spleen, bone marrow and blood. Over the past years, the rapid expansion of sequencing technologies allowing the genome-wide assessment of genomic, epigenetic and transcriptional changes has revolutionized our understanding of the biological basis of splenic marginal zone lymphoma by providing a comprehensive and unbiased view of the genes/pathways that are deregulated in this disease. NF-κB is a family of transcription factors that plays critical roles in development, survival, and activation of B lymphocytes. Consistent with the physiological involvement of NF-κB signalling in proliferation and commitment of mature B-cells to the marginal zone of the spleen, many oncogenic mutations involved in constitutive activation of the NF-κB pathway were recently identified in splenic marginal zone lymphoma. This review describes the progress in understanding the mechanism of NF-κB activation in splenic marginal zone lymphoma, including molecular, epigenetic and post-transcriptional modifications of NF-κB genes and of upstream pathways, and discusses how information gained from these efforts has provided new insights on potential targets of diagnostic, prognostic and therapeutic relevance for splenic marginal zone lymphoma.
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Affiliation(s)
- Valeria Spina
- Hematology, Institute of Oncology Research and Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
| | - Davide Rossi
- Hematology, Institute of Oncology Research and Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
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41
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Cacoub P, Comarmond C. New insights into HCV-related rheumatologic disorders: A review. J Adv Res 2016; 8:89-97. [PMID: 28149645 PMCID: PMC5272935 DOI: 10.1016/j.jare.2016.07.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Revised: 07/17/2016] [Accepted: 07/18/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infected patients are known to be exposed to major liver complications i.e. cirrhosis and hepatocellular carcinoma. In addition, many extrahepatic manifestations including rheumatologic disorders have been reported in up to two-third of HCV infected patients. These manifestations include frank auto-immune and rheumatic diseases (such as arthralgia, myalgia, arthritis, sicca syndrome and vasculitis) which may dominate the course of infection. Until recently, the standard of care of HCV has been the use of interferon-alpha based regimens, which not only had limited effectiveness in HCV cure but were poorly tolerated. In patients with rheumatic diseases interferon-based regimens may be problematic given their association with a wide variety of autoimmune toxicities. Recent therapeutic advances with new direct anti-HCV therapies (interferon-free) which are more effective and better tolerated, make screening for this comorbidity in patients with rheumatic disorders more important than ever. This review aimed to outline main HCV extrahepatic with a special focus on rheumatologic manifestations.
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Affiliation(s)
- Patrice Cacoub
- Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75005 Paris, France; INSERM, UMR_S 959, F-75013 Paris, France; CNRS, FRE3632, F-75005 Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, F-75013 Paris, France
| | - Cloé Comarmond
- Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75005 Paris, France; INSERM, UMR_S 959, F-75013 Paris, France; CNRS, FRE3632, F-75005 Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, F-75013 Paris, France
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42
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Peveling-Oberhag J, Arcaini L, Bankov K, Zeuzem S, Herrmann E. The anti-lymphoma activity of antiviral therapy in HCV-associated B-cell non-Hodgkin lymphomas: a meta-analysis. J Viral Hepat 2016; 23:536-44. [PMID: 26924533 DOI: 10.1111/jvh.12518] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2015] [Accepted: 12/15/2015] [Indexed: 12/29/2022]
Abstract
Many epidemiological studies provide solid evidence for an association of chronic hepatitis C virus (HCV) infection with B-cell non-Hodgkin's lymphoma (B-NHL). However, the most convincing evidence for a causal relationship between HCV infection and lymphoma development is the observation of B-NHL regression after HCV eradication by antiviral therapy (AVT). We conducted a literature search to identify studies that included patients with HCV-associated B-NHL (HCV-NHL) who received AVT, with the intention to treat lymphoma and viral disease at the same time. The primary end point was the correlation of sustained virological response (SVR) under AVT with lymphoma response. Secondary end points were overall lymphoma response rates and HCV-NHL response in correlation with lymphoma subtypes. We included 20 studies that evaluated the efficacy of AVT in HCV-NHL (n = 254 patients). Overall lymphoma response rate through AVT was 73% [95%>confidence interval, (CI) 67-78%]. Throughout studies there was a strong association between SVR and lymphoma response (83% response rate, 95%>CI, 76-88%) compared to a failure in achieving SVR (53% response rate, 95%>CI, 39-67%, P = 0.0002). There was a trend towards favourable response for AVT in HCV-associated marginal zone lymphomas (response rate 81%, 95%>CI, 74-87%) compared to nonmarginal zone origin (response rate 71%, 95%>CI, 61-79%, P = 0.07). In conclusion, in the current meta-analysis, the overall response rate of HCV-NHL under AVT justifies the recommendation for AVT as first-line treatment in patients who do not need immediate conventional treatment. The strong correlation of SVR and lymphoma regression supports the hypothesis of a causal relationship of HCV and lymphomagenesis.
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Affiliation(s)
- J Peveling-Oberhag
- Department of Internal Medicine 1, Goethe-University Hospital, Frankfurt, Germany
| | - L Arcaini
- Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.,Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - K Bankov
- Department of Internal Medicine 1, Goethe-University Hospital, Frankfurt, Germany
| | - S Zeuzem
- Department of Internal Medicine 1, Goethe-University Hospital, Frankfurt, Germany
| | - E Herrmann
- Institute for Biostatistics and Mathematical Modelling, Goethe-University, Frankfurt, Germany
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miR-2861 acts as a tumor suppressor via targeting EGFR/AKT2/CCND1 pathway in cervical cancer induced by human papillomavirus virus 16 E6. Sci Rep 2016; 6:28968. [PMID: 27364926 PMCID: PMC4929448 DOI: 10.1038/srep28968] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 06/13/2016] [Indexed: 12/13/2022] Open
Abstract
Persistent infection with oncogenic human papillomavirus viruses (HPVs) is a casual factor for cervical cancer and its precursors, and the abnormal constitutive expression of viral oncoprotein E6 is a key event during the malignant transformation. Here, we performed miRNA microarray to identify changes of miRNAs following ectopic HPV16 E6 overexpression in HEK293T cells and found miR-2861 was greatly decreased in both HEK293T and HaCaT cells expressing HPV16 E6 compared to vector control. Further, we demonstrated a biological link among HPV16 E6, miR-2861, EGFR, AKT2, and CCND1 in cervical cancer cells. We showed that miR-2861 was downregulated in cervical cancer tissues and negatively correlated with advanced tumor stage and lymph node metastasis. Overexpression of miR-2861 suppressed cervical cancer cell proliferation and invasion and enhanced apoptosis. Subsequent investigation revealed that EGFR, AKT2, and CCND1 were all the direct targets of miR-2861. Importantly, silencing EGFR, AKT2, and/or CCND1 recapitulated the cellular effects seen upon miR-2861 overexpression. Restoration of EGFR, AKT2, and/or CCND1 counteracted the effects of miR-2861 expression. Thus, we identified a new pathway employing miR-2861, EGFR, AKT2, and CCND1 that may mediate HPV16 E6 induced initiation and progression of cervical cancer.
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Due H, Svendsen P, Bødker JS, Schmitz A, Bøgsted M, Johnsen HE, El-Galaly TC, Roug AS, Dybkær K. miR-155 as a Biomarker in B-Cell Malignancies. BIOMED RESEARCH INTERNATIONAL 2016; 2016:9513037. [PMID: 27294145 PMCID: PMC4884835 DOI: 10.1155/2016/9513037] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Accepted: 04/03/2016] [Indexed: 12/22/2022]
Abstract
MicroRNAs have the potential to be useful biomarkers in the development of individualized treatment since they are easy to detect, are relatively stable during sample handling, and are important determinants of cellular processes controlling pathogenesis, progression, and response to treatment of several types of cancers including B-cell malignancies. miR-155 is an oncomiR with a crucial role in tumor initiation and development of several B-cell malignancies. The present review elucidates the potential of miR-155 as a diagnostic, prognostic, or predictive biomarker in B-cell malignancies using a systematic search strategy to identify relevant literature. miR-155 was upregulated in several malignancies compared to nonmalignant controls and overexpression of miR-155 was further associated with poor prognosis. Elevated expression of miR-155 shows potential as a diagnostic and prognostic biomarker in diffuse large B-cell lymphoma and chronic lymphocytic leukemia. Additionally, in vitro and in vivo studies suggest miR-155 as an efficient therapeutic target, supporting its oncogenic function. The use of inhibiting anti-miR structures indicates promising potential as novel anticancer therapeutics. Reports from 53 studies prove that miR-155 has the potential to be a molecular tool in personalized medicine.
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Affiliation(s)
- Hanne Due
- Department of Haematology, Aalborg University Hospital, Hobrovej 18-22, 9100 Aalborg, Denmark
- Department of Haematology, Aarhus University Hospital, Tage-Hansens Gade 2, 8000 Aarhus C, Denmark
| | - Pernille Svendsen
- Department of Haematology, Aalborg University Hospital, Hobrovej 18-22, 9100 Aalborg, Denmark
| | - Julie Støve Bødker
- Department of Haematology, Aalborg University Hospital, Hobrovej 18-22, 9100 Aalborg, Denmark
| | - Alexander Schmitz
- Department of Haematology, Aalborg University Hospital, Hobrovej 18-22, 9100 Aalborg, Denmark
| | - Martin Bøgsted
- Department of Haematology, Aalborg University Hospital, Hobrovej 18-22, 9100 Aalborg, Denmark
- Department of Mathematical Sciences, Aalborg University, Fredrik Bajers Vej 5, 9100 Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Fredrik Bajers Vej 5, 9100 Aalborg, Denmark
| | - Hans Erik Johnsen
- Department of Haematology, Aalborg University Hospital, Hobrovej 18-22, 9100 Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Fredrik Bajers Vej 5, 9100 Aalborg, Denmark
- Clinical Cancer Research Center, Aalborg University Hospital, Hobrovej 18-22, 9100 Aalborg, Denmark
| | - Tarec Christoffer El-Galaly
- Department of Haematology, Aalborg University Hospital, Hobrovej 18-22, 9100 Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Fredrik Bajers Vej 5, 9100 Aalborg, Denmark
- Clinical Cancer Research Center, Aalborg University Hospital, Hobrovej 18-22, 9100 Aalborg, Denmark
| | - Anne Stidsholt Roug
- Department of Haematology, Aarhus University Hospital, Tage-Hansens Gade 2, 8000 Aarhus C, Denmark
| | - Karen Dybkær
- Department of Haematology, Aalborg University Hospital, Hobrovej 18-22, 9100 Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Fredrik Bajers Vej 5, 9100 Aalborg, Denmark
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Splenic marginal zone lymphoma: from genetics to management. Blood 2016; 127:2072-81. [DOI: 10.1182/blood-2015-11-624312] [Citation(s) in RCA: 104] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2015] [Accepted: 03/07/2016] [Indexed: 12/16/2022] Open
Abstract
AbstractSplenic marginal zone lymphoma (SMZL) is a rare B-cell malignancy involving the spleen, bone marrow, and frequently the blood. SMZL lymphomagenesis involves antigen and/or superantigen stimulation and molecular deregulation of genes (NOTCH2 and KLF2) involved in the physiological differentiation of spleen marginal zone B cells. Diagnosis requires either spleen histology or, alternatively, the documentation of a typical cell morphology and immunophenotype on blood cells coupled with the detection of intrasinusoidal infiltration by CD20+ cells in the bone marrow. Among B-cell tumors, deletion of 7q and NOTCH2 mutations are almost specific lesions of SMZL, thus representing promising diagnostic biomarkers of this lymphoma. Although the majority of SMZLs show an indolent course with a median survival of approximately 10 years, nearly 30% of patients experience a poor outcome. No randomized trials are reported for SMZL, and few prospective trials are available. A watch-and-wait approach is advisable for asymptomatic patients. Treatment options for symptomatic patients ranges from splenectomy to rituximab alone or combined with chemotherapy. In some geographic areas, a subset of patients with SMZL associates with hepatitis C virus infection, prompting virus eradication as an effective lymphoma treatment. It would be worthwhile to explore deregulated cellular programs of SMZL as therapeutic targets in the future; improved clinical and biological prognostication will be essential for identifying patients who may benefit from novel approaches.
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46
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Yan Y, Yi S, Qiu L. [Advances in molecular genetics pathogenesis of splenic marginal zone lymphoma]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2016; 37:348-52. [PMID: 27094004 PMCID: PMC7343092 DOI: 10.3760/cma.j.issn.0253-2727.2016.04.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Indexed: 11/05/2022]
Affiliation(s)
| | | | - Lugui Qiu
- Institute of Hematology and Blood Diseases Hospital. CAMS & PUMC, Tianjin 300020, China
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47
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Su TH, Liu CJ, Tseng TC, Chou SW, Liu CH, Yang HC, Wu SJ, Chen PJ, Chen DS, Chen CL, Kao JH. Hepatitis C viral infection increases the risk of lymphoid-neoplasms: A population-based cohort study. Hepatology 2016; 63:721-30. [PMID: 26662347 DOI: 10.1002/hep.28387] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 12/04/2015] [Indexed: 12/16/2022]
Abstract
UNLABELLED Chronic hepatitis C viral (HCV) infection has been associated with non-Hodgkin's lymphoma (NHL); however, the results are inconsistent among regions with different HCV prevalence rates. The temporal relationship, risk estimates, and association between HCV and lymphoid-neoplasms remain unclear. This study investigated the temporal relationship between HCV infection and lymphoid-neoplasms using a nationwide population-based cohort. Patients with chronic HCV infection were retrieved from the Taiwan National Health Insurance Research Database during 2001-2005 and designated as the HCV cohort. Those with prior malignancies or coinfected with hepatitis B or human immunodeficiency virus were excluded. The age, sex, and comorbidities, including rheumatological disorders and diabetes, were matched by propensity scores to another non-HCV cohort. Both cohorts were followed longitudinally until 2009 for a new diagnosis of any lymphoid-neoplasms or NHL. A total of 11,679 HCV and 46,716 non-HCV patients were included and followed for 8 years. The incidence rates of any lymphoid-neoplasms and NHL were significantly greater in the HCV cohort than the non-HCV cohort (48.4 versus 22.1, and 37.0 versus 17.5 per 100,000 person-years, respectively, both P < 0.001), even after we excluded lymphoid-neoplasms developed within the first year of follow-up. Cox proportional hazards regression analysis (after adjustment for age, sex, numbers of annual medical visits during follow-up, and comorbidities) indicated that HCV infection was associated with an increased risk of either any lymphoid-neoplasms (hazard ratio = 2.30, 95% confidence interval 1.55-3.43, P < 0.0001) or NHL (hazard ratio = 2.00, 95% confidence interval 1.27-3.16, P = 0.003). CONCLUSION After adjustment for confounders and biases, chronic HCV infection is temporally associated with a two-fold increased risk of lymphoid-neoplasms, especially NHL, in Asian patients; additional large studies are needed to explore whether HCV eradication can reduce the incidence of lymphoid-neoplasms.
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Affiliation(s)
- Tung-Hung Su
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Tai-Chung Tseng
- Division of Gastroenterology, Department of Internal Medicine, Taipei Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, Taipei, Taiwan
| | - Shih-Wan Chou
- National Taiwan University Health Data Research Center, Taipei, Taiwan
| | - Chen-Hua Liu
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Hung-Chih Yang
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Shang-Ju Wu
- Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.,Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Ding-Shinn Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.,Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Chi-Ling Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Jia-Horng Kao
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.,Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
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48
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Vannata B, Arcaini L, Zucca E. Hepatitis C virus-associated B-cell non-Hodgkin's lymphomas: what do we know? Ther Adv Hematol 2015; 7:94-107. [PMID: 27054025 DOI: 10.1177/2040620715623924] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Epidemiological studies have shown an increased risk of developing B-cell lymphomas in patients with chronic hepatitis C virus (HCV) infection. There is, however, a great geographic variability and it remains unclear whether additional environmental and genetic factors are involved or whether the international discrepancies represent simply a consequence of the variable prevalence of HCV infection in different countries. Other confounding factors may affect the comparability of the different studies, including the method of HCV assessment, the selection of normal controls, the lymphoma classification used and the year of publication. The most convincing evidence for a causal relationship comes from the observation, mainly limited to some indolent subtypes, of B-cell lymphoma regressions after successful HCV eradication with antiviral treatment. Yet, the molecular mechanism of HCV-induced lymphomagenesis are mainly hypothetical. According to most plausible models, lymphoma growth is a consequence of continuous antigenic stimulation induced by the chronic viral infection. This review will summarize the current knowledge on HCV-associated lymphomas and their management.
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Affiliation(s)
- Barbara Vannata
- Lymphoma Unit, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
| | - Luca Arcaini
- Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo and Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Emanuele Zucca
- Lymphoma Unit, Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona 6500, Switzerland
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49
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Peveling-Oberhag J, Wolters F, Döring C, Walter D, Sellmann L, Scholtysik R, Lucioni M, Schubach M, Paulli M, Biskup S, Zeuzem S, Küppers R, Hansmann ML. Whole exome sequencing of microdissected splenic marginal zone lymphoma: a study to discover novel tumor-specific mutations. BMC Cancer 2015; 15:773. [PMID: 26498442 PMCID: PMC4619476 DOI: 10.1186/s12885-015-1766-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2015] [Accepted: 10/10/2015] [Indexed: 12/14/2022] Open
Abstract
Background Splenic marginal zone lymphoma (SMZL) is an indolent B-cell non-Hodgkin lymphoma and represents the most common primary malignancy of the spleen. Its precise molecular pathogenesis is still unknown and specific molecular markers for diagnosis or possible targets for causal therapies are lacking. Methods We performed whole exome sequencing (WES) and copy number analysis from laser-microdissected tumor cells of two primary SMZL discovery cases. Selected somatic single nucleotide variants (SNVs) were analyzed using pyrosequencing and Sanger sequencing in an independent validation cohort. Results Overall, 25 nonsynonymous somatic SNVs were identified, including known mutations in the NOTCH2 and MYD88 genes. Twenty-three of the mutations have not been associated with SMZL before. Many of these seem to be subclonal. Screening of 24 additional SMZL for mutations at the same positions found mutated in the WES approach revealed no recurrence of mutations for ZNF608 and PDE10A, whereas the MYD88 L265P missense mutation was identified in 15 % of cases. An analysis of the NOTCH2 PEST domain and the whole coding region of the transcription factor SMYD1 in eight cases identified no additional case with a NOTCH2 mutation, but two additional cases with SMYD1 alterations. Conclusions In this first WES approach from microdissected SMZL tissue we confirmed known mutations and discovered new somatic variants. Recurrence of MYD88 mutations in SMZL was validated, but NOTCH2 PEST domain mutations were relatively rare (10 % of cases). Recurrent mutations in the transcription factor SMYD1 have not been described in SMZL before and warrant further investigation. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1766-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jan Peveling-Oberhag
- Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, Frankfurt am Main, Germany.
| | - Franziska Wolters
- Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, Frankfurt am Main, Germany.
| | - Claudia Döring
- Senckenbergisches Institut für Pathologie, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, Frankfurt am Main, Germany.
| | - Dirk Walter
- Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, Frankfurt am Main, Germany.
| | - Ludger Sellmann
- Institute of Cell Biology (Cancer Research), Medical School, University of Duisburg-Essen, Essen, Germany.
| | - René Scholtysik
- Institute of Cell Biology (Cancer Research), Medical School, University of Duisburg-Essen, Essen, Germany.
| | - Marco Lucioni
- Department of Human Pathology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.
| | - Max Schubach
- Institute of Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, Germany.
| | - Marco Paulli
- Department of Human Pathology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.
| | - Saskia Biskup
- CeGaT GmbH, Paul-Ehrlich-Straße 23, Tübingen, Germany.
| | - Stefan Zeuzem
- Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, Frankfurt am Main, Germany.
| | - Ralf Küppers
- Institute of Cell Biology (Cancer Research), Medical School, University of Duisburg-Essen, Essen, Germany. .,German Cancer Consortium (DKTK), Heidelberg, Germany.
| | - Martin-Leo Hansmann
- Senckenbergisches Institut für Pathologie, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, Frankfurt am Main, Germany. .,German Cancer Consortium (DKTK), Heidelberg, Germany.
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50
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Zignego AL, Gragnani L, Piluso A, Sebastiani M, Giuggioli D, Fallahi P, Antonelli A, Ferri C. Virus-driven autoimmunity and lymphoproliferation: the example of HCV infection. Expert Rev Clin Immunol 2015; 11:15-31. [PMID: 25534977 DOI: 10.1586/1744666x.2015.997214] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
HCV chronic infection is characterized by possible development of both hepatic and extrahepatic manifestations. The infection by this both hepatotropic and lymphotropic virus is responsible for polyoligoclonal B-lymphocyte expansion, leading to several immune-mediated disorders. Mixed cryoglobulinemia syndrome that in some cases may evolve to frank B-cell non-Hodgkin's lymphoma is the prototype of HCV-driven autoimmune and lymphoproliferative disorders. The HCV oncogenic potential has been suggested by several clinicoepidemiological and laboratory studies; it includes hepatocellular carcinoma, B-cell non-Hodgkin's lymphoma and papillary thyroid cancer. The definition HCV syndrome refers to the complex of HCV-driven diseases; these latter are characterized by heterogeneous geographical distribution, suggesting a role of other important genetic and/or environmental cofactors. The natural history of HCV syndrome is the result of a multifactorial and multistep pathogenetic process, which may evolve from mild manifestations to systemic autoimmune disorders, and less frequently to malignant neoplasias. The present updated review analyzes the clinical and pathogenetic aspects of the main HCV-associated diseases.
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Affiliation(s)
- Anna Linda Zignego
- Center for Systemic Manifestations of Hepatitis Viruses (MASVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
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