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Lv X, Zhang PB, Zhang EL, Yang S. Predictive factors and prognostic models for Hepatic arterial infusion chemotherapy in Hepatocellular carcinoma: a comprehensive review. World J Surg Oncol 2025; 23:166. [PMID: 40287734 PMCID: PMC12034129 DOI: 10.1186/s12957-025-03765-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 03/23/2025] [Indexed: 04/29/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a prevalent and lethal cancer, often diagnosed at advanced stages where traditional treatments such as surgical resection, liver transplantation, and locoregional therapies provide limited benefits. Hepatic arterial infusion chemotherapy (HAIC) has emerged as a promising treatment modality for advanced HCC, enhancing anti-tumor efficacy through targeted drug delivery while minimizing systemic side effects. However, the heterogeneous nature of HCC leads to variable responses to HAIC, highlighting the necessity for reliable predictive indicators to tailor personalized treatment strategies. This review explores the factors influencing HAIC success, including patient demographics, tumor characteristics, biomarkers, genomic profiles, and advanced imaging techniques such as radiomics and deep learning models. Additionally, the synergistic potential of HAIC combined with immunotherapy and molecular targeted therapies is examined, demonstrating improved survival outcomes. Prognostic scoring systems and nomograms that integrate clinical, molecular, and imaging data are discussed as superior tools for individualized prognostication compared to traditional staging systems. Understanding these predictors is essential for optimizing HAIC efficacy and enhancing survival and quality of life for patients with advanced HCC. Future research directions include large-scale prospective studies, integration of multi-omics data, and advancements in artificial intelligence to refine predictive models and further personalize treatment approaches.
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Affiliation(s)
- Xing Lv
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Peng-Bo Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Er-Lei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - S Yang
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
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Hetta HF, Hamed HM, Mekky MA, Abdel-Malek MO, Hassan WA. Circulating microRNA-21, microRNA-122, and microRNA-222 as diagnostic biomarkers for hepatitis c virus-related hepatocellular carcinoma. EGYPTIAN LIVER JOURNAL 2024; 14:78. [DOI: 10.1186/s43066-024-00385-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 10/27/2024] [Indexed: 01/03/2025] Open
Abstract
Abstract
Background and aim
MicroRNAs (miRs) are now a well-known subject in various tumor genesis and are studied as early diagnostic biomarker. Many arrays of miRs were incorporated in the pathogenesis of HCV-related hepatocellular carcinomas (HCV-HCC). In this respect, we aimed to evaluate the diagnostic role of circulating miR-21, miR-122, and miR-222 in Egyptian patients with HCV-HCC.
Patient and methods
Between June 2018 and April 2019, a cross-sectional comparative study was designed to evaluate the circulating miR-21, miR-122, and miR-222 by quantitative Real-Time PCR. For analytical purposes, patients were categorized into three groups: chronic HCV group (CHC-group, n = 22), HCV-related liver cirrhosis (LC-group, n = 22), and HCV-related hepatocellular carcinoma (HCV-HCC-group, n = 54).
Results
Serum levels of miR-21 and miR-222 increased with the progressive course from CHC to LC and HCC; p < .001. Serum levels of miR-122 in HCC patients were significantly lower than non-HCC patients (CHC and LC patients, n = 44); p < .001. However, the differences in levels of serum miR-122 between CHC and LC were not statistically significant; P = 0.8.
ROC curve analysis showed that the sensitivity and specificity of miR-21 were 61.1% and 95.5%, miR-222 were 71.7% and 93.2%, and miR-122 were 98.2% and 100%. The positive predictive value for miRNA-21, miRNA-122, and miRNA-222 were 13.4%, 93.3%, and 10.5% respectively. The Negative predictive value for miRNA-21, miRNA-122, and miRNA-222 were 94.3%, 97.8%, and 92.7% respectively.
Conclusion
MiR-21 and miR-222 could be potential markers for advanced liver damage, while miR-122 had the best diagnostic accuracy and could be a promising marker for detection of HCC.
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Hosseini FS, Ahmadi A, Kesharwani P, Hosseini H, Sahebkar A. Regulatory effects of statins on Akt signaling for prevention of cancers. Cell Signal 2024; 120:111213. [PMID: 38729324 DOI: 10.1016/j.cellsig.2024.111213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 05/01/2024] [Accepted: 05/06/2024] [Indexed: 05/12/2024]
Abstract
Statins, which are primarily used as lipid-lowering drugs, have been found to exhibit anti-tumor effects through modulating and interfering with various signaling pathways. In observational studies, statin use has been associated with a significant reduction in the progression of various cancers, including colon, lung, prostate, pancreas, and esophagus cancer, as well as melanoma and B and T cell lymphoma. The mevalonate pathway, which is affected by statins, plays a crucial role in activating Rho, Ras, and Rab proteins, thereby impacting the proliferation and apoptosis of tumor cells. Statins block this pathway, leading to the inhibition of isoprenoid units, which are critical for the activation of these key proteins, thereby affecting cancer cell behavior. Additionally, statins affect MAPK and Cdk2, which in turn reduce the expression of p21 and p27 cyclin-dependent kinase inhibitors. Akt signaling plays a crucial role in key cancer cell features like proliferation, invasion, and apoptosis by activating multiple effectors in downstream pathways such as FOXO, PTEN, NF-κB, GSK3β, and mTOR. The PI3K/Akt signaling is necessary for many events in the metastatic pathway and has been implicated in the resistance to cytostatic drugs. The Akt/PTEN axis is currently attracting great interest for its role in carcinogenesis. Statins have been shown to activate the purinergic receptor P2X7 and affect Akt signaling, which may have important anti-cancer effects. Hence, targeting Akt shows promise as an effective approach to cancer prevention and therapy. This review aims to provide a comprehensive discussion on the specific impact of statins through Akt signaling in different types of cancer.
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Affiliation(s)
- Fatemeh Sadat Hosseini
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abdolreza Ahmadi
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India.
| | - Hossein Hosseini
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Murshed A, Alnoud MAH, Ahmad S, Khan SU, Alissa M, Alsuwat MA, Ahmed AE, Khan MU. Genetic Alchemy unveiled: MicroRNA-mediated gene therapy as the Artisan craft in the battlefront against hepatocellular carcinoma-a comprehensive chronicle of strategies and innovations. Front Genet 2024; 15:1356972. [PMID: 38915826 PMCID: PMC11194743 DOI: 10.3389/fgene.2024.1356972] [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: 12/16/2023] [Accepted: 05/03/2024] [Indexed: 06/26/2024] Open
Abstract
Investigating therapeutic miRNAs is a rewarding endeavour for pharmaceutical companies. Since its discovery in 1993, our understanding of miRNA biology has advanced significantly. Numerous studies have emphasised the disruption of miRNA expression in various diseases, making them appealing candidates for innovative therapeutic approaches. Hepatocellular carcinoma (HCC) is a significant malignancy that poses a severe threat to human health, accounting for approximately 70%-85% of all malignant tumours. Currently, the efficacy of several HCC therapies is limited. Alterations in various biomacromolecules during HCC progression and their underlying mechanisms provide a basis for the investigation of novel and effective therapeutic approaches. MicroRNAs, also known as miRNAs, have been identified in the last 20 years and significantly impact gene expression and protein translation. This atypical expression pattern is strongly associated with the onset and progression of various malignancies. Gene therapy, a novel form of biological therapy, is a prominent research area. Therefore, miRNAs have been used in the investigation of tumour gene therapy. This review examines the mechanisms of action of miRNAs, explores the correlation between miRNAs and HCC, and investigates the use of miRNAs in HCC gene therapy.
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Affiliation(s)
- Abduh Murshed
- Department of Intensive Care Unit, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Mohammed A. H. Alnoud
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Saleem Ahmad
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Safir Ullah Khan
- Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Mohammed Alissa
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Meshari A. Alsuwat
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Ahmed Ezzat Ahmed
- Department of Biology, College of Science, King Khalid University, Abha, Saudi Arabia
- Prince Sultan Bin Abdelaziz for Environmental Research and Natural Resources Sustainability Center, King Khalid University, Abha, Saudi Arabia
| | - Munir Ullah Khan
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, International Research Center for XPolymers, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China
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Shabangu CS, Su WH, Li CY, Yu ML, Dai CY, Huang JF, Chuang WL, Wang SC. Systematic integration of molecular and clinical approaches in HCV-induced hepatocellular carcinoma. J Transl Med 2024; 22:268. [PMID: 38475805 PMCID: PMC10935926 DOI: 10.1186/s12967-024-04925-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 01/23/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) play a crucial role in gene expression and regulation, with dysregulation of miRNA function linked to various diseases, including hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). There is still a gap in understanding the regulatory relationship between miRNAs and mRNAs in HCV-HCC. This study aimed to investigate the function and effects of persistent HCV-induced miRNA expression on gene regulation in HCC. METHODS MiRNA array data were used to identify differentially expressed miRNAs and their targets, and miRNAs were analyzed via DIANA for KEGG pathways, gene ontology (GO) functional enrichment, and Ingenuity Pathways Analysis (IPA) for hepatotoxicity, canonical pathways, associated network functions, and interactive networks. RESULTS Seventeen miRNAs in L-HCV and 9 miRNAs in S-HCV were differentially expressed, and 5 miRNAs in L-HCV and 5 miRNAs in S-HCV were significantly expressed in liver hepatocellular carcinoma (LIHC) tumors. Grouped miRNA survival analysis showed that L-HCV miRNAs were associated with survival in LIHC, and miRNA‒mRNA targets regulated viral carcinogenesis and cell cycle alteration through cancer pathways in LIHC. MiRNA-regulated RCN1 was suppressed through miRNA-oncogene interactions, and suppression of RCN1 inhibited invasion and migration in HCC. CONCLUSION Persistent HCV infection induced the expression of miRNAs that act as tumor suppressors by inhibiting oncogenes in HCC. RCN1 was suppressed while miRNAs were upregulated, demonstrating an inverse relationship. Therefore, hsa-miR-215-5p, hsa-miR-10b-5p, hsa-let-7a-5p and their target RCN1 may be ideal biomarkers for monitoring HCV-HCC progression.
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Affiliation(s)
- Ciniso Sylvester Shabangu
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Wen-Hsiu Su
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Chia-Yang Li
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-Sen University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Chia-Yen Dai
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Jee-Fu Huang
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Wan-Long Chuang
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Shu-Chi Wang
- Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-Sen University, Kaohsiung, Taiwan.
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
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Milosevic I, Todorovic N, Filipovic A, Simic J, Markovic M, Stevanovic O, Malinic J, Katanic N, Mitrovic N, Nikolic N. HCV and HCC Tango-Deciphering the Intricate Dance of Disease: A Review Article. Int J Mol Sci 2023; 24:16048. [PMID: 38003240 PMCID: PMC10671156 DOI: 10.3390/ijms242216048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 10/12/2023] [Accepted: 10/25/2023] [Indexed: 11/26/2023] Open
Abstract
Hepatitis C virus (HCV) is a major cause of hepatocellular carcinoma (HCC) accounting for around one-third of all HCC cases. Prolonged inflammation in chronic hepatitis C (CHC), maintained through a variety of pro- and anti-inflammatory mediators, is one of the aspects of carcinogenesis, followed by mitochondrial dysfunction and oxidative stress. Immune response dysfunction including the innate and adaptive immunity also plays a role in the development, as well as in the recurrence of HCC after treatment. Some of the tumor suppressor genes inhibited by the HCV proteins are p53, p73, and retinoblastoma 1. Mutations in the telomerase reverse transcriptase promoter and the oncogene catenin beta 1 are two more important carcinogenic signaling pathways in HCC associated with HCV. Furthermore, in HCV-related HCC, numerous tumor suppressor and seven oncogenic genes are dysregulated by epigenetic changes. Epigenetic regulation of gene expression is considered as a lasting "epigenetic memory", suggesting that HCV-induced changes persist and are associated with liver carcinogenesis even after cure. Epigenetic changes and immune response dysfunction are recognized targets for potential therapy of HCC.
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Affiliation(s)
- Ivana Milosevic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Nevena Todorovic
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Ana Filipovic
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Jelena Simic
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Marko Markovic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Olja Stevanovic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Jovan Malinic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Natasa Katanic
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
- Faculty of Medicine, University of Pristina Situated in Kosovska Mitrovica, 28000 Kosovska Mitrovica, Serbia
| | - Nikola Mitrovic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Natasa Nikolic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
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Abdo SM, Shousha WG, Mohamed AA, Elshobaky M, Saleh M, Ali MMA. Bio-diagnostic performances of microRNAs set related to DNA damage response pathway among hepatitis C virus-associated hepatocellular carcinoma patients. J Genet Eng Biotechnol 2023; 21:85. [PMID: 37587273 PMCID: PMC10432369 DOI: 10.1186/s43141-023-00537-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 07/31/2023] [Indexed: 08/18/2023]
Abstract
BACKGROUND Up to date, a well-defined microRNAs (miRNAs) profile involved in hepatocellular carcinoma (HCC) pathogenesis remains indecisive. Thus, employing miRNAs for HCC diagnosis is demanded for early therapeutic interventions. We aimed to evaluate the usage of miRNAs set related to the SuperPath: miRNAs involved in DNA damage response pathway as effective biomarkers for HCV-related HCC diagnosis. RESULTS The study enrolled 97 patients with HCV-related HCC, 84 with hepatitis C virus (HCV), 97 with liver cirrhosis (LC), and 84 healthy individuals. Serum miRNA-23a, miRNA-203, miRNA-100-5p, and miRNA-16 were quantified using qRT-PCR experiments, AFP and routine LFTs were estimated via standard techniques. Pathway enrichment analysis along with the construction of miRNAs regulatory network were performed. With respect to healthy individuals, miRNA-203, miRNA-100-5p, and miRNA-16 were significantly downregulated in HCC, HCV, and LC groups, while miRNA-23a showed significant upregulation (p < 0.001). miRNAs exhibited significant correlations with AFP, ALT, AST, and albumin. Also, elevated levels of miRNA-23a were recognized in patients with multiple focal lesions and/or lesion size > 5 cm. Additionally, the diagnostic performance of miRNA-23a expression level at a selected cut-off value of 3.99 overtakes AFP, while expressions of miR-203, miRNA-100-5p, and miRNA-16 represent poor diagnostic outcomes. CONCLUSIONS Keeping in mind the individual variability and high level of heterogeneity in HCC, our data revealed the diagnostic value of miRNA-23a expression in HCV-related HCC patients. Further extra in silico HCC-specific microRNAs sets are demanded in diagnosis.
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Affiliation(s)
- Sara M Abdo
- Biochemistry Division, Chemistry Department, Faculty of Science, Helwan University, Cairo, Egypt.
| | - Wafaa Gh Shousha
- Biochemistry Division, Chemistry Department, Faculty of Science, Helwan University, Cairo, Egypt
| | - Amal Ahmed Mohamed
- Biochemistry Department, National Hepatology and Tropical Medicine Research Institute, Cairo University, Cairo, Egypt
| | - Mohamed Elshobaky
- Internal Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamed Saleh
- Internal Medicine department, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
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Megahed F, Tabll A, Atta S, Ragheb A, Smolic R, Petrovic A, Smolic M. MicroRNAs: Small Molecules with Significant Functions, Particularly in the Context of Viral Hepatitis B and C Infection. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:173. [PMID: 36676797 PMCID: PMC9862007 DOI: 10.3390/medicina59010173] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 01/10/2023] [Accepted: 01/12/2023] [Indexed: 01/18/2023]
Abstract
A MicroRNA (miRNA) is defined as a small molecule of non-coding RNA (ncRNA). Its molecular size is about 20 nucleotides (nt), and it acts on gene expression's regulation at the post-transcription level through binding to the 3'untranslated regions (UTR), coding sequences, or 5'UTR of the target messenger RNAs (mRNAs), which leads to the suppression or degradation of the mRNA. In recent years, a huge evolution has identified the origin and function of miRNAs, focusing on their important effects in research and clinical applications. For example, microRNAs are key players in HCV infection and have important host cellular factors required for HCV replication and cell growth. Altered expression of miRNAs affects the pathogenicity associated with HCV infection through regulating different signaling pathways that control HCV/immunity interactions, proliferation, and cell death. On the other hand, circulating miRNAs can be used as novel biomarkers and diagnostic tools for HCV pathogenesis and early therapeutic response. Moreover, microRNAs (miRNA) have been involved in hepatitis B virus (HBV) gene expression and advanced antiviral discovery. They regulate HBV/HCV replication and pathogenesis with different pathways involving facilitation, inhibition, activation of the immune system (innate and adaptive), and epigenetic modifications. In this short review, we will discuss how microRNAs can be used as prognostic, diagnostic, and therapeutic tools, especially for chronic hepatitis viruses (HBV and HCV), as well as how they could be used as new biomarkers during infection and advanced treatment.
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Affiliation(s)
- Fayed Megahed
- Nucleic Acid Research Department, Genetic Engineering and Biotechnological Research Institute (GEBRI), City for Scientific Researches and Technological Applications (SRTA-City), Alexandria 21934, Egypt
| | - Ashraf Tabll
- Microbial Biotechnology Department, National Research Centre, Giza 12622, Egypt
- Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo 11517, Egypt
| | - Shimaa Atta
- Department of Immunology, Theodor Bilharz Research Institute, Cairo 12411, Egypt
| | - Ameera Ragheb
- Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo 11517, Egypt
| | - Robert Smolic
- Faculty of Dental Medicine and Health Osijek, University of Osijek, Crkvena 21, 31000 Osijek, Croatia
| | - Ana Petrovic
- Faculty of Dental Medicine and Health Osijek, University of Osijek, Crkvena 21, 31000 Osijek, Croatia
| | - Martina Smolic
- Faculty of Dental Medicine and Health Osijek, University of Osijek, Crkvena 21, 31000 Osijek, Croatia
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9
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The Role of microRNAs in Inflammation. Int J Mol Sci 2022; 23:ijms232415479. [PMID: 36555120 PMCID: PMC9779565 DOI: 10.3390/ijms232415479] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/02/2022] [Accepted: 12/03/2022] [Indexed: 12/12/2022] Open
Abstract
Inflammation is a biological response of the immune system to various insults, such as pathogens, toxic compounds, damaged cells, and radiation. The complex network of pro- and anti-inflammatory factors and their direction towards inflammation often leads to the development and progression of various inflammation-associated diseases. The role of small non-coding RNAs (small ncRNAs) in inflammation has gained much attention in the past two decades for their regulation of inflammatory gene expression at multiple levels and their potential to serve as biomarkers and therapeutic targets in various diseases. One group of small ncRNAs, microRNAs (miRNAs), has become a key regulator in various inflammatory disease conditions. Their fine-tuning of target gene regulation often turns out to be an important factor in controlling aberrant inflammatory reactions in the system. This review summarizes the biogenesis of miRNA and the mechanisms of miRNA-mediated gene regulation. The review also briefly discusses various pro- and anti-inflammatory miRNAs, their targets and functions, and provides a detailed discussion on the role of miR-10a in inflammation.
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10
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Yu X, Eischeid-Scholz H, Meder L, Kondylis V, Büttner R, Odenthal M. SQSTM1/p62 promotes miR-198 loading into extracellular vesicles and its autophagy-related secretion. Hum Cell 2022; 35:1766-1784. [PMID: 36050615 PMCID: PMC9515045 DOI: 10.1007/s13577-022-00765-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 07/31/2022] [Indexed: 11/30/2022]
Abstract
MicroRNA dysregulation is a hallmark of hepatocellular carcinoma (HCC), leading to tumor growth and metastasis. Previous screening on patient specimens identified miR-198 as the most downregulated miRNA in HCC. Here, we show that miR-198 compensation leads to self-release into extracellular vesicles (EVs). Importantly, the vesicular secretion is mediated by autophagy-related pathway, initiated by sequestration of p62/miR-198 complexes in autophagosome-associated vesicle fractions. miR-198 is selectively recognized and loaded by p62 into autophagosomal fractions, whereas mutated miR-198 forms neither induce autophagy and nor interact with p62. Gain and loss of function experiments, using a CRIPR/Cas knockout (KO) and transgenic site-specific p62 mutants, identified p62 as an essential repressor of cellular miR-198 abundancy. Notably, EVs, harboring miR-198/p62 protein complexes, can be uptaken by cells in the close vicinity, leading to change of gene expression in recipient cells. In conclusion, miR-198 enhances autophagy; conversely autophagic protein p62 reduces the miR-198 levels by sorting into extracellular space.
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Affiliation(s)
- Xiaojie Yu
- Faculty of Medicine, Institute for Pathology and University Hospital Cologne, University of Cologne, 50924, Cologne, Germany. .,Faculty of Medicine, Center for Molecular Medicine Cologne (CMMC), and University Hospital Cologne, University of Cologne, 50924, Cologne, Germany.
| | - Hannah Eischeid-Scholz
- Faculty of Medicine, Institute for Pathology and University Hospital Cologne, University of Cologne, 50924, Cologne, Germany
| | - Lydia Meder
- Faculty of Medicine, Center for Molecular Medicine Cologne (CMMC), and University Hospital Cologne, University of Cologne, 50924, Cologne, Germany.,Faculty of Medicine Department I of Internal Medicine, University Hospital Cologne, University of Cologne, 50931, Cologne, Germany
| | - Vangelis Kondylis
- Faculty of Medicine, Institute for Pathology and University Hospital Cologne, University of Cologne, 50924, Cologne, Germany.,Cologne Excellence Cluster On Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany
| | - Reinhard Büttner
- Faculty of Medicine, Institute for Pathology and University Hospital Cologne, University of Cologne, 50924, Cologne, Germany.,Faculty of Medicine, Center for Molecular Medicine Cologne (CMMC), and University Hospital Cologne, University of Cologne, 50924, Cologne, Germany.,Faculty of Medicine, Center of Integrative Oncology and University Hospital Cologne, University of Cologne, 50924, Cologne, Germany
| | - Margarete Odenthal
- Faculty of Medicine, Institute for Pathology and University Hospital Cologne, University of Cologne, 50924, Cologne, Germany. .,Faculty of Medicine, Center for Molecular Medicine Cologne (CMMC), and University Hospital Cologne, University of Cologne, 50924, Cologne, Germany. .,Faculty of Medicine, Center of Integrative Oncology and University Hospital Cologne, University of Cologne, 50924, Cologne, Germany.
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11
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Elgeshy KM, Abdel Wahab AHA. The Role, Significance, and Association of MicroRNA-10a/b in Physiology of Cancer. Microrna 2022; 11:118-138. [PMID: 35616665 DOI: 10.2174/2211536611666220523104408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 03/21/2022] [Accepted: 04/04/2022] [Indexed: 01/01/2023]
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that regulate the translation of mRNA and protein, mainly at the posttranscriptional level. Global expression profiling of miRNAs has demonstrated a broad spectrum of aberrations that correlated with several diseases, and miRNA- 10a and miRNA-10b were the first examined miRNAs to be involved in abnormal activities upon dysregulation, including many types of cancers and progressive diseases. It is expected that the same miRNAs behave inconsistently within different types of cancer. This review aims to provide a set of information about our updated understanding of miRNA-10a and miRNA-10b and their clinical significance, molecular targets, current research gaps, and possible future applications of such potent regulators.
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Affiliation(s)
- Khaled M Elgeshy
- Department of Botany and Microbiology, Faculty of Science, Cairo University, Cairo, Egypt
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12
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Stella L, Santopaolo F, Gasbarrini A, Pompili M, Ponziani FR. Viral hepatitis and hepatocellular carcinoma: From molecular pathways to the role of clinical surveillance and antiviral treatment. World J Gastroenterol 2022; 28:2251-2281. [PMID: 35800182 PMCID: PMC9185215 DOI: 10.3748/wjg.v28.i21.2251] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 12/08/2021] [Accepted: 04/26/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a global health challenge. Due to the high prevalence in low-income countries, hepatitis B virus (HBV) and hepatitis C virus infections remain the main risk factors for HCC occurrence, despite the increasing frequencies of non-viral etiologies. In addition, hepatitis D virus coinfection increases the oncogenic risk in patients with HBV infection. The molecular processes underlying HCC development are complex and various, either independent from liver disease etiology or etiology-related. The reciprocal interlinkage among non-viral and viral risk factors, the damaged cellular microenvironment, the dysregulation of the immune system and the alteration of gut-liver-axis are known to participate in liver cancer induction and progression. Oncogenic mechanisms and pathways change throughout the natural history of viral hepatitis with the worsening of liver fibrosis. The high risk of cancer incidence in chronic viral hepatitis infected patients compared to other liver disease etiologies makes it necessary to implement a proper surveillance, both through clinical-biochemical scores and periodic ultrasound assessment. This review aims to outline viral and microenvironmental factors contributing to HCC occurrence in patients with chronic viral hepatitis and to point out the importance of surveillance programs recommended by international guidelines to promote early diagnosis of HCC.
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Affiliation(s)
- Leonardo Stella
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Maurizio Pompili
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
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13
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Letafati A, Najafi S, Mottahedi M, Karimzadeh M, Shahini A, Garousi S, Abbasi-Kolli M, Sadri Nahand J, Tamehri Zadeh SS, Hamblin MR, Rahimian N, Taghizadieh M, Mirzaei H. MicroRNA let-7 and viral infections: focus on mechanisms of action. Cell Mol Biol Lett 2022; 27:14. [PMID: 35164678 PMCID: PMC8853298 DOI: 10.1186/s11658-022-00317-9] [Citation(s) in RCA: 82] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 01/26/2022] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are fundamental post-transcriptional modulators of several critical cellular processes, a number of which are involved in host defense mechanisms. In particular, miRNA let-7 functions as an essential regulator of the function and differentiation of both innate and adaptive immune cells. Let-7 is involved in several human diseases, including cancer and viral infections. Several viral infections have found ways to dysregulate the expression of miRNAs. Extracellular vesicles (EV) are membrane-bound lipid structures released from many types of human cells that can transport proteins, lipids, mRNAs, and miRNAs, including let-7. After their release, EVs are taken up by the recipient cells and their contents released into the cytoplasm. Let-7-loaded EVs have been suggested to affect cellular pathways and biological targets in the recipient cells, and can modulate viral replication, the host antiviral response, and the action of cancer-related viruses. In the present review, we summarize the available knowledge concerning the expression of let-7 family members, functions, target genes, and mechanistic involvement in viral pathogenesis and host defense. This may provide insight into the development of new therapeutic strategies to manage viral infections.
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Affiliation(s)
- Arash Letafati
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Sajad Najafi
- Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehran Mottahedi
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Karimzadeh
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Shahini
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Setareh Garousi
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Abbasi-Kolli
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Javid Sadri Nahand
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, 2028 South Africa
| | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
- Department of Internal Medicine, School of Medicine, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Taghizadieh
- Department of Pathology, School of Medicine, Center for Women’s Health Research Zahra, Tabriz University of Medical Sciences, Tabriz, Islamic Republic of Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
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14
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Gouda G, Gupta MK, Donde R, Behera L, Vadde R. Metabolic pathway-based target therapy to hepatocellular carcinoma: a computational approach. THERANOSTICS AND PRECISION MEDICINE FOR THE MANAGEMENT OF HEPATOCELLULAR CARCINOMA, VOLUME 2 2022:83-103. [DOI: 10.1016/b978-0-323-98807-0.00003-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/06/2023]
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15
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Kaushik P, Kumar A. Emerging role and function of miR-198 in human health and diseases. Pathol Res Pract 2021; 229:153741. [PMID: 34952425 DOI: 10.1016/j.prp.2021.153741] [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: 08/13/2021] [Revised: 12/09/2021] [Accepted: 12/16/2021] [Indexed: 01/10/2023]
Abstract
Ever since their discovery, microRNAs (miRNAs/miRs) have astonished us by the plethora of processes they regulate, and thus adding another dimension to the gene regulation. They have been implicated in several diseases affecting cardiovascular, neurodegenerative, hepatic, autoimmune and inflammatory functions. A primate specific exonic miRNA, miR-198 has been vastly studied during the past decade, and shown to have a critical role in wound healing. The aberrant expression of miR-198 was first reported in schizophrenia, linking it to neural development. Later, its dysregulation and tumor suppressive role was reported in hepatocellular carcinoma. However, this was just a beginning, and after which there was an explosion of reports linking miR-198 deregulation to cancers and other ailments. The first target to be identified for miR-198 was Cyclin T1 in monocytes affecting HIV1 replication. Depending on the type of cancer, miR-198 has been shown to function either as a tumor suppressor or an oncomir. Interestingly, miR-198 is not only known to regulate multiple targets and pathways, but also is itself regulated by several circular RNAs and long-non-coding RNAs, highlighting a complex regulatory network. This review highlights the currently understood mechanism and regulation of miR-198 in different diseases, and its possible diagnostic and therapeutic potential.
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Affiliation(s)
- Pankhuri Kaushik
- Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India
| | - Arun Kumar
- Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India.
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16
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Molecular classification of hepatocellular carcinoma: prognostic importance and clinical applications. J Cancer Res Clin Oncol 2021; 148:15-29. [PMID: 34623518 DOI: 10.1007/s00432-021-03826-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 10/03/2021] [Indexed: 01/17/2023]
Abstract
Hepatocellular carcinoma (HCC) is a lethal human malignancy with a very low overall and long-term survival rate. Poor prognostic outcomes are predominantly associated with HCC due to a huge landscape of heterogeneity found in the deadliest disease. However, molecular subtyping of HCC has significantly improved the knowledge of the underlying mechanisms that contribute towards the heterogeneity and progression of the disease. In this review, we have extensively summarized the current information available about molecular classification of HCC. This review can be of great significance for providing the insight information needed for development of novel, efficient and personalized therapeutic options for the treatment of HCC patients globally.
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17
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ONAN E, AKKIZ H, SANDIKCI MU, ÜSKÜDAR O, ÖZTÜRK AB. Importance of circulating microRNA-122 for hepatocellular carcinoma. CUKUROVA MEDICAL JOURNAL 2021. [DOI: 10.17826/cumj.934776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
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18
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Xiong J, Zhang L, Tang R, Zhu Z. MicroRNA-301b-3p facilitates cell proliferation and migration in colorectal cancer by targeting HOXB1. Bioengineered 2021; 12:5839-5849. [PMID: 34488545 PMCID: PMC8806818 DOI: 10.1080/21655979.2021.1962483] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Previous studies revealed that miR-301b-3p was essential to the onset and development of several cancers, but the implied functions of miR-301b-3p in colorectal cancer (CRC) remained largely unclear. The current study is aimed to exploring the potential roles and possible mechanism of miR-301b-3p in CRC. The abundance of miR-301b-3p and HOXB1 in CRC clinical specimens and cell lines was verified using RT-qPCR. The CCK-8, colony formation, wound healing and transwell assays were adopted to evaluate cell proliferation and migration. The interactivity of miR-301b-3p and homeobox B1 (HOXB1) was identified using bioinformatics analysis and dual-luciferase reporter. The results of RT-qPCR indicated that miR-301b-3p was significantly upregulated in CRC clinical specimens and cell lines. Furthermore, overexpression of miR-301b-3p speeds up CRC cell proliferation and migration. Bioinformatics analysis and dual-luciferase reporter verified that HOXB1 acted as the downstream targeted mRNA. Furthermore, silencing of HOXB1 also obviously accelerated the proliferation and migration ability of CRC cells. miR-301b-3p facilitated cell proliferation and migration in CRC, which was partly reversed by overexpressing HOXB1. In conclusion, our findings demonstrated that miR-301b-3p facilitated CRC cell growth and migration via targeting HOXB1. Our results identified that miR-301b-3p served as a significant oncogene in CRC, which may provide a novel biomarker for diagnosis and therapeutic objective for CRC.
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Affiliation(s)
- Jianyong Xiong
- Second Abdominal Surgery Department, Jiangxi Cancer Hospital of Nanchang University, Nanchang, Jiangxi, China.,Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Lijuan Zhang
- Department of Medical Record Statistics, Jiangxi Cancer Hospital, Nanchang, Jiangxi, China
| | - Ren Tang
- Second Abdominal Surgery Department, Jiangxi Cancer Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Zhengming Zhu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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19
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Ma Y, Cao X, Shi G, Shi T. MiRNA-145 and Its Direct Downstream Targets in Digestive System Cancers: A Promising Therapeutic Target. Curr Pharm Des 2021; 27:2264-2273. [PMID: 33121400 DOI: 10.2174/1381612826666201029095702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 09/24/2020] [Indexed: 11/22/2022]
Abstract
MicroRNAs (miRNAs) play a vital role in the onset and development of many diseases, including cancers. Emerging evidence shows that numerous miRNAs have the potential to be used as diagnostic biomarkers for cancers, and miRNA-based therapy may be a promising therapy for the treatment of malignant neoplasm. MicroRNA-145 (miR-145) has been considered to play certain roles in various cellular processes, such as proliferation, differentiation and apoptosis, via modulating the expression of direct target genes. Recent reports show that miR-145 participates in the progression of digestive system cancers, and plays crucial and novel roles in cancer treatment. In this review, we summarize the recent knowledge concerning the function of miR-145 and its direct targets in digestive system cancers. We discuss the potential role of miR-145 as a valuable biomarker for digestive system cancers and how miR-145 regulates these digestive system cancers via different targets to explore the potential strategy of targeting miR-145.
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Affiliation(s)
- Yini Ma
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Xiu Cao
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China
| | - Guojuan Shi
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Tianlu Shi
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
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20
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Nadda N, Paul SB, Yadav DP, Kumar S, Sreenivas V, Saraya A, Gamanagatti S, Acharya SK, Shalimar, Nayak B. Prognostic and Therapeutic Potentials of OncomiRs Modulating mTOR Pathways in Virus-Associated Hepatocellular Carcinoma. Front Oncol 2021; 10:604540. [PMID: 33614488 PMCID: PMC7890014 DOI: 10.3389/fonc.2020.604540] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 12/16/2020] [Indexed: 01/07/2023] Open
Abstract
Background Dysregulated oncomiRs are attributed to hepatocellular carcinoma (HCC) through targeting mTOR signaling pathway responsible for cell growth and proliferation. The potential of these oncomiRs as biomarker for tumor response or as target for therapy needs to be evaluated. AIM Tumor response assessment by OncomiR changes following locoregional therapy (LRT) and targeting of these oncomiRs modulating pathway Methods All consecutive viral-HCC patients of BCLC stage-A/B undergoing LRT were included. OncomiRs (miR-21, -221, and -16) change in circulation and AFP-ratio at 1-month post-LRT to baseline was estimated to differentiate various categories of response as per mRECIST criteria. OncomiR modulating mTOR pathway was studied by generating miR-21 and miR-221 overexpressing Huh7 stable cell lines. Results Post-LRT tumor response was assessed in 90 viral-HCC patients (CR, 40%; PR, 31%, and PD, 29%). Significant increase of miRNA-21 and -221 expression was observed in PD (p = 0.040, 0.047) and PR patients (miR-21, p = 0.045). Fold changes of miR-21 can differentiate response in group (CR from PR+PD) at AUROC 0.718 (95% CI, 0.572–0.799) and CR from PD at AUROC 0.734 (95% CI, 0.595–0.873). Overexpression of miR-21 in hepatoma cell line had shown increased phosphorylation p70S6K, the downstream regulator of cell proliferation in mTOR pathway. Upregulation of AKT, mTOR, and RPS6KB1 genes were found significant (P < 0.005) and anti-miR-21 specifically reduced mTOR gene (P = 0.02) expression. Conclusions The miR-21 fold change correlates well with imaging in predicting tumor response. Overexpression of miR-21 has a role in HCC through mTOR pathway activation and can be targeted.
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Affiliation(s)
- Neeti Nadda
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Shashi Bala Paul
- Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India
| | - Dawesh P Yadav
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Sonu Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | | | - Anoop Saraya
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | | | - Subrat Kumar Acharya
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Shalimar
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Baibaswata Nayak
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
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21
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Ansari MA, Thiruvengadam M, Farooqui Z, Rajakumar G, Sajid Jamal QM, Alzohairy MA, Almatroudi A, Alomary MN, Chung IM, Al-Suhaimi EA. Nanotechnology, in silico and endocrine-based strategy for delivering paclitaxel and miRNA: Prospects for the therapeutic management of breast cancer. Semin Cancer Biol 2021; 69:109-128. [PMID: 31891780 DOI: 10.1016/j.semcancer.2019.12.022] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 12/06/2019] [Accepted: 12/25/2019] [Indexed: 02/07/2023]
Abstract
Breast cancer is one of the most prevalent and reoccurring cancers and the second most common reason of death in women. Despite advancements in therapeutic strategies for breast cancer, early tumor recurrence and metastasis in patients indicate resistance to chemotherapeutic medicines, such as paclitaxel due to the abnormal expression of ER and EGF2 in breast cancer cells. Therefore, the development of alternatives to paclitaxel is urgently needed to overcome challenges involving drug resistance. An increasing number of studies has revealed miRNAs as novel natural alternative substances that play a crucial role in regulating several physiological processes and have a close, adverse association with several diseases, including breast cancer. Due to the therapeutic potential of miRNA and paclitaxel in cancer research, the current review focuses on the differential roles of various miRNAs in breast cancer development and treatment. miRNA delivery to a specific target site, the development of paclitaxel and miRNA formulations, and nanotechnological strategies for the delivery of nanopaclitaxel in the management of breast cancer are discussed. These strategies involve improving the cellular uptake and bioavailability and reducing the toxicity of free paclitaxel to achieve accumulation tumor site. Furthermore, a molecular docking study was performed to ascertain the enhanced anticancer activity of the nanoformulation of ANG1005 and Abraxane. An in silico analysis revealed that ANG1005 and Abraxane nanoformulations have superior and significantly enhanced interactions with the proteins α-tubulin and Bcl-2. Therefore, ANG1005 and Abraxane may be more suitable in the therapeutic management of breast cancer than the existing free paclitaxel. miRNAs can revert abnormal gene expression to normalcy; since miRNAs serve as tumor suppressors. Therefore, restoration of particular miRNAs levels as a replacement therapy may be an effective endocrine potential strategy for treating ER positive/ negative breast cancers.
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Affiliation(s)
- Mohammad Azam Ansari
- Department of Epidemic Diseases Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam, 31441, Saudi Arabia.
| | - Muthu Thiruvengadam
- Department of Crop Science, College of Sanghuh Life Science, Konkuk University, Seoul 05029, Republic of Korea.
| | - Zeba Farooqui
- College of Pharmacy, University of Houston, Houston, TX, 77204, United States
| | - Govindaswamy Rajakumar
- Department of Crop Science, College of Sanghuh Life Science, Konkuk University, Seoul 05029, Republic of Korea.
| | - Qazi Mohammad Sajid Jamal
- Department of Health Informatics, College of Public Health and Health Informatics, Qassim University, Al-Bukayriyah, Saudi Arabia
| | - Mohammad A Alzohairy
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Qassim 51431, Saudi Arabia
| | - Ahmad Almatroudi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Qassim 51431, Saudi Arabia
| | - Mohammad N Alomary
- National Center of Biotechnology, Life Science and Environmental Research Institute, King Abdulaziz City for Science and Technology, P.O. Box 6086, Riyadh, Saudi Arabia
| | - Ill-Min Chung
- Department of Crop Science, College of Sanghuh Life Science, Konkuk University, Seoul 05029, Republic of Korea.
| | - Ebtesam Abdullah Al-Suhaimi
- Department of Biology, College of Science, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam, Saudi Arabia; Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam, 31441, Saudi Arabia
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22
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Morishita A, Oura K, Tadokoro T, Fujita K, Tani J, Masaki T. MicroRNAs in the Pathogenesis of Hepatocellular Carcinoma: A Review. Cancers (Basel) 2021; 13:cancers13030514. [PMID: 33572780 PMCID: PMC7866004 DOI: 10.3390/cancers13030514] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/22/2021] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is one of the most frequently occurring cancers, and the prognosis for late-stage HCC remains poor. A better understanding of the pathogenesis of HCC is expected to improve outcomes. MicroRNAs (miRNAs) are small, noncoding, single-stranded RNAs that regulate the expression of various target genes, including those in cancer-associated genomic regions or fragile sites in various human cancers. We summarize the central roles of miRNAs in the pathogenesis of HCC and discuss their potential utility as valuable biomarkers and new therapeutic agents for HCC. Abstract Hepatocellular carcinoma (HCC) is the seventh most frequent cancer and the fourth leading cause of cancer mortality worldwide. Despite substantial advances in therapeutic strategies, the prognosis of late-stage HCC remains dismal because of the high recurrence rate. A better understanding of the etiology of HCC is therefore necessary to improve outcomes. MicroRNAs (miRNAs) are small, endogenous, noncoding, single-stranded RNAs that modulate the expression of their target genes at the posttranscriptional and translational levels. Aberrant expression of miRNAs has frequently been detected in cancer-associated genomic regions or fragile sites in various human cancers and has been observed in both HCC cells and tissues. The precise patterns of aberrant miRNA expression differ depending on disease etiology, including various causes of hepatocarcinogenesis, such as viral hepatitis, alcoholic liver disease, or nonalcoholic steatohepatitis. However, little is known about the underlying mechanisms and the association of miRNAs with the pathogenesis of HCC of various etiologies. In the present review, we summarize the key mechanisms of miRNAs in the pathogenesis of HCC and emphasize their potential utility as valuable diagnostic and prognostic biomarkers, as well as innovative therapeutic targets, in HCC diagnosis and treatment.
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23
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Nomura K, Kitanaka A, Iwama H, Tani J, Nomura T, Nakahara M, Ohura K, Tadokoro T, Fujita K, Mimura S, Yoneyama H, Kobara H, Morishita A, Okano K, Suzuki Y, Tsutsi K, Himoto T, Masaki T. Association between microRNA-527 and glypican-3 in hepatocellular carcinoma. Oncol Lett 2021; 21:229. [PMID: 33613718 PMCID: PMC7856685 DOI: 10.3892/ol.2021.12490] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 09/19/2020] [Indexed: 12/15/2022] Open
Abstract
The present study aimed to identify the specific microRNAs (miRNAs/miRs) and their corresponding target genes involved in hepatocellular carcinomas (HCCs). Microarray analysis was performed to examine the miRNA expression profiles of four paired HCC and corresponding non-cancerous (N) liver tissues using 985 miRNA probes. The Human miRNA Target database was used to identify the target genes of differentially expressed miRNAs between the HCC and N tissues. The protein expression levels of target genes in the HCC tissues and cell lines were evaluated using western blotting. miRNA-mediated suppression of target gene expression was evaluated by transiently transfecting the miRNA into the HCC cell lines. Of the 985 miRNAs evaluated, four miRNAs were differentially expressed (three upregulated and one downregulated miRNAs). Of these four miRNAs, miRNA-527 was highly downregulated in the HCC tissues. Glypican-3 (GPC-3) was predicted as a target gene of miRNA-527. Western blotting revealed that GPC-3 protein is highly expressed in the HCC tissues and HCC cell lines compared with N and normal cell lines. Transfection with miR-527 resulted in suppression of GPC-3 protein expression in the Cos7 cells. Furthermore, transfection with miR-527 also inhibited the intrinsic expression of GPC-3 in the Huh-7 cell line. This indicated that miR-527 in the HCC tissues may be an important novel miRNA that targets the GPC-3 gene expression. GPC-3, whose expression is regulated by miR-527, may be involved in the development and progression of HCC.
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Affiliation(s)
- Kei Nomura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Akira Kitanaka
- Department of Laboratory Medicine, Kawasaki Medical School, Kurashiki, Okayama 701-0192, Japan
| | - Hisakazu Iwama
- Information Technology Center, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Takako Nomura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Kyoko Ohura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Shima Mimura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Keiichi Okano
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Yasuyuki Suzuki
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Kunihiko Tsutsi
- Department of Healthy Science, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Takashi Himoto
- Department of Clinical Examination, Faculty of Health Sciences, Kagawa Prefectural University of Health Sciences, Takamatsu, Kagawa 761-0123, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
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24
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Krupa R, Malecki W, Czarny P, Strycharz J, Jablkowski M, Kordek R, Szemraj J, Sliwinski T. MicroRNA profile and iron-related gene expression in hepatitis C-related hepatocellular carcinoma: a preliminary study. Arch Med Sci 2021; 17:1175-1183. [PMID: 34522246 PMCID: PMC8425257 DOI: 10.5114/aoms.2019.86613] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 08/24/2018] [Indexed: 11/18/2022] Open
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is very difficult to diagnose, especially in its early stages. Non-invasive diagnostic and prognostic factors for this cancer are urgently needed. The purpose of our study was to investigate whether the microRNAs (miRNAs) regulating genes involved in iron homeostasis, whose disruption is a hallmark of HCC, offer potential as diagnostic or prognostic factors of HCV-related hepatocellular carcinoma. MATERIAL AND METHODS Serum and tumor samples, and adjacent liver specimens, were obtained from 65 HCC patients. Additionally, serum samples were obtained from 65 healthy controls. In total, 28 circulating and eight tissue microRNA expression profiles were estimated by TaqMan qPCR. RESULTS The expression profiles of all tested miRNAs were altered in the hepatocellular carcinoma patients. Iron level was negatively related to serum miR-96 level in healthy controls. Although the expression of iron metabolism proteins correlated with the level of serum miRNA in the controls, this was not observed in cancer patients. In the group of cancer patients, Let-7a, miR-29b, and miR-133a were positively related to ferroportin, transferrin and ferritin levels, while miR-31, miR-221 and miR-532 were negatively related to ferroportin, transferrin receptor 1 and ferritin levels. According to ROC curve analyses, 15 miRNAs are able to discriminate with 100% sensitivity and specificity between hepatocellular carcinoma patients and healthy subjects, which is more efficient than α-fetoprotein. CONCLUSIONS Circulating miRNAs that regulate the expression of iron metabolism proteins should be evaluated as promising candidates for HCV-related HCC diagnostic agents.
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Affiliation(s)
- Renata Krupa
- Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
| | - Wojciech Malecki
- Department of Infectious and Liver Disease, Medical University of Lodz, Lodz, Poland
| | - Piotr Czarny
- Department of Medical Biochemistry, Medical University of Lodz, Lodz, Poland
| | - Justyna Strycharz
- Department of Medical Biochemistry, Medical University of Lodz, Lodz, Poland
| | - Maciej Jablkowski
- Department of Infectious and Liver Disease, Medical University of Lodz, Lodz, Poland
| | - Radzislaw Kordek
- Department of Pathology, Medical University of Lodz, Lodz, Poland
| | - Janusz Szemraj
- Department of Medical Biochemistry, Medical University of Lodz, Lodz, Poland
| | - Tomasz Sliwinski
- Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
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25
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Cabral B, Hoffmann L, Bottaro T, Costa P, Ramos A, Coelho H, Villela-Nogueira C, Ürményi T, Faffe D, Silva R. Circulating microRNAs associated with liver fibrosis in chronic hepatitis C patients. Biochem Biophys Rep 2020; 24:100814. [PMID: 33015376 PMCID: PMC7520427 DOI: 10.1016/j.bbrep.2020.100814] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Revised: 09/06/2020] [Accepted: 09/14/2020] [Indexed: 12/21/2022] Open
Abstract
A major challenge in hepatitis C research is the detection of early potential for progressive liver disease. MicroRNAs (miRNAs) are small RNAs that regulate gene expression and can be biomarkers of pathological processes. In this study, we compared circulating miRNAs identified in hepatitis C virus (HCV)-infected patients presenting two extremes of liver disease: mild/moderate fibrosis and cirrhosis. The patients in the cirrhosis group subsequently developed hepatocellular carcinoma (HCC). We identified 163 mature miRNAs in the mild/moderate fibrosis group and 171 in the cirrhosis group, with 144 in common to both groups. Differential expression analysis revealed 5 upregulated miRNAs and 2 downregulated miRNAs in the cirrhosis group relative to the mild/moderate fibrosis group. Functional analyses of regulatory networks (target gene and miRNA) identified gene categories involved in cell cycle biological processes and metabolic pathways related to cell cycle, cancer, and apoptosis. These results suggest that the differentially expressed circulating miRNAs observed in this work (miR-215-5p, miR-483-5p, miR-193b-3p, miR-34a-5p, miR-885-5p, miR-26b-5p and miR -197-3p) may be candidates for biomarkers in the prognosis of liver disease.
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Affiliation(s)
- B.C.A. Cabral
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - L. Hoffmann
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Departamento de Biotecnologia, Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro, Rio de Janeiro, Brazil
| | - T. Bottaro
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - P.F. Costa
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - A.L.A. Ramos
- Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - H.S.M. Coelho
- Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - C.A. Villela-Nogueira
- Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - T.P. Ürményi
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - D.S. Faffe
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - R. Silva
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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26
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Wang J, Liu Y, Li Y, Zheng X, Gan J, Wan Z, Zhang J, Liu Y, Wang Y, Hu W, Li Y, Liu Y. Exosomal‑miR‑10a derived from colorectal cancer cells suppresses migration of human lung fibroblasts, and expression of IL‑6, IL‑8 and IL‑1β. Mol Med Rep 2020; 23:84. [PMID: 33236127 PMCID: PMC7716406 DOI: 10.3892/mmr.2020.11723] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 10/21/2020] [Indexed: 01/10/2023] Open
Abstract
MicroRNAs (miRs) carried in exosomes serve an important role in the pre‑metastatic microenvironment and in intercellular interactions. However, the function of exosomal‑miR‑10a derived from primary colorectal cancer (CRC) cells on fibroblasts in the lung metastatic microenvironment of patients with CRC remains unclear. Reverse transcription‑quantitative PCR was performed using samples from patients with CRC, and demonstrated that the expression levels of miR‑10a were significantly lower in serum and cancer tissue samples from patients with CRC compared with in serum from healthy individuals and paired non‑cancerous tissues, respectively. In addition, the expression levels of miR‑10a were inversely associated with the invasion depth of CRC. Exosomal‑miR‑10a derived from CRC cells reduced the proliferative and migratory activities of primary normal human lung fibroblasts (NHLFs), and the expression levels of IL‑6, IL‑8 and IL‑1β in NHLFs. The present study provided insight into the phenotypic alterations of NHLFs induced by exosomal‑miR‑10a derived from CRC cells, which may aid understanding of the mechanism underlying the process of CRC lung metastasis.
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Affiliation(s)
- Jian Wang
- Department of Gastrointestinal Surgery, Tangshan People's Hospital, Tangshan, Hebei 063001, P.R. China
| | - Yuanting Liu
- Department of Gastrointestinal Surgery, Tangshan People's Hospital, Tangshan, Hebei 063001, P.R. China
| | - Ying Li
- Nuclear Medicine Clinical Laboratory, Tangshan People's Hospital, Tangshan, Hebei 063001, P.R. China
| | - Xuan Zheng
- Nuclear Medicine Clinical Laboratory, Tangshan People's Hospital, Tangshan, Hebei 063001, P.R. China
| | - Jianhui Gan
- Department of Anesthesiology, Tangshan People's Hospital, Tangshan, Hebei 063001, P.R. China
| | - Zhaoyuan Wan
- The Cancer Institute, Tangshan People's Hospital, Tangshan, Hebei 063001, P.R. China
| | - Jun Zhang
- The Cancer Institute, Tangshan People's Hospital, Tangshan, Hebei 063001, P.R. China
| | - Yan Liu
- The Cancer Institute, Tangshan People's Hospital, Tangshan, Hebei 063001, P.R. China
| | - Yaqi Wang
- Department of Breast Surgery, Tangshan People's Hospital, Tangshan, Hebei 063001, P.R. China
| | - Wanning Hu
- The Cancer Institute, Tangshan People's Hospital, Tangshan, Hebei 063001, P.R. China
| | - Yufeng Li
- The Cancer Institute, Tangshan People's Hospital, Tangshan, Hebei 063001, P.R. China
| | - Yankun Liu
- The Cancer Institute, Tangshan People's Hospital, Tangshan, Hebei 063001, P.R. China
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27
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Lim HK, Jeffrey GP, Ramm GA, Soekmadji C. Pathogenesis of Viral Hepatitis-Induced Chronic Liver Disease: Role of Extracellular Vesicles. Front Cell Infect Microbiol 2020; 10:587628. [PMID: 33240824 PMCID: PMC7683521 DOI: 10.3389/fcimb.2020.587628] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 10/13/2020] [Indexed: 12/11/2022] Open
Abstract
Extracellular vesicles are encapsulated lipid nanoparticles secreted by a variety of cell types in living organisms. They are known to carry proteins, metabolites, nucleic acids, and lipids as their cargoes and are important mediators of intercellular communication. The role of extracellular vesicles in chronic liver disease has been reported. Chronic liver disease such as viral hepatitis accounts for a significant mortality and morbidity burden worldwide. Hepatic fibrosis has been commonly associated with the chronic form of viral hepatitis, which results in end-stage liver disease, including cirrhosis, liver failure, and carcinoma in some patients. In this review, we discuss the potential role of extracellular vesicles in mediating communication between infectious agents (hepatitis B and C viruses) and host cells, and how these complex cell-cell interactions may facilitate the development of chronic liver disease. We will further discuss how understanding their biological mechanism of action might be beneficial for developing therapeutic strategies to treat chronic liver disease.
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Affiliation(s)
- Hong Kiat Lim
- Hepatic Fibrosis Group, Department of Cellular and Molecular Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Gary P Jeffrey
- Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia.,Sir Charles Gairdner Hospital, Nedlands, Hepatology Department and Liver Transplant Service, Perth, WA, Australia
| | - Grant A Ramm
- Hepatic Fibrosis Group, Department of Cellular and Molecular Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Carolina Soekmadji
- Hepatic Fibrosis Group, Department of Cellular and Molecular Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
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28
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Li YZ, Sun Z, Xu HR, Zhang QG, Zeng CQ. Osthole inhibits proliferation of kainic acid‑activated BV‑2 cells by modulating the Notch signaling pathway. Mol Med Rep 2020; 22:3759-3766. [PMID: 33000274 PMCID: PMC7533434 DOI: 10.3892/mmr.2020.11455] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 07/20/2020] [Indexed: 11/29/2022] Open
Abstract
Epilepsy is a syndrome involving chronic recurrent transient brain dysfunction. Activation and proliferation of microglia serve important roles in epilepsy pathogenesis and may be targets for treatment. Although osthole, an active constituent isolated from Cnidium monnieri (L.) Cusson, has been demonstrated to improve epilepsy in rats, its underlying mechanism remains to be elucidated. The present study investigated the effect of osthole on proliferation of kainic acid (KA)‑activated BV‑2 cells and explored the molecular mechanism by which it inhibited their proliferation. Using Cell Counting Kit‑8, enzyme‑linked immunosorbent assay, reverse transcription‑quantitative PCR, western blot analysis and immunofluorescence staining, it was identified that following exposure of KA‑activated BV‑2 cells to 131.2 µM osthole for 24 h, cell proliferation and release of tumor necrosis factor α, interleukin 6 and nitric oxide synthase/induced nitric oxide synthase were significantly inhibited (P<0.05). Further experiments revealed that osthole significantly downregulated mRNA and protein levels of Notch signaling components in KA‑activated BV‑2 cells (P<0.05). Therefore, it was hypothesized that osthole inhibited the proliferation of microglia by modulating the Notch signaling pathway, which may be useful for the treatment of epilepsy and other neurodegenerative diseases characterized by Notch upregulation.
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Affiliation(s)
- Yu-Zhu Li
- Department of Medical College, Dalian University, Dalian, Liaoning 116622, P.R. China
| | - Zheng Sun
- Beijing International Travel Health Care Center of Beijing Entry-Exit Inspection and Quarantine Bureau, Beijing 100088, P.R. China
| | - Hong-Rui Xu
- Department of Medical College, Dalian University, Dalian, Liaoning 116622, P.R. China
| | - Qing-Gao Zhang
- Department of Medical College, Dalian University, Dalian, Liaoning 116622, P.R. China
| | - Chang-Qian Zeng
- Department of Medical College, Dalian University, Dalian, Liaoning 116622, P.R. China
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29
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Mutalifu N, Du P, Zhang J, Akbar H, Yan B, Alimu S, Tong L, Luan X. Circ_0000215 Increases the Expression of CXCR2 and Promoted the Progression of Glioma Cells by Sponging miR-495-3p. Technol Cancer Res Treat 2020; 19:1533033820957026. [PMID: 33089764 PMCID: PMC7586024 DOI: 10.1177/1533033820957026] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND In recent years, accumulating studies have found that circular RNA (circRNA) exerts a great effect on tumor progression. Circ_0000215, a novel circRNA, remains largely unknown in terms of its effect and mechanism in glioma. METHOD Quantitative real-time polymerase chain reaction (qRT-PCR) was carried out to detect the expressions of circ_0000215, miR-495-3p and CXCR2 in human glial cell line HEB and glioma cell lines (A172, U251, U87, SHG-44, LN-18), human glioma tissues and adjacent healthy tissues. Gain- and loss-assays of circ_0000215 were conducted. Cell proliferation ability was detected via the CCK8 assay, and cell invasion ability was examined by Transwell assay. CXCR2 expression was evaluated via RT-PCR and Western blot. Moreover, bioinformatics was applied to analyze the targeting molecules of circ_0000215 and CXCR2. Verification of the relationship between these molecules were supported through the dual-luciferase reporter gene and RNA immunocoprecipitation (RIP) assay. RESULTS Circ_0000215 and CXCR2 were remarkably upregulated in glioma tissues and cells. Overexpression of circ_0000215 notably promoted the proliferation, invasion and epithelial-mesenchymal transition (EMT) but inhibited apoptosis of glioma cells, while knocking down circ_0000215 had the opposite effects. Additionally, miR-495-3p, a sponge RNA of circ_0000215, inhibited the growth, invasion and EMT of glioma cells. Mechanistically, miR-495-3p targeted CXCR2 and negatively regulated CXCR2/PI3K/Akt pathway. However, the effects of miR-495-3p were all dampened by overexpression of circ_0000215. CONCLUSION These data demonstrated that circ_0000215 functions as a competitive endogenous RNA by sponging miR-495-3p, thus accelerating glioma progression through CXCR2 axis.
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Affiliation(s)
- Nurehemaiti Mutalifu
- Department of Neurosurgery, Second Affiliated Hospital, 223527Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Peng Du
- Department of Neurosurgery, Second Affiliated Hospital, 223527Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Jingjing Zhang
- Department of Neurosurgery, Second Affiliated Hospital, 223527Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Halik Akbar
- Department of Neurosurgery, Second Affiliated Hospital, 223527Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Baofeng Yan
- Department of Neurosurgery, Second Affiliated Hospital, 223527Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Sulaiman Alimu
- Department of Neurosurgery, Second Affiliated Hospital, 223527Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Lingxiao Tong
- Department of Neurosurgery, Second Affiliated Hospital, 223527Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Xinping Luan
- Department of Neurosurgery, Second Affiliated Hospital, 223527Xinjiang Medical University, Urumqi, Xinjiang, China
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30
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Wang B, Zhang L, Li J, Hua P, Zhang Y. Down-Regulation of miR-2053 Inhibits the Development and Progression of Esophageal Carcinoma by Targeting Fyn-Related Kinase (FRK). Dig Dis Sci 2020; 65:2853-2862. [PMID: 31894485 DOI: 10.1007/s10620-019-06015-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 12/12/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND MicroRNAs (miRNAs) play essential roles in the regulation and pathophysiology of various types of cancers including esophageal carcinoma (ESCA). Increasing numbers of miRNAs have been identified to be important regulators in the progression of ESCA by regulating gene expression. However, functional miRNAs and the underlying mechanisms involved in ESCA need sufficient elucidation. AIMS In the present study, the function of miR-2053 was investigated in ESCA cells. METHODS The expression of miR-2053 was detected in four different ESCA cell lines (Eca109, Ec9706, KYSE30, and TE-1 cells) and normal cell line (HEEC) by qRT-PCR. Cell proliferation, migration, and invasion abilities after knockdown of miR-2053 were assessed by CCK-8 assay, scratch assay, and transwell assay, respectively. Cell cycle of ESCA cells was detected by flow cytometric analysis. Expression of proteins in ESCA cells was detected by Western blot analysis. RESULTS The results showed that the expression of miR-2053 was remarkably up-regulated in ESCA tissues and cells lines. Down-regulation of miR-2053 markedly inhibited cell proliferation, migration, and invasion and markedly induced cell cycle arrest and cell apoptosis in ESCA cell lines. Fyn-related kinase (FRK) was a target gene of miR-2053. Moreover, down-regulation of miR-2053 mediated the protein kinase B (AKT)/mammalian target of rapamycin and Wnt3a/β-catenin signaling pathway in ESCA cell lines. CONCLUSIONS Our results together suggest the potential of regulating miR-2053 expression against development and progression of esophageal carcinoma by targeting FRK.
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Affiliation(s)
- Bin Wang
- Department of Thoracic Surgery, The Second Hospital of Jilin University, No. 218 Ziqiang Street, Changchun City, 130041, Jilin Province, People's Republic of China
| | - Li Zhang
- Department of Anesthesiology, The Second Hospital of Jilin University, Changchun City, 130041, Jilin Province, People's Republic of China
| | - Jindong Li
- Department of Thoracic Surgery, The Second Hospital of Jilin University, No. 218 Ziqiang Street, Changchun City, 130041, Jilin Province, People's Republic of China
| | - Peiyan Hua
- Department of Thoracic Surgery, The Second Hospital of Jilin University, No. 218 Ziqiang Street, Changchun City, 130041, Jilin Province, People's Republic of China
| | - Yan Zhang
- Department of Thoracic Surgery, The Second Hospital of Jilin University, No. 218 Ziqiang Street, Changchun City, 130041, Jilin Province, People's Republic of China.
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31
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Hu J, Wang Z, Wang J, Jian Y, Dai J, Wang X, Xiong W. MicroRNA-182 Promotes Cell Migration by Targeting Programmed Cell Death 4 in Hepatocellular Carcinoma Cells. Onco Targets Ther 2020; 13:9159-9167. [PMID: 32982304 PMCID: PMC7502386 DOI: 10.2147/ott.s258251] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 08/17/2020] [Indexed: 01/30/2023] Open
Abstract
Purpose Hepatocellular carcinoma (HCC) is the most common primary liver tumor and the third greatest cause of cancer-related death worldwide. Programmed cell death 4 (PDCD4) was reported as a potential tumor-suppressor in hepatocarcinogenesis. However, relatively little is known about mechanisms that regulate PDCD4 expression in HCC. The aim of the present study is to investigate the expression of PDCD4 and miR-182 in human HCC cell lines and clinical HCC specimens and determine whether PDCD4 is a direct target of miR-182 in HCC cell lines. Materials The expression of miR-182 and PDCD4 in human HCC cell lines and HCC tissues were examined using qRT-PCR and Western blot method. Transwell and wound healing assays were carried out to explore the influence of miR-182 on hepatoma cells migration. A luciferase reporter assay was conducted to confirm target association. Results In our research, we found that PDCD4 was downregulated, whereas miR-182 was upregulated in liver cancer cell lines and HCC tissues. Transwell and wound healing assays illustrated that miR-182 contributed to migration activities of liver cancer cell lines. Loss or increase of miR-182 can lead to a negative expression of PDCD4 protein level. The luciferase reporter assay showed that PDCD4 is a direct target of miR-182. Conclusion All these findings suggest that miR-182 may act as an oncogenic role in liver cancer cells by directly and negatively regulating expression of PDCD4.
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Affiliation(s)
- Junwei Hu
- Department of Gastroenterology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, People's Republic of China.,Department of Digestive Endoscopy, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, People's Republic of China
| | - Zeyu Wang
- Department of Gastroenterology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, People's Republic of China
| | - Jinjun Wang
- Department of Gerontology, Shanghai Putuo Central Hospital Affiliated to Shanghai Traditional Chinese Medicine University, Shanghai 200062, People's Republic of China
| | - Yicheng Jian
- Department of Gastroenterology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, People's Republic of China.,Department of Digestive Endoscopy, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, People's Republic of China
| | - Jiarun Dai
- Department of Gastroenterology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, People's Republic of China.,Department of Digestive Endoscopy, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, People's Republic of China
| | - Xiaoping Wang
- Department of Gastroenterology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, People's Republic of China.,Department of Digestive Endoscopy, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, People's Republic of China
| | - Wujun Xiong
- Department of Hepatology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, People's Republic of China
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32
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Wang XK, Liao XW, Huang R, Huang JL, Chen ZJ, Zhou X, Yang CK, Han CY, Zhu GZ, Peng T. Clinical significance of long non-coding RNA DUXAP8 and its protein coding genes in hepatocellular carcinoma. J Cancer 2020; 11:6140-6156. [PMID: 32922554 PMCID: PMC7477403 DOI: 10.7150/jca.47902] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 08/16/2020] [Indexed: 12/14/2022] Open
Abstract
Backgrounds: Hepatocellular carcinoma (HCC) is a lethal malignancy worldwide that is difficult to diagnose during the early stages and its tumors are recurrent. Long non-coding RNAs (lncRNAs) have increasingly been associated with tumor biomarkers for diagnosis and prognosis. This study attempts to explore the potential clinical significance of lncRNA DUXAP8 and its co-expression related protein coding genes (PCGs) for HCC. Method: Data from a total of 370 HCC patients from The Cancer Genome Atlas were utilized for the analysis. DUXAP8 and its top 10 PCGs were explored for their diagnostic and prognostic implications for HCC. A risk score model and nomogram were constructed for prognosis prediction using prognosis-related genes and DUXAP8. Molecular mechanisms of DUXAP8 and its PCGs involved in HCC initiation and progression were investigated. Then, potential target drugs were identified using genome-wide DUXAP8-related differentially expressed genes in a Connectivity Map database. Results: The top 10 PCGs were identified as: RNF2, MAGEA1, GABRA3, MKRN3, FAM133A, MAGEA3, CNTNAP4, MAGEA6, MALRD1, and DGKI. Diagnostic analysis indicated that DUXAP8, MEGEA1, MKRN3, and DGKI show diagnostic implications (all area under curves ≥0.7, p≤0.05). Prognostic analysis indicated that DUXAP8 and RNF2 had prognostic implications for HCC (adjusted p=0.014 and 0.008, respectively). The risk score model and nomogram showed an advantage for prognosis prediction. A total of 3 target drugs were determined: cinchonine, bumetanide and amiprilose and they may serve as potential therapeutic targets for HCC. Conclusion: Functioning as an oncogene, DUXAP8 is overexpressed in tumor tissue and may serve as both a diagnostic and prognosis biomarker for HCC. MEGEA1, MKRN3, and DGKI maybe potential diagnostic biomarkers and DGKI may also be potentially prognostic biomarkers for HCC.
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Affiliation(s)
- Xiang-Kun Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Xi-Wen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Rui Huang
- Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, People's Republic of China
| | - Jian-Lu Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China.,Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Guangxi Medical University, Nanning 530031, Guangxi Province, China
| | - Zi-Jun Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Xin Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Cheng-Kun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Chuang-Ye Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Guang-Zhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
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Kohno T, Morishita A, Iwama H, Fujita K, Tani J, Takuma K, Nakahara M, Oura K, Tadokoro T, Nomura T, Yoneyama H, Kato K, Okano K, Suzuki Y, Nishiyama A, Himoto T, Masaki T. Comprehensive analysis of circulating microRNAs as predictive biomarkers for sorafenib therapy outcome in hepatocellular carcinoma. Oncol Lett 2020; 20:1727-1733. [PMID: 32724415 PMCID: PMC7377167 DOI: 10.3892/ol.2020.11696] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 12/17/2019] [Indexed: 12/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Clinical management has improved the prognosis of early HCC, but that of advanced HCC remains poor. Sorafenib, an oral multikinase inhibitor, provided a treatment option for advanced-stage HCC, and prolonged the survival and inhibited tumor progression as first-line therapy in patients with advanced HCC. In this study, we investigated if specific microRNAs could act as predictive biomarkers of sorafenib effectiveness and indicate the best time to switch to second-line therapies. Sorafenib inhibited the proliferation of the Li-7, Hep3B, HepG2 and Huh7 liver cancer cell lines (effective group), but not that of the HLE, HLF and ALEX cancer cell lines (non-effective group). A microRNA (miRNA/miR) analysis was performed comparing sorafenib-effective and non-effective cells lines as well as serum samples from patients with HCC from sorafenib-effective (complete response/partial response) and -non-effective (progressive disease) groups before sorafenib administration and detected three differentially-expressed miRNAs that were common among the in vivo and in vitro samples. The increase rate (effective/non-effective) of hsa-miR-30d in the medium was higher than that in the cancer cells. hsa-miR-30d was highly expressed in the serum and exosomes of patients with HCC in the effective group when compared to those of the non-effective group. Additionally, the hsa-miR-30d expression in the medium of cancer cell lines was highly upregulated in the effective group compared with the non-effective group. These results suggested that hsa-miR-30d might be secreted by the cancer cells to the serum through the exosomes. We identified a specific circulating miRNA that is related to refractory HCC under sorafenib therapy. Therefore, hsa-miR-30d might serve as a predictive biomarker for the efficacy of sorafenib therapy in HCC.
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Affiliation(s)
- Tomoki Kohno
- Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kita-gun, Kagawa 761-0793, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kita-gun, Kagawa 761-0793, Japan
| | - Hisakazu Iwama
- Life Science Research Center, Kagawa University Faculty of Medicine, Kita-gun, Kagawa 761-0793, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kita-gun, Kagawa 761-0793, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kita-gun, Kagawa 761-0793, Japan
| | - Kei Takuma
- Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kita-gun, Kagawa 761-0793, Japan
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kita-gun, Kagawa 761-0793, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kita-gun, Kagawa 761-0793, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kita-gun, Kagawa 761-0793, Japan
| | - Takako Nomura
- Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kita-gun, Kagawa 761-0793, Japan
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kita-gun, Kagawa 761-0793, Japan
| | - Kiyohito Kato
- Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kita-gun, Kagawa 761-0793, Japan
| | - Keiichi Okano
- Department of Gastroenterological Surgery, Kagawa University Faculty of Medicine, Kita-gun, Kagawa 761-0793, Japan
| | - Yasuyuki Suzuki
- Department of Gastroenterological Surgery, Kagawa University Faculty of Medicine, Kita-gun, Kagawa 761-0793, Japan
| | - Akira Nishiyama
- Department of Pharmacology, Kagawa University Faculty of Medicine, Kita-gun, Kagawa 761-0793, Japan
| | - Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Takamatsu, Kagawa 761-0123, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kita-gun, Kagawa 761-0793, Japan
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Salehi S, Tavabie OD, Verma S, McPhail MJW, Farzaneh F, Bernal W, Menon K, Agarwal K, Aluvihare VR. Serum MicroRNA Signatures in Recovery From Acute and Chronic Liver Injury and Selection for Liver Transplantation. Liver Transpl 2020; 26:811-822. [PMID: 32297687 DOI: 10.1002/lt.25781] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 02/15/2020] [Accepted: 03/12/2020] [Indexed: 01/11/2023]
Abstract
We previously demonstrated a distinct hepatic microRNA (miRNA) signature (down-regulation of miRNA-23a, -150, - 200b, -503, and -663 and up-regulation of miRNA-20a) is associated with successful regeneration in auxiliary liver transplantation (ALT). This study aimed to evaluate whether the serum expression of this regeneration-linked miRNA signature is associated with clinical outcomes in acute and chronic liver disease. These were represented by patients with acetaminophen-induced acute liver failure (ALF; n = 18) and patients with hepatitis C virus (HCV) undergoing treatment with direct-acting antivirals (n = 56), respectively. Patients were grouped depending on their clinical outcome. Global serum miRNA expression was analyzed using polymerase chain reaction (PCR) arrays and selected miRNA expression using targeted PCR. We demonstrate that specific regeneration-linked miRNAs discriminate outcomes in both clinical scenarios. We further show that miRNA-20a, -23a, -150, -200b, -503, and -663 undergo concordant changes in expression in 3 distinct clinical settings: liver regeneration accompanying successful ALT, clinical recovery after ALF, and clinical recompensation after cure of HCV. This miRNA signature represents a potentially novel biomarker to predict outcome and optimize patient selection for liver transplantation in both acute and chronic liver disease.
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Affiliation(s)
- Siamak Salehi
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Oliver D Tavabie
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Suman Verma
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Mark J W McPhail
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Farzin Farzaneh
- Department of Haematological Medicine, The Rayne Institute, King's College London, London, United Kingdom
| | - William Bernal
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Krish Menon
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Kosh Agarwal
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Varuna R Aluvihare
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
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Li Y, Luo JT, Liu YM, Wei WB. miRNA-145/miRNA-205 inhibits proliferation and invasion of uveal melanoma cells by targeting NPR1/CDC42. Int J Ophthalmol 2020; 13:718-724. [PMID: 32420217 DOI: 10.18240/ijo.2020.05.04] [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: 01/26/2020] [Accepted: 03/15/2020] [Indexed: 12/14/2022] Open
Abstract
AIM To investigate the role of microRNA-145 (miRNA-145) and microRNA-205 (miRNA-205) in proliferation and invasion of uveal melanoma (UM) cells. METHODS The expression level of miRNA-145 and miRNA-205 from samples of UM patients were determined by real-time polymerase chain reaction (RT-PCR). The growth and invasion inhibitory effects were observed by the transfection of UM cells with miRNA-145 and miRNA-205. Several epithelial-to-mesenchymal transition (EMT)-related proteins were screened by Western blotting. UM clinical samples from The Cancer Genome Atlas (TCGA) were applied to search for potential protein interaction. Pearson's correlation analysis was applied to estimate co-expression between genes. Dual-luciferase reporter assay was used to verify the binding sites on target protein for miRNA-145 and miRNA-205. RESULTS The expression levels of miRNA-145 and miRNA-205 in the samples from patients with UM were significantly lower than those in the normal tissue samples. Significant growth and invasion inhibitory effects were observed in human UM cells with miRNA-145 and miRNA-205 overexpression. The miRNA-145 and miRNA-205 could decrease the expression level of cell division control protein 42 (CDC42). After database searching and sequence alignment, we identified that Neuropilin 1 (NRP1) had binding sites for both miRNA-145 and miRNA-205. CONCLUSION The miRNA-145 and miRNA-205 can reduce the proliferation, migration and invasion of UM cells by targeting the mRNA of its upstream protein NRP1 to down-regulate the expression level of CDC42.
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Affiliation(s)
- Yang Li
- Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Jing-Ting Luo
- Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Yue-Ming Liu
- Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Wen-Bin Wei
- Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
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36
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Morishita A, Fujita K, Iwama H, Chiyo T, Fujihara S, Oura K, Tadokoro T, Mimura S, Nomura T, Tani J, Yoneyama H, Kobayashi K, Kamada H, Guan Y, Nishiyama A, Okano K, Suzuki Y, Himoto T, Shimotohno K, Masaki T. Role of microRNA-210-3p in hepatitis B virus-related hepatocellular carcinoma. Am J Physiol Gastrointest Liver Physiol 2020; 318:G401-G409. [PMID: 31905024 DOI: 10.1152/ajpgi.00269.2019] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatitis B virus (HBV)-related hepatocarcinogenesis is not necessarily associated with the liver fibrotic stage and is occasionally seen at early fibrotic stages. MicroRNAs (miRNAs) are essentially 18- to 22-nucleotide-long endogenous noncoding RNAs. Aberrant miRNA expression is a common feature of various human cancers. The aberrant expression of specific miRNAs has been shown in hepatocellular carcinoma (HCC) tissue compared with nontumor tissue. Thus, we examined targetable miRNAs as a potential new biomarker related to the high risk of HBV-related hepatocarcinogenesis, toward the prevention of cancer-related deaths. HCC tissue samples from 29 patients who underwent hepatectomy at our hospital in 2002-2013 were obtained. We extracted the total RNA and analyzed it by microRNA array, real-time RT-PCR, and three comparisons: 1) HBV-related HCC and adjacent nontumor tissue, 2) HCV-related HCC and adjacent nontumor tissue, and 3) non-HBV-, non-HCV-related HCC and adjacent nontumor tissue. We also performed a functional analysis of miRNAs specific for HBV-related HCC by using HBV-positive HCC cell lines. MiR-210-3p expression was significantly increased only in the HBV-related HCC tissue samples. MiR-210-3p expression was upregulated, and the levels of its target genes were reduced in the HBV-positive HCC cells. The inhibition of miR-210-3p enhanced its target gene expression in the HBV-positive HCC cells. In addition, miR-210-3p regulated the HBx expression in HBV-infected Huh7/NTCP cells. The enhanced expression of miR-210-3p was detected specifically in HBV-related HCC and regulated various target genes, including HBx in the HBV-positive HCC cells. MiR-210-3p might, thus, be a new biomarker for the risk of HBV-related HCC.NEW & NOTEWORTHY Our present study demonstrated that miR-210-3p is the only microRNA with enhanced expression in HBV-related HCC, and the enhanced expression of miR-210-3p upregulates HBx expression. Therefore, miR-210-3p might be a pivotal biomarker of HBV-related hepatocarcinogenesis, and the inhibition of miR-210-3p could prevent inducing hepatocarcinogenesis related to HBV infection.
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Affiliation(s)
- Asahiro Morishita
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Hisakazu Iwama
- Life Science Research Center, Kagawa University, Kagawa, Japan
| | - Taiga Chiyo
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Shintaro Fujihara
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Shima Mimura
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Takako Nomura
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Kiyoyuki Kobayashi
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Hideki Kamada
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Yu Guan
- Department of Pharmacology, Kagawa University, Kagawa, Japan
| | - Akira Nishiyama
- Department of Pharmacology, Kagawa University, Kagawa, Japan
| | - Keiichi Okano
- Department of Gastroenterological Surgery, Kagawa University, Kagawa, Japan
| | - Yasuyuki Suzuki
- Department of Gastroenterological Surgery, Kagawa University, Kagawa, Japan
| | - Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Takamatsu, Kagawa, Japan
| | - Kunitada Shimotohno
- Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
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Dong W, Wu P, Zhou D, Huang J, Qin M, Yang X, Wan M, Zong Y. Ultrasound-Mediated Gene Therapy of Hepatocellular Carcinoma Using Pre-microRNA Plasmid-Loaded Nanodroplets. ULTRASOUND IN MEDICINE & BIOLOGY 2020; 46:90-107. [PMID: 31668943 DOI: 10.1016/j.ultrasmedbio.2019.09.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 09/19/2019] [Accepted: 09/20/2019] [Indexed: 05/19/2023]
Abstract
The PIK3 CA gene encodes the p110α protein subunit and is one of the most efficient cancer genes in solid and hematological tumors including hepatocellular carcinoma (HCC). There are currently ongoing therapies against tumors based on PIK3 CA inhibition. Because microRNAs (miRNAs) play an important role in post-transcriptional regulation and are also involved in the inhibition of PIK3 CA expression to suppress cancer cell proliferation, overexpression of tumor-suppressive miRNA is a promising therapeutic approach for HCC therapy. The successful and localized delivery of miRNA overexpression vectors (pre-miRNA plasmids) is very important in improving the therapeutic efficacy of this miRNA therapy strategy. In the study described here, submicron acoustic phase-shifted nanodroplets were used to efficiently deliver pre-miRNA plasmid in vitro and in vivo for HCC therapy under focused ultrasound (US) activation. Briefly, six miRNAs, inhibiting PIK3 CA and downregulated in HCC, were selected through summary and analysis of the currently existing literature data. Quantitative real-time polymerase chain reaction (qRT-PCR), Western blot and cell apoptosis assay revealed that pre-miR-139, -203a, -378a and -422a plasmids among the six miRNA overexpression vectors could suppress growth of the hepatoma cell line SMMC-7721. These four pre-miRNA plasmids were then electrostatically adhered to positively charged lipid-shelled nanodroplets to obtain plasmid-loaded nanodroplets (PLNDs). The PLND-generated microbubbles oscillated and even collapsed under US exposure to release the loaded pre-miRNA plasmids and enhance their cellular uptake through consequent sonoporation, that is, formation of small pores on the cell membrane induced by the mechanical effects of PLND cavitation. Fluorescence microscopy results revealed that PLNDs could effectively deliver the aforementioned four pre-miRNA plasmids into SMMC-7721 cells in vitro under 1.2-MHz 60-cycle sinusoid US exposure with a peak negative pressure >5.5 MPa at a 40-Hz pulse repetition frequency. Plasmid delivery efficiency and cell viability positively correlated with the inertial cavitation dose that was determined mainly by peak negative pressure. Furthermore, PLNDs combined with US were evaluated in vivo to deliver these four pre-miRNAs plasmids and verify their therapeutic efficacy in subcutaneous tumor of the mouse xenograft HCC model. The results revealed that the PLNDs loaded with pre-miR-139 and -378a plasmids could effectively suppress tumor growth after US treatment. Thus, combination of pre-miRNA PLNDs with US activation seems to constitute a potential strategy for HCC therapy.
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Affiliation(s)
- Wei Dong
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Department of Biomedical Engineering, School of Life Science and Technology, Xi' an Jiaotong University, Xi' an, China
| | - Pengying Wu
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Department of Biomedical Engineering, School of Life Science and Technology, Xi' an Jiaotong University, Xi' an, China
| | - Di Zhou
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Department of Biomedical Engineering, School of Life Science and Technology, Xi' an Jiaotong University, Xi' an, China
| | - Jixiu Huang
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Department of Biomedical Engineering, School of Life Science and Technology, Xi' an Jiaotong University, Xi' an, China
| | - Mengfan Qin
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Department of Biomedical Engineering, School of Life Science and Technology, Xi' an Jiaotong University, Xi' an, China
| | - Xinxing Yang
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Department of Biomedical Engineering, School of Life Science and Technology, Xi' an Jiaotong University, Xi' an, China; Department of Ultrasound, First Affiliated Hospital of AFMU (Xijing Hospital), Air Force Medical University, Xi' an, China
| | - Mingxi Wan
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Department of Biomedical Engineering, School of Life Science and Technology, Xi' an Jiaotong University, Xi' an, China
| | - Yujin Zong
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Department of Biomedical Engineering, School of Life Science and Technology, Xi' an Jiaotong University, Xi' an, China.
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Vyas HS, Upadhyay KK, Devkar RV. miRNAs Signatures In Patients With Acute Liver Injury: Clinical Concerns and Correlations. Curr Mol Med 2019; 20:325-335. [PMID: 31823701 DOI: 10.2174/1566524020666191211153546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 11/25/2019] [Accepted: 11/27/2019] [Indexed: 11/22/2022]
Abstract
Non-coding RNAs can be highly exploited for their biological significance in living systems. miRNAs are in the upstream position of cellular regulation cascade and hold merit in its state. A plethora of information is available on a wide variety of miRNAs that undergo alterations in experimentally induced models of liver injuries. The underlying mechanisms governed by these miRNAs have been inferred through cellbased experiments but the scientific knowledge on miRNA signatures in patients with liver injury are primordial and lack scientific clarity. Hence, it is crucial to get insight into the status and synergy of miRNAs in patients, with varying degrees of acute toxic manifestations in the liver. Though some miRNAs are being investigated in clinical trials, a major research lacuna exists with regard to the functional role of other miRNAs in liver diseases. This review article is a meticulous compilation of disease based or drug/alcohol based acute liver injuries in patients and resultant alteration in their miRNA profile. Investigative reports on underlying miRNA-liver crosstalk in cell-based or murine models are also discussed herein to draw a correlation with clinical findings.
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Affiliation(s)
- Hitarthi S Vyas
- Division of Metabolic Endocrinology, Department of Zoology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat 390002, India
| | - Kapil K Upadhyay
- Division of Metabolic Endocrinology, Department of Zoology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat 390002, India
| | - Ranjitsinh V Devkar
- Division of Metabolic Endocrinology, Department of Zoology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat 390002, India
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Nasser MZ, Zayed NA, Mohamed AM, Attia D, Esmat G, Khairy A. Circulating microRNAs (miR-21, miR-223, miR-885-5p) along the clinical spectrum of HCV-related chronic liver disease in Egyptian patients. Arab J Gastroenterol 2019; 20:198-204. [PMID: 31806407 DOI: 10.1016/j.ajg.2019.11.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 11/23/2019] [Accepted: 11/24/2019] [Indexed: 12/27/2022]
Abstract
BACKGROUND AND STUDY AIMS MicroRNAs (miRNAs), small single stranded RNAs, function in the post-transcriptional regulation of gene expression and incorporated in pathogenesis of HCV related chronic liver disease. This study was designed to evaluate the significance of serum miR-21, miR-223, and miR-885-5p as biomarkers in various clinicopathological stages of HCV related chronic liver disease. PATIENTS AND METHODS Serum miR-21, miR-223, and miR-885-5p were quantified by quantitative RT PCR in 60 patients with HCV-related liver disease (presumably genotype 4), in addition to 25 healthy controls. HCV patients were classified into: chronic non-cirrhotic HCV (n = 15), HCV related liver cirrhosis (n = 15), and hepatocellular carcinoma (HCC) (n = 30). RESULTS Serum levels of miR-885-5p in cirrhotic patients ± HCC (n = 45) were significantly higher than the non-cirrhotic patients (n = 15); p = 0.007 and healthy control; p = 0.001. However, no such significance was detected between HCC and non-HCC HCV patients; p = 0.12. Serum miRNA-885-5p was able to discriminate cirrhosis ± HCC from healthy controls using ROC analysis; AUC 0.85, 87% sensitivity and 80% specificity. On the other hand, HCC patients had significantly higher serum miR-2 1evels than non-HCC patients (non-cirrhotic and cirrhotic groups, n = 30); p = 0.048 and the control group; p = 0.002. ROC could differentiate HCC from control group; AUC 0.89, 80% sensitivity, 80% specificity. Both serum bilirubin and albumin showed significant weak correlation with miRNA-885-5p (r = 0.42, p = 0.001) and (r = -0.27, p = 0.04), respectively but no such correlation was observed with serum miRNA-21. In contrast, miRNA-223 showed no significant difference across the studied groups. CONCLUSION Along the spectrum of HCV-related chronic liver disease, miR-885-5p could be a potential marker for advanced liver damage while miR-21 could be a helpful diagnostic marker for HCC.
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Affiliation(s)
- Mona Zaky Nasser
- Clinical Pathology Department, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Naglaa Ali Zayed
- Endemic Medicine and Hepatology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | | | - Dina Attia
- Department of Gastroenterology, Hepatology and Endemic Medicine, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Gamal Esmat
- Endemic Medicine and Hepatology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Ahmed Khairy
- Endemic Medicine and Hepatology Department, Faculty of Medicine, Cairo University, Cairo, Egypt.
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He QL, Qin SY, Tao L, Ning HJ, Jiang HX. Prognostic value and prospective molecular mechanism of miR-100-5p in hepatocellular carcinoma: A comprehensive study based on 1,258 samples. Oncol Lett 2019; 18:6126-6142. [PMID: 31788087 PMCID: PMC6865135 DOI: 10.3892/ol.2019.10962] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 09/06/2019] [Indexed: 02/07/2023] Open
Abstract
The prognostic value and molecular mechanism of microRNA-100-5p (miR-100-5p) in hepatocellular carcinoma (HCC) are still unclear. To explore the prognostic value and the mechanism of miR-100-5p in HCC, the present study analyzed the results of 18 previous studies and bioinformatic datasets. The clinical significance of miR-100-5p and its targets in HCC were investigated using The Cancer Genome Atlas and the Gene Expression Omnibus, as well as relevant literature. In total, 12 online tools were used to predict the target genes of miR-100-5p. Bioinformatics analysis and Spearman correlation analysis were performed, and genomic alterations of the hub genes were evaluated. A meta-analysis with 1,258 samples revealed that miR-100-5p was significantly downregulated in HCC [standard mean difference (SMD), -0.94; 95% confidence interval (CI), -1.14 to -0.74; I2, 35.2%]. Lower miR-100-5p expression was associated with poorer clinical characteristics and a poorer prognosis for patients with HCC. Additionally, bioinformatics analysis revealed that the 'regulation of transcription', 'chromatin remodeling complex', 'transcription regulator activity', 'pathways in cancer' and 'heparan sulfate biosynthesis' were the most enriched terms. Furthermore, expression of histone deacetylase (HDAC)2, HDAC3, SHC-transforming protein 1 (SHC1), Ras-related protein Rac1 (RAC1) and E3 ubiquitin-protein ligase CBL (CBL) was negatively correlated with miR-100-5p expression. Among these, upregulated HDAC2 [hazard ratio (HR), 1.910; 95% CI, 1.309-2.787; P=0.0007], HDAC3 (HR, 1.474; 95% CI, 1.012-2.146; P=0.0435), SHC1 (HR, 1.52; 95% CI, 1.043-2.215; P=0.0281) and RAC1 (HR, 1.817; 95% CI, 1.248-2.645; P=0.0022) were associated with shorter survival. Alterations in HDAC2, SHC1, RAC1 and IGF1R were linked with a poorer outcome for HCC, and alternative splicing of SHC and RAC1 were significantly decreased and increased in HCC, respectively. In summary, the downregulation of miR-100-5p may be involved in the progression and prognosis of HCC. The upregulation of HDAC2, HDAC3, SHC1 and RAC1 may indicate a poorer survival rate for patients with HCC. Thus, miR-100-5p and these 4 potential target genes may provide novel therapeutic targets and prognostic predictors for patients with HCC.
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Affiliation(s)
- Qing-Lin He
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Shan-Yu Qin
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Lin Tao
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Hong-Jian Ning
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Hai-Xing Jiang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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Ranjpour M, Wajid S, Jain SK. Elevated Expression of A-Raf and FA2H in Hepatocellular Carcinoma is Associated with Lipid Metabolism Dysregulation and Cancer Progression. Anticancer Agents Med Chem 2019; 19:236-247. [PMID: 30324893 DOI: 10.2174/1871520618666181015142810] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 05/08/2018] [Accepted: 09/25/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Identification of events leading to hepatocellular carcinoma (HCC) progression is essential for understanding its pathophysiology. The aims of this study are to identify and characterize differentially expressed proteins in serum of HCC-bearing rats and the corresponding controls during cancer initiation, progression and tumorigenesis. METHODS Chemical carcinogens, N-Nitrosodiethylamine and 2-aminoacetylfluorine are administered to induce HCC to male Wistar rats. The 2D-Electrophoresis and PD-Quest analyses are performed to identify several differentially expressed proteins in serum of HCC-bearing animals. These proteins are further characterized by MALDI-TOF-MS/MS analyses. Using pathwaylinker a HCC-specific network is analyzed among the MALDITOF- MS/MS characterized proteins and their interactors. RESULTS Carcinogen administration caused inflammation leading to liver injury and HCC development. Liver inflammation was confirmed by increase in the levels of TNF-α and IL-6 in carcinogen treated rats. We report significant increase in expression of two differentially expressed proteins, namely, A-Raf and Fatty Acid 2- Hydroxylase (FA2H), at early stage of HCC initiation, during its progression and at tumor stage. Real-time PCR analysis of mRNA for these proteins confirmed up-regulation of their transcripts. Further, we validated our experimental data with sera of clinically confirmed liver cancer patients. CONCLUSION The study suggests that FA2H and A-Raf play a major role in the progression of HCC.
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Affiliation(s)
- Maryam Ranjpour
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi 110062, India
| | - Saima Wajid
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi 110062, India
| | - Swatantra K Jain
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi 110062, India.,Department of Medical Biochemistry, HIMSR, Jamia Hamdard, New Delhi 110062, India
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Klieser E, Mayr C, Kiesslich T, Wissniowski T, Fazio PD, Neureiter D, Ocker M. The Crosstalk of miRNA and Oxidative Stress in the Liver: From Physiology to Pathology and Clinical Implications. Int J Mol Sci 2019; 20:5266. [PMID: 31652839 PMCID: PMC6862076 DOI: 10.3390/ijms20215266] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 10/14/2019] [Accepted: 10/21/2019] [Indexed: 02/07/2023] Open
Abstract
The liver is the central metabolic organ of mammals. In humans, most diseases of the liver are primarily caused by an unhealthy lifestyle-high fat diet, drug and alcohol consumption- or due to infections and exposure to toxic substances like aflatoxin or other environmental factors. All these noxae cause changes in the metabolism of functional cells in the liver. In this literature review we focus on the changes at the miRNA level, the formation and impact of reactive oxygen species and the crosstalk between those factors. Both, miRNAs and oxidative stress are involved in the multifactorial development and progression of acute and chronic liver diseases, as well as in viral hepatitis and carcinogenesis, by influencing numerous signaling and metabolic pathways. Furthermore, expression patterns of miRNAs and antioxidants can be used for biomonitoring the course of disease and show potential to serve as possible therapeutic targets.
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Affiliation(s)
- Eckhard Klieser
- Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Cancer Cluster Salzburg, 5020 Salzburg, Austria.
| | - Christian Mayr
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Institute of Physiology and Pathophysiology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
| | - Tobias Kiesslich
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Institute of Physiology and Pathophysiology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
| | - Till Wissniowski
- Department of Gastroenterology and Endocrinology, Philipps University Marburg, 35043 Marburg, Germany.
| | - Pietro Di Fazio
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, 35043 Marburg, Germany.
| | - Daniel Neureiter
- Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Cancer Cluster Salzburg, 5020 Salzburg, Austria.
| | - Matthias Ocker
- Translational Medicine Oncology, Bayer AG, 13353 Berlin, Germany.
- Department of Gastroenterology CBF, Charité University Medicine Berlin, 12200 Berlin, Germany.
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Peng J, Chen XL, Cheng HZ, Xu ZY, Wang H, Shi ZZ, Liu J, Ning XG, Peng H. Silencing of KCNK15-AS1 inhibits lung cancer cell proliferation via upregulation of miR-202 and miR-370. Oncol Lett 2019; 18:5968-5976. [PMID: 31788071 PMCID: PMC6865154 DOI: 10.3892/ol.2019.10944] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Accepted: 08/01/2019] [Indexed: 02/07/2023] Open
Abstract
Lung cancer is the most common cause of cancer-associated mortality globally. Long non-coding RNAs (lncRNAs) are transcripts with a length of >200 nucleotides, which are not translated into proteins. Growing evidence has indicated that certain lncRNAs are associated with various biological processes in cancer. However, the functions of KCNK15 and WISP2 antisense RNA 1 (KCNK15-AS1) in lung cancer carcinogenesis and progression have remained elusive. The present study indicated that KCNK15-AS1 was overexpressed in lung adenocarcinoma tissues compared with paracancerous normal tissues, and the high expression of KCNK15-AS1 was significantly associated with poor prognosis compared with the patients with low expression (P<0.001). Furthermore, the knockdown of KCNK15-AS1 was performed in A549 and H460 lung cancer cells with small interfering RNA, resulting in a significant inhibition of the proliferation, a decrease in the mRNA and protein expression of cyclin D1 (CCND1) and epidermal growth factor receptor (EGFR), in addition to the phosphorylation of protein kinase B, with a concomitant increase in the expression of microRNA (miR)-202 and miR-370 compared with negative control group. Rescue experiments demonstrated that the inhibition of miR-202 or miR-370 partially recovered the EGFR and CCND1 expression and the proliferation rates, which were reduced by KCNK15-AS1 silencing. In conclusion, these results suggested that KCNK15-AS1 functions as an oncogene via regulating the miR-202/miR-370/EGFR axis in lung cancer and may provide a potential target for lung cancer treatment.
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Affiliation(s)
- Jun Peng
- Department of Thoracic Surgery, The First People's Hospital of Yunnan Province, Kunming, Yunnan 650032, P.R. China
| | - Xin-Long Chen
- Department of Thoracic Surgery, The First People's Hospital of Yunnan Province, Kunming, Yunnan 650032, P.R. China
| | - Hong-Zhong Cheng
- Department of Thoracic Surgery, The First People's Hospital of Yunnan Province, Kunming, Yunnan 650032, P.R. China
| | - Zhe-Yuan Xu
- Department of Thoracic Surgery, The First People's Hospital of Yunnan Province, Kunming, Yunnan 650032, P.R. China
| | - Han Wang
- Department of Thoracic Surgery, The First People's Hospital of Yunnan Province, Kunming, Yunnan 650032, P.R. China
| | - Zhi-Zhou Shi
- Faculty of Medicine, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China
| | - Jun Liu
- Department of Thoracic Surgery, The First People's Hospital of Yunnan Province, Kunming, Yunnan 650032, P.R. China
| | - Xian-Gu Ning
- Department of Thoracic Surgery, The First People's Hospital of Yunnan Province, Kunming, Yunnan 650032, P.R. China
| | - Hao Peng
- Department of Thoracic Surgery, The First People's Hospital of Yunnan Province, Kunming, Yunnan 650032, P.R. China
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Han J, Li J, Qian Y, Liu W, Liang J, Huang Z, Wang S, Zhao C. Identification of plasma miR-148a as a noninvasive biomarker for hepatocellular carcinoma. Clin Res Hepatol Gastroenterol 2019; 43:585-593. [PMID: 30824368 DOI: 10.1016/j.clinre.2018.12.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 12/12/2018] [Accepted: 12/19/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND The detection of microRNA (miRNA) markers in plasma is a potential strategy for hepatocellular carcinoma (HCC) screening. The aim of this study was to characterize miR-148a in the peripheral plasma as a non-invasive biomarker for the diagnosis of HCC. METHODS AND METHODS Quantification of miR-148a was performed on 346 plasma samples, including 155 patients with HCC, 96 patients with liver cirrhosis and 95 healthy controls using quantitative real-time PCR (qRT-PCR). Plasma miR-148a was compared before and after the removal of the tumor in 97 cases of HCC. Receiver operating characteristic (ROC) curves were generated to analyze predictive value of plasma miR148a in HCC. RESULTS Plasma miR-148a levels were significantly lower in HCC patients compared to those with liver cirrhosis (P < 0.01) or healthy controls (P < 0.01). The area under receiver operating characteristic (AUROC) curve for plasma miR-148a was 0.919, with a sensitivity of 89.6 % and a specificity of 89.0% for HCC patients compared with liver cirrhosis. In HCC patients with negative or low AFP, AUROC values for plasma miR-148a were 0.949, with a sensitivity of 90.6% and a specificity of 92.6%. The removal of primary HCC tumor led to increased plasma miR-148a levels (P < 0.0001), indicating that miR-148a is a HCC-specific biomarker. CONCLUSION Plasma miR-148a is a potential non-invasive biomarker for HCC screening, especially for those with negative or low AFP. Detection of miR-148a might be a complementary approach to AFP for predicting HCC occurrence.
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Affiliation(s)
- Juqiang Han
- Department of Liver Disease, PLA Army General Hospital, Beijing city, Beijing, PR China
| | - Jiarui Li
- Department of Interventional Radiography, The First Hospital of Jilin University, Changchun city, Jilin Province, PR China
| | - Yun Qian
- Department of Digestive Disease, Shenzhen University General Hospital, Shenzhen city, Guangdong Province, PR China
| | - Wenpeng Liu
- Department of Infectious disease, The Third Hospital of Hebei Medical University, Shijiazhuang city, Hebei Province, PR China
| | - Jiguang Liang
- Department of Interventional Radiography, The First Hospital of Jilin University, Changchun city, Jilin Province, PR China
| | - Zhigang Huang
- Department of Epidemiology, Guangdong Medical University, Dongguan city, Guangdong Province, PR China
| | - Shuai Wang
- Department of Liver Disease, PLA Army General Hospital, Beijing city, Beijing, PR China
| | - Caiyan Zhao
- Department of Infectious disease, The Third Hospital of Hebei Medical University, Shijiazhuang city, Hebei Province, PR China.
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Horii R, Honda M, Shirasaki T, Shimakami T, Shimizu R, Yamanaka S, Murai K, Kawaguchi K, Arai K, Yamashita T, Sakai Y, Yamashita T, Okada H, Nakamura M, Mizukoshi E, Kaneko S. MicroRNA-10a Impairs Liver Metabolism in Hepatitis C Virus-Related Cirrhosis Through Deregulation of the Circadian Clock Gene Brain and Muscle Aryl Hydrocarbon Receptor Nuclear Translocator-Like 1. Hepatol Commun 2019; 3:1687-1703. [PMID: 31832575 PMCID: PMC6887665 DOI: 10.1002/hep4.1431] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 09/04/2019] [Indexed: 12/13/2022] Open
Abstract
The circadian rhythm of the liver plays an important role in maintaining its metabolic homeostasis. We performed comprehensive expression analysis of microRNAs (miRNAs) using TaqMan polymerase chain reaction of liver biopsy tissues to identify the miRNAs that are significantly up‐regulated in advanced chronic hepatitis C (CHC). We found miR‐10a regulated various liver metabolism genes and was markedly up‐regulated by hepatitis C virus infection and poor nutritional conditions. The expression of miR‐10a was rhythmic and down‐regulated the expression of the circadian rhythm gene brain and muscle aryl hydrocarbon receptor nuclear translocator‐like 1 (Bmal1) by directly suppressing the expression of RA receptor‐related orphan receptor alpha (RORA). Overexpression of miR‐10a in hepatocytes blunted circadian rhythm of Bmal1 and inhibited the expression of lipid synthesis genes (sterol regulatory element binding protein [SREBP]1, fatty acid synthase [FASN], and SREBP2), gluconeogenesis (peroxisome proliferator‐activated receptor gamma coactivator 1 alpha [PGC1α]), protein synthesis (mammalian target of rapamycin [mTOR] and ribosomal protein S6 kinase [S6K]) and bile acid synthesis (liver receptor homolog 1 [LRH1]). The expression of Bmal1 was significantly correlated with the expression of mitochondrial biogenesis‐related genes and reduced Bmal1 was associated with increased serum alanine aminotransferase levels and progression of liver fibrosis in CHC. Thus, impaired circadian rhythm expression of Bmal1 by miR‐10a disturbs metabolic adaptations, leading to liver damage, and is closely associated with the exacerbation of abnormal liver metabolism in patients with advanced CHC. In patients with hepatitis C‐related liver cirrhosis, liver tissue miR‐10a levels were significantly associated with hepatic reserve, fibrosis markers, esophageal varix complications, and hepatitis C‐related hepatocellular carcinoma recurrence. Conclusion: MiRNA‐10a is involved in abnormal liver metabolism in cirrhotic liver through down‐regulation of the expression of the circadian rhythm gene Bmal1. Therefore, miR‐10a is a possible useful biomarker for estimating the prognosis of liver cirrhosis.
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Affiliation(s)
- Rika Horii
- Department of Gastroenterology Kanazawa University Graduate School of Medicine Kanazawa Japan
| | - Masao Honda
- Department of Gastroenterology Kanazawa University Graduate School of Medicine Kanazawa Japan.,Department of Laboratory Medicine Kanazawa University Graduate School of Health Medicine Kanazawa Japan
| | - Takayoshi Shirasaki
- Department of Laboratory Medicine Kanazawa University Graduate School of Health Medicine Kanazawa Japan
| | - Tetsuro Shimakami
- Department of Gastroenterology Kanazawa University Graduate School of Medicine Kanazawa Japan
| | - Ryogo Shimizu
- Department of Laboratory Medicine Kanazawa University Graduate School of Health Medicine Kanazawa Japan
| | - Souma Yamanaka
- Department of Laboratory Medicine Kanazawa University Graduate School of Health Medicine Kanazawa Japan
| | - Kazuhisa Murai
- Department of Laboratory Medicine Kanazawa University Graduate School of Health Medicine Kanazawa Japan
| | - Kazunori Kawaguchi
- Department of Gastroenterology Kanazawa University Graduate School of Medicine Kanazawa Japan
| | - Kuniaki Arai
- Department of Gastroenterology Kanazawa University Graduate School of Medicine Kanazawa Japan
| | - Tatsuya Yamashita
- Department of Gastroenterology Kanazawa University Graduate School of Medicine Kanazawa Japan
| | - Yoshio Sakai
- Department of Gastroenterology Kanazawa University Graduate School of Medicine Kanazawa Japan
| | - Taro Yamashita
- Department of Gastroenterology Kanazawa University Graduate School of Medicine Kanazawa Japan
| | - Hikari Okada
- Department of Gastroenterology Kanazawa University Graduate School of Medicine Kanazawa Japan
| | - Mikiko Nakamura
- Department of Gastroenterology Kanazawa University Graduate School of Medicine Kanazawa Japan
| | - Eishiro Mizukoshi
- Department of Gastroenterology Kanazawa University Graduate School of Medicine Kanazawa Japan
| | - Shuichi Kaneko
- Department of Gastroenterology Kanazawa University Graduate School of Medicine Kanazawa Japan
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Manvati S, Mangalhara KC, Kalaiarasan P, Chopra R, Agarwal G, Kumar R, Saini SK, Kaushik M, Arora A, Kumari U, Bamezai RNK, Dhar PK. miR-145 supports cancer cell survival and shows association with DDR genes, methylation pattern, and epithelial to mesenchymal transition. Cancer Cell Int 2019; 19:230. [PMID: 31516387 PMCID: PMC6731614 DOI: 10.1186/s12935-019-0933-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Accepted: 08/18/2019] [Indexed: 12/12/2022] Open
Abstract
Background Despite several reports describing the dual role of miR-145 as an oncogene and a tumor suppressor in cancer, not much has been resolved and understood. Method In this study, the potential targets of miR-145 were identified bio-informatically using different target prediction tools. The identified target genes were validated in vitro by dual luciferase assay. Wound healing and soft agar colony assay assessed cell proliferation and migration. miR-145 expression level was measured quantitatively by RT-PCR at different stages of breast tumor. Western blot was used to verify the role of miR-145 in EMT transition using key marker proteins. Result Wound healing and soft agar colony assays, using miR-145 over-expressing stably transfected MCF7 cells, unraveled its role as a pro-proliferation candidate in cancerous cells. The association between miR-145 over-expression and differential methylation patterns in representative target genes (DR5, BCL2, TP53, RNF8, TIP60, CHK2, and DCR2) supported the inference drawn. These in vitro observations were validated in a representative set of nodal positive tumors of stage 3 and 4 depicting higher miR-145 expression as compared to early stages. Further, the role of miR-145 in epithelial-mesenchymal (EMT) transition found support through the observation of two key markers, Vimentin and ALDL, where a positive correlation with Vimentin protein and a negative correlation with ALDL mRNA expression were observed. Conclusion Our results demonstrate miR-145 as a pro-cancerous candidate, evident from the phenotypes of aggressive cellular proliferation, epithelial to mesenchymal transition, hypermethylation of CpG sites in DDR and apoptotic genes and upregulation of miR-145 in later stages of tumor tissues.
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Affiliation(s)
- Siddharth Manvati
- 1School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
| | - Kailash Chandra Mangalhara
- 2National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
| | | | - Rupali Chopra
- 2National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Gaurav Agarwal
- 3Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Rakesh Kumar
- 4School of Biotechnology, Shri Mata Vaishno Devi University, Kakryal, Katra, Jammu and Kashmir India
| | - Sunil Kumar Saini
- 1School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
| | - Monika Kaushik
- 1School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
| | - Ankita Arora
- 1School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
| | - Usha Kumari
- 5Faculty of Medicine, AIMST University, Bedong, Malaysia
| | - Rameshwar Nath Koul Bamezai
- 2National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Pawan Kumar Dhar
- 1School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
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Ye Y, Zhang L, Song Y, Zhuang J, Wang G, Ni J, Zhang S, Xia W. MicroRNA‑373 exerts anti‑tumor functions in human liver cancer by targeting Rab22a. Mol Med Rep 2019; 20:3874-3882. [PMID: 31485646 DOI: 10.3892/mmr.2019.10600] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 10/12/2018] [Indexed: 11/06/2022] Open
Abstract
Liver cancer is a one of the most frequent types of tumor worldwide. It has long been recognized that microRNAs are important participants in the progression of various types of cancer. The present study explored the role of microRNA‑373 (miR‑373) in liver cancer development. Reverse transcription‑quantitative polymerase chain reaction was performed to evaluate the transcription level of miR‑373 in 96 liver cancer tissues and adjacent normal liver tissues. The association of miR‑373 with clinicopathological characteristics was analyzed using the χ2 test. Kaplan‑Meier univariate analysis and multivariate hazard analysis were performed to identify the clinical potential of miR‑373 in the prognosis of liver cancer patients. Transfection of miR‑373 mimics into Hep3B and HepG2 liver cancer cell lines was conducted to reveal the underlying mechanism in regulating liver cancer progression. The functional assays included proliferation, migration, invasion and luciferase assays. The findings of the present study demonstrated that miR‑373 transcription level was markedly downregulated in liver cancer tissues compared with the adjacent normal tissues and was associated with the clinical prognosis of liver cancer patients. Overexpressing miR‑373 mimics in liver cancer cell lines decreased cell proliferation and invasion, suggesting that miR‑373 exerts anti‑tumor effects in liver cancer. In addition, data from the present study demonstrated the direct effect of miR373 on inhibiting the expression and signaling of Ras‑related protein Rab22a, a well‑known oncoprotein. Taken together, the results from the present study suggested that miR‑373 suppresses liver cancer progression and may serve as a promising prognosis prediction biomarker.
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Affiliation(s)
- Ying Ye
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200000, P.R. China
| | - Lijun Zhang
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200000, P.R. China
| | - Yanan Song
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200000, P.R. China
| | - Juhua Zhuang
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200000, P.R. China
| | - Guoyu Wang
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200000, P.R. China
| | - Jing Ni
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200000, P.R. China
| | - Suiliang Zhang
- Department of Oncology, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200000, P.R. China
| | - Wei Xia
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200000, P.R. China
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Wang X, Zhou X, Liu J, Liu Z, Zhang L, Gong Y, Huang J, Yu L, Wang Q, Yang C, Liao X, Yu T, Han C, Zhu G, Ye X, Peng T. Genome‑wide investigation of the clinical implications and molecular mechanism of long noncoding RNA LINC00668 and protein‑coding genes in hepatocellular carcinoma. Int J Oncol 2019; 55:860-878. [PMID: 31432149 PMCID: PMC6741837 DOI: 10.3892/ijo.2019.4858] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 07/31/2019] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of tumor‑related mortalities worldwide. Long noncoding RNAs have been reported to be associated with tumor initiation, progression and prognosis. The present study aimed to explore the association between long noncoding RNA LINC00668 and its co‑expression correlated protein‑coding genes (PCGs) in HCC. Data of 370 HCC patients from The Cancer Genome Atlas database were used for analysis. LINC00668 and its top 10 PCGs were selected to determine their diagnostic and prognostic value. Molecular mechanisms were explored to identify metabolic processes that LINC00668 and its PCGs are involved in. Prognosis‑related clinical factors and PCGs were used to construct a nomogram for predicting prognosis in HCC. A Connectivity Map was constructed to identify candidate target drugs for HCC. The top 10 PCGs identified were: Pyrimidineregic receptor P2Y4 (P2RY4), signal peptidase complex subunit 2 (SPCS2), family with sequence similarity 86 member C1 (FAM86C1), tudor domain containing 5 (TDRD5), ferritin light chain (FTL), stratifin (SFN), nucleolar complex associated 2 homolog (NOC2L), peroxiredoxin 1 (PRDX1), cancer/testis antigen 2 CTAG2 and leucine zipper and CTNNBIP1 domain containing (LZIC). FAM86C1, CTAG2 and SFN had significant diagnostic value for HCC (total area under the curve ≥0.7, P≤0.05); LINC00668, FAM86C1, TDRD5, FTL and SFN were of significant prognostic value for HCC (all P≤0.05). Investigation into the molecular mechanism indicated that LINC00668 affects cell division, cell cycle, mitotic nuclear division, and drug metabolism cytochrome P450 (all P≤0.05). The Connectivity Map identified seven candidate target drugs for the treatment of HCC, which were: Indolylheptylamine, mimosine, disopyramide, lidocaine, NU‑1025, bumetanide, and DQNLAOWBTJPFKL‑PKZXCIMASA‑N (all P≤0.05). Our findings indicated that LINC00668 may function as an oncogene and its overexpression indicates poor prognosis of HCC. FAM86C1, CTAG2 and SFN are of diagnostic significance, while FAM86C1, TDRD5, FTL and SFN are of prognostic significance for HCC.
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Affiliation(s)
- Xiangkun Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Xin Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Junqi Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Zhengqian Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Linbo Zhang
- Health Management and Division of Physical Examination, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Yizhen Gong
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Jianlu Huang
- Department of Hepatobiliary Surgery, Third Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530031, P.R. China
| | - Long Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Qiaoqi Wang
- Department of Medical Cosmetology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530000, P.R. China
| | - Chengkun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Xiwen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Tingdong Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Chuangye Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Guangzhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Xinping Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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Toh TB, Lim JJ, Chow EKH. Epigenetics of hepatocellular carcinoma. Clin Transl Med 2019; 8:13. [PMID: 31056726 PMCID: PMC6500786 DOI: 10.1186/s40169-019-0230-0] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 04/08/2019] [Indexed: 12/13/2022] Open
Abstract
In recent years, large scale genomics and genome-wide studies using comprehensive genomic tools have reshaped our understanding of cancer evolution and heterogeneity. Hepatocellular carcinoma, being one of the most deadly cancers in the world has been well established as a disease of the genome that harbours a multitude of genetic and epigenetic aberrations during the process of liver carcinogenesis. As such, in depth understanding of the cancer epigenetics in cancer specimens and biopsy can be useful in clinical settings for molecular subclassification, prognosis, and prediction of therapeutic responses. In this review, we present a concise discussion on recent progress in the field of liver cancer epigenetics and some of the current works that contribute to the progress of liver cancer therapeutics.
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Affiliation(s)
- Tan Boon Toh
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, MD6 #12-01, Singapore, 117599, Singapore
| | - Jhin Jieh Lim
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, MD6 #12-01, Singapore, 117599, Singapore
| | - Edward Kai-Hua Chow
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, MD6 #12-01, Singapore, 117599, Singapore. .,Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Drive, Level 5, Singapore, 117597, Singapore.
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50
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Li J, Qiyu S, Wang T, Jin B, Li N. Improving the Detection of Hepatocellular Carcinoma Using Serum AFP Expression in Combination with GPC3 and Micro-RNA MiR-122 Expression. Open Life Sci 2019; 14:53-61. [PMID: 33817137 PMCID: PMC7874791 DOI: 10.1515/biol-2019-0007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 01/14/2019] [Indexed: 12/11/2022] Open
Abstract
Early diagnosis of hepatocellular carcinoma (HCC) greatly improves the survival and prognosisfor patients. In this study weevaluate the diagnostic promise of combining serum alpha-fetoprotein (AFP) expression with two potential biomarkers, serum glypican-3 (GPC3) and expression of the micro-RNA miR-122 for hepatitis C virus (HCV) related early-stage HCC. For this study serum samples from 47 patients with early-stage HCC, 54 chronic HCV (CH) carriers, 35 patients with liver cirrhosis (LC) and 54 health controls (HC) were collected. In addition to routine laboratory investigations, serum AFP, GPC3 and miR-122 were measured in all patients and healthy controls. Receiver operating characteristic (ROC) curves were used to present sensitivity and specificity for the biomarkers. The three markers were all significantly elevated in the serum samples from HCC patients. ROC curves showed the three markers had similar diagnostic capacities for distinguishing early-stage HCC from HCV-positive controls (LC + CH). In order to distinguish early-stage HCC from high-risk LC patients, the expression of miR-122 was superior to GPC3. Combination of the three markers as a panel showed a better diagnostic performance than any of the single markers (P <0.05). Overall, this study revealed that serum expression of GPC3 and miR-122 may be useful biomarkers to combine with serum AFP expression for the diagnosis of HCV related early-stage HCC.
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Affiliation(s)
- Jian Li
- Department of Hepatobiliary Surgery, Hospital Affiliated to Chengde Medical University, 36 Nanyingzi Road, Chengde, 067000, China
| | - Sun Qiyu
- Department of Hepatobiliary Surgery, Hospital Affiliated to Chengde Medical University, 36 Nanyingzi Road, Chengde, 067000, China
| | - Tiezheng Wang
- Department of Hepatobiliary Surgery, YouAn Hospital Affiliated to Capital Medical University, 8 Xitoutiao Road, Fengtai District, Beijing, 100069, China
| | - Boxun Jin
- Department of Hepatobiliary Surgery, YouAn Hospital Affiliated to Capital Medical University, 8 Xitoutiao Road, Fengtai District, Beijing, 100069, China
| | - Ning Li
- Department of Hepatobiliary Surgery, YouAn Hospital Affiliated to Capital Medical University, 8 Xitoutiao Road, Fengtai District, Beijing, 100069, China
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