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1
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Sartorius K, Wang Y, Sartorius B, Antwi SO, Li X, Chuturgoon A, Yu C, Lu Y, Wang Y. The interactive role of microRNA and other non-coding RNA in hepatitis B (HBV) associated fibrogenesis. Funct Integr Genomics 2025; 25:24. [PMID: 39847120 DOI: 10.1007/s10142-024-01519-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/27/2024] [Accepted: 12/27/2024] [Indexed: 01/24/2025]
Abstract
One of the outstanding features of chronic hepatitis B infection (CHB) is its strong association with liver fibrosis. CHB induced inflammation and injury trigger multiple biochemical and physical changes that include the promotion of a wide range of cytokines, chemokines and growth factors that activate hepatic stellate cells (HSCs) CHB induced activation of hepatic stellate cells (HSCs) is regarded as a central event in fibrogenesis to directly promote the synthesis of myofibroblasts and the expression of a range of materials to repair injured liver tissue. Fibrogenesis is modulated by the mainstream epigenetic machinery, as well as by non-coding RNA (ncRNA) that are often referred to as an ancillary epigenetic response to fine tune gene expression. Although extensive research has explained the regulatory role of ncRNA in liver fibrogenesis, most of this research relates to non-CHB etiologies. This review paper outlines the complex interactive regulatory role of microRNA (miRNA) and their interaction with long non-coding RNA (lncRNA), circular RNA (circRNA) and the mainstream epigenetic machinery in CHB induced liver fibrosis. The paper also illustrates some of the difficulties involved in translating candidate ncRNA into approved drugs or diagnostic tools. In conclusion, the important regulatory role of ncRNA in CHB induced liver fibrosis warrants further investigation to exploit their undoubted potential as diagnostic and therapeutic agents.
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Affiliation(s)
- Kurt Sartorius
- Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg, South Africa.
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA.
| | - Yanglong Wang
- Department of General Surgery, Xinyi People's Hospital, Xinyi, Jiangsu, China
| | - Benn Sartorius
- School of Public Health, University of Queensland, Brisbane, Australia
| | - Samuel O Antwi
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA
- Division of Epidemiology Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, AL, USA
| | - Xiaodong Li
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA
| | - Anil Chuturgoon
- School of Laboratory Medicine and Molecular Sciences, UKZN, Durban, South Africa
| | - Chongyuan Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yunjie Lu
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA.
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
| | - Yu Wang
- Department of Hepatobiliary Surgery, Jintan Affiliated Hospital of Jiangsu University, 213200, Changzhou, Jiangsu, China.
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2
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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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3
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Yoo JS, Kang MK. Clinical significance of exosomal noncoding RNAs in hepatocellular carcinoma: a narrative review. JOURNAL OF YEUNGNAM MEDICAL SCIENCE 2024; 42:4. [PMID: 38325815 PMCID: PMC11812098 DOI: 10.12701/jyms.2023.01186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/20/2023] [Accepted: 12/30/2023] [Indexed: 02/09/2024]
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide, with poor prognosis owing to its high frequency of recurrence and metastasis. Moreover, most patients are diagnosed at an advanced stage owing to a lack of early detection markers. Exosomes, which are characterized by their cargos of stable intracellular messengers, such as DNA, RNA, proteins, and lipids, play a crucial role in regulating cell differentiation and HCC development. Recently, exosomal noncoding RNAs (ncRNAs), including microRNAs, long ncRNAs, and circular RNAs, have become increasingly important diagnostic, prognostic, and predictive markers of HCC. Herein, we discuss the clinical implications of exosomal ncRNAs, specifically those within the HCC regulatory network.
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Affiliation(s)
- Jae Sung Yoo
- Department of Gastroenterology and Hepatology, The Catholic University of Korea, Seoul St Mary’s Hospital, Seoul, Korea
| | - Min Kyu Kang
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
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4
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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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5
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Matulić M, Gršković P, Petrović A, Begić V, Harabajsa S, Korać P. miRNA in Molecular Diagnostics. Bioengineering (Basel) 2022; 9:bioengineering9090459. [PMID: 36135005 PMCID: PMC9495386 DOI: 10.3390/bioengineering9090459] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 08/05/2022] [Accepted: 09/07/2022] [Indexed: 11/17/2022] Open
Abstract
MicroRNAs are a class of small non-coding RNA molecules that regulate gene expression on post-transcriptional level. Their biogenesis consists of a complex series of sequential processes, and they regulate expression of many genes involved in all cellular processes. Their function is essential for maintaining the homeostasis of a single cell; therefore, their aberrant expression contributes to development and progression of many diseases, especially malignant tumors and viral infections. Moreover, they can be associated with certain states of a specific disease, obtained in the least invasive manner for patients and analyzed with basic molecular methods used in clinical laboratories. Because of this, they have a promising potential to become very useful biomarkers and potential tools in personalized medicine approaches. In this review, miRNAs biogenesis, significance in cancer and infectious diseases, and current available test and methods for their detection are summarized.
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Affiliation(s)
- Maja Matulić
- Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
| | - Paula Gršković
- Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
| | - Andreja Petrović
- Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
- Institute of Clinical Pathology and Cytology, Merkur University Hospital, 10000 Zagreb, Croatia
| | - Valerija Begić
- Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
- Primary School “Sesvetski Kraljevec”, 10361 Sesvetski Kraljevec, Croatia
| | - Suzana Harabajsa
- Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
- Department of Pathology and Cytology, Division of Pulmonary Cytology Jordanovac, University Hospital Centre Zagreb, 10000 Zagreb, Croatia
| | - Petra Korać
- Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
- Correspondence: ; Tel.: +385-1-4606-278
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6
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Saavedra K, Leal K, Saavedra N, Prado Y, Paez I, Ubilla CG, Rojas G, Salazar LA. MicroRNA-20a-5p Downregulation by Atorvastatin: A Potential Mechanism Involved in Lipid-Lowering Therapy. Int J Mol Sci 2022; 23:ijms23095022. [PMID: 35563413 PMCID: PMC9104095 DOI: 10.3390/ijms23095022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/14/2022] [Accepted: 04/22/2022] [Indexed: 02/05/2023] Open
Abstract
The treatment of hypercholesterolemia is mainly based on statins. However, the response to pharmacological therapy shows high inter-individual variability, resulting in variable effects in both lipid lowering and risk reduction. Thus, a better understanding of the lipid-lowering mechanisms and response variability at the molecular level is required. Previously, we demonstrated a deregulation of the microRNA expression profile in HepG2 cells treated for 24 h with atorvastatin, using a microarray platform. In the present study, we evaluated the expression of hsa-miR-17-5p, hsa-miR-20a-5p and hsa-miR-106a-5p in hypercholesterolemic patients before and after atorvastatin treatment and in HepG2 cells treated for 24 h with atorvastatin The miRNA hsa-mir-20a-5p was repressed after atorvastatin treatment in hypercholesteremic subjects and in HepG2 cells in culture. Repression of hsa-mir-20a-5p increased LDLR gene and protein expression in HepG2 cells, while hsa-mir-20a-5p overexpression reduced LDLR gene and protein expression.
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Affiliation(s)
- Kathleen Saavedra
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile; (K.S.); (K.L.); (N.S.); (Y.P.); (I.P.); (C.G.U.); (G.R.)
- Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile
| | - Karla Leal
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile; (K.S.); (K.L.); (N.S.); (Y.P.); (I.P.); (C.G.U.); (G.R.)
| | - Nicolás Saavedra
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile; (K.S.); (K.L.); (N.S.); (Y.P.); (I.P.); (C.G.U.); (G.R.)
- Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile
| | - Yalena Prado
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile; (K.S.); (K.L.); (N.S.); (Y.P.); (I.P.); (C.G.U.); (G.R.)
| | - Isis Paez
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile; (K.S.); (K.L.); (N.S.); (Y.P.); (I.P.); (C.G.U.); (G.R.)
| | - Carmen G. Ubilla
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile; (K.S.); (K.L.); (N.S.); (Y.P.); (I.P.); (C.G.U.); (G.R.)
| | - Gabriel Rojas
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile; (K.S.); (K.L.); (N.S.); (Y.P.); (I.P.); (C.G.U.); (G.R.)
| | - Luis A. Salazar
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile; (K.S.); (K.L.); (N.S.); (Y.P.); (I.P.); (C.G.U.); (G.R.)
- Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile
- Correspondence:
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7
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Khare S, Khare T, Ramanathan R, Ibdah JA. Hepatocellular Carcinoma: The Role of MicroRNAs. Biomolecules 2022; 12:biom12050645. [PMID: 35625573 PMCID: PMC9138333 DOI: 10.3390/biom12050645] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 04/21/2022] [Accepted: 04/25/2022] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. HCC is diagnosed in its advanced stage when limited treatment options are available. Substantial morphologic, genetic and epigenetic heterogeneity has been reported in HCC, which poses a challenge for the development of a targeted therapy. In this review, we discuss the role and involvement of several microRNAs (miRs) in the heterogeneity and metastasis of hepatocellular carcinoma with a special emphasis on their possible role as a diagnostic and prognostic tool in the risk prediction, early detection, and treatment of hepatocellular carcinoma.
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Affiliation(s)
- Sharad Khare
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA; (S.K.); (T.K.); (R.R.)
- Harry S. Truman Veterans Hospital, Columbia, MO 65201, USA
| | - Tripti Khare
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA; (S.K.); (T.K.); (R.R.)
| | - Raghu Ramanathan
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA; (S.K.); (T.K.); (R.R.)
- Harry S. Truman Veterans Hospital, Columbia, MO 65201, USA
| | - Jamal A. Ibdah
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA; (S.K.); (T.K.); (R.R.)
- Harry S. Truman Veterans Hospital, Columbia, MO 65201, USA
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA
- Correspondence: ; Tel.: 1-573-882-7349; Fax: 1-573-884-4595
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8
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Circulating MicroRNA-21 As A Novel Noninvasive Biomarker for Hepatocellular Carcinoma Compared with Alpha Fetoprotein Gold Test. JOURNAL OF PURE AND APPLIED MICROBIOLOGY 2021. [DOI: 10.22207/jpam.15.4.75] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the greatest traditional kind of pre-eminent cancer worldwide, which happens mainly in chronic liver disease and cirrhotic patients. The available surveillance strategies for suspected HCC patients include serum alpha-fetoprotein (AFP) and liver imaging have been mainly recommended. However, the sensitivity and selectivity of these diagnostic strategies especially in the early stages of HCC have many obstacles. MicroRNAs (miRNAs) are non-coding RNAs that are 18–25 nucleotides in length. Plasma miRNAs may be a promising new biomarker for cancer detection and prognosis in the early stages. Assessment of Plasma MicroRNA-21 (miRNA-21) significance as a noninvasive Hepatocellular carcinoma marker compared with AFP gold standard test to improve HCC early diagnostic power. This is a prospective research project that included 90 patients in total, split into three classes., liver cirrhosis patients (LC) without any malignancies and (HCC) patients in addition to the healthy control group. Patients and controls were subjected to the clinical studies, routine investigations, imaging studies, and detection of plasma miRNA-21 & AFP. miRNA-21 showed a highly significant difference in the 3 studied groups. Control group with LC group, control group with HCC group, and LC group with HCC group P value (P 0.0001, P1 0.0001, P2 0.0001and P3 0.0001) respectively. Also, a highly significant difference was observed between pre-TACE and post-TACE miRNA-21 in the HCC group P value (0.0001). Circulating miRNA-21 may be used as a noninvasive co biomarker with AFP to increase HCC diagnostic accuracy in its early stages.
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9
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Elpek GO. Molecular pathways in viral hepatitis-associated liver carcinogenesis: An update. World J Clin Cases 2021; 9:4890-4917. [PMID: 34307543 PMCID: PMC8283590 DOI: 10.12998/wjcc.v9.i19.4890] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 03/14/2021] [Accepted: 05/26/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of cancer among primary malignant tumors of the liver and is a consequential cause of cancer-related deaths worldwide. In recent years, uncovering the molecular mechanisms involved in the development and behavior of this tumor has led to the identification of multiple potential treatment targets. Despite the vast amount of data on this topic, HCC remains a challenging tumor to treat due to its aggressive behavior and complex molecular profile. Therefore, the number of studies aiming to elucidate the mechanisms involved in both carcinogenesis and tumor progression in HCC continues to increase. In this context, the close association of HCC with viral hepatitis has led to numerous studies focusing on the direct or indirect involvement of viruses in the mechanisms contributing to tumor development and behavior. In line with these efforts, this review was undertaken to highlight the current understanding of the molecular mechanisms by which hepatitis B virus (HBV) and hepatitis C virus (HCV) participate in oncogenesis and tumor progression in HCC and summarize new findings. Cumulative evidence indicates that HBV DNA integration promotes genomic instability, resulting in the overexpression of genes related to cancer development, metastasis, and angiogenesis or inactivation of tumor suppressor genes. In addition, genetic variations in HBV itself, especially preS2 deletions, may play a role in malignant transformation. Epigenetic dysregulation caused by both viruses might also contribute to tumor formation and metastasis by modifying the methylation of DNA and histones or altering the expression of microRNAs. Similarly, viral proteins of both HBV and HCV can affect pathways that are important anticancer targets. The effects of these two viruses on the Hippo-Yap-Taz pathway in HCC development and behavior need to be investigated. Additional, comprehensive studies are also needed to determine these viruses' interaction with integrins, farnesoid X, and the apelin system in malignant transformation and tumor progression. Although the relationship of persistent inflammation caused by HBV and HCV hepatitis with carcinogenesis is well defined, further studies are warranted to decipher the relationship among inflammasomes and viruses in carcinogenesis and elucidate the role of virus-microbiota interactions in HCC development and progression.
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Affiliation(s)
- Gulsum Ozlem Elpek
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Turkey
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10
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Govindaraj V, Kar S. Role of microRNAs in oncogenesis: Insights from computational and systems‐level modeling approaches. COMPUTATIONAL AND SYSTEMS ONCOLOGY 2021. [DOI: 10.1002/cso2.1028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Affiliation(s)
| | - Sandip Kar
- Department of Chemistry IIT Bombay Mumbai India
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11
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Suresh M, Menne S. Application of the woodchuck animal model for the treatment of hepatitis B virus-induced liver cancer. World J Gastrointest Oncol 2021; 13:509-535. [PMID: 34163570 PMCID: PMC8204361 DOI: 10.4251/wjgo.v13.i6.509] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 05/02/2021] [Accepted: 05/15/2021] [Indexed: 02/06/2023] Open
Abstract
This review describes woodchucks chronically infected with the woodchuck hepatitis virus (WHV) as an animal model for hepatocarcinogenesis and treatment of primary liver cancer or hepatocellular carcinoma (HCC) induced by the hepatitis B virus (HBV). Since laboratory animal models susceptible to HBV infection are limited, woodchucks experimentally infected with WHV, a hepatitis virus closely related to HBV, are increasingly used to enhance our understanding of virus-host interactions, immune response, and liver disease progression. A correlation of severe liver pathogenesis with high-level viral replication and deficient antiviral immunity has been established, which are present during chronic infection after WHV inoculation of neonatal woodchucks for modeling vertical HBV transmission in humans. HCC in chronic carrier woodchucks develops 17 to 36 mo after neonatal WHV infection and involves liver tumors that are comparable in size, morphology, and molecular gene signature to those of HBV-infected patients. Accordingly, woodchucks with WHV-induced liver tumors have been used for the improvement of imaging and ablation techniques of human HCC. In addition, drug efficacy studies in woodchucks with chronic WHV infection have revealed that prolonged treatment with nucleos(t)ide analogs, alone or in combination with other compounds, minimizes the risk of liver disease progression to HCC. More recently, woodchucks have been utilized in the delineation of mechanisms involved in innate and adaptive immune responses against WHV during acute, self-limited and chronic infections. Therapeutic interventions based on modulating the deficient host antiviral immunity have been explored in woodchucks for inducing functional cure in HBV-infected patients and for reducing or even delaying associated liver disease sequelae, including the onset of HCC. Therefore, woodchucks with chronic WHV infection constitute a well-characterized, fully immunocompetent animal model for HBV-induced liver cancer and for preclinical evaluation of the safety and efficacy of new modalities, which are based on chemo, gene, and immune therapy, for the prevention and treatment of HCC in patients for which current treatment options are dismal.
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Affiliation(s)
- Manasa Suresh
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20057, United States
| | - Stephan Menne
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20057, United States
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12
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Tripathi A, Kashyap A, Tripathi G, Yadav J, Bibban R, Aggarwal N, Thakur K, Chhokar A, Jadli M, Sah AK, Verma Y, Zayed H, Husain A, Bharti AC, Kashyap MK. Tumor reversion: a dream or a reality. Biomark Res 2021; 9:31. [PMID: 33958005 PMCID: PMC8101112 DOI: 10.1186/s40364-021-00280-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 03/30/2021] [Indexed: 02/07/2023] Open
Abstract
Reversion of tumor to a normal differentiated cell once considered a dream is now at the brink of becoming a reality. Different layers of molecules/events such as microRNAs, transcription factors, alternative RNA splicing, post-transcriptional, post-translational modifications, availability of proteomics, genomics editing tools, and chemical biology approaches gave hope to manipulation of cancer cells reversion to a normal cell phenotype as evidences are subtle but definitive. Regardless of the advancement, there is a long way to go, as customized techniques are required to be fine-tuned with precision to attain more insights into tumor reversion. Tumor regression models using available genome-editing methods, followed by in vitro and in vivo proteomics profiling techniques show early evidence. This review summarizes tumor reversion developments, present issues, and unaddressed challenges that remained in the uncharted territory to modulate cellular machinery for tumor reversion towards therapeutic purposes successfully. Ongoing research reaffirms the potential promises of understanding the mechanism of tumor reversion and required refinement that is warranted in vitro and in vivo models of tumor reversion, and the potential translation of these into cancer therapy. Furthermore, therapeutic compounds were reported to induce phenotypic changes in cancer cells into normal cells, which will contribute in understanding the mechanism of tumor reversion. Altogether, the efforts collectively suggest that tumor reversion will likely reveal a new wave of therapeutic discoveries that will significantly impact clinical practice in cancer therapy.
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Affiliation(s)
- Avantika Tripathi
- Amity Stem Cell Institute, Amity Medical School, Amity University Haryana, Panchgaon, Haryana, Manesar (Gurugram), -122413, India
| | - Anjali Kashyap
- Department of Biotechnology, Thapar Institute of Engineering & Technology, Patiala, Punjab, India
| | - Greesham Tripathi
- Amity Stem Cell Institute, Amity Medical School, Amity University Haryana, Panchgaon, Haryana, Manesar (Gurugram), -122413, India
| | - Joni Yadav
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), New Delhi, 110007, India
| | - Rakhi Bibban
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), New Delhi, 110007, India
| | - Nikita Aggarwal
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), New Delhi, 110007, India
| | - Kulbhushan Thakur
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), New Delhi, 110007, India
| | - Arun Chhokar
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), New Delhi, 110007, India
| | - Mohit Jadli
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), New Delhi, 110007, India
| | - Ashok Kumar Sah
- Department of Medical Laboratory Technology, Amity Medical School, Amity University Haryana, Panchgaon, Haryana, Manesar (Gurugram), India
- Department of Pathology and Laboratory Medicine, Medanta-The Medicity, Haryana, Gurugram, India
| | - Yeshvandra Verma
- Department of Toxicology, C C S University, Meerut, UP, 250004, India
| | - Hatem Zayed
- Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
| | - Amjad Husain
- Centre for Science & Society, Indian Institute of Science Education and Research (IISER), Bhopal, India
- Innovation and Incubation Centre for Entrepreneurship (IICE), Indian Institute of Science Education and Research (IISER), Bhopal, India
| | - Alok Chandra Bharti
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), New Delhi, 110007, India.
| | - Manoj Kumar Kashyap
- Amity Stem Cell Institute, Amity Medical School, Amity University Haryana, Panchgaon, Haryana, Manesar (Gurugram), -122413, India.
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), New Delhi, 110007, India.
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13
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Sartorius K, An P, Winkler C, Chuturgoon A, Li X, Makarova J, Kramvis A. The Epigenetic Modulation of Cancer and Immune Pathways in Hepatitis B Virus-Associated Hepatocellular Carcinoma: The Influence of HBx and miRNA Dysregulation. Front Immunol 2021; 12:661204. [PMID: 33995383 PMCID: PMC8117219 DOI: 10.3389/fimmu.2021.661204] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 04/15/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) pathogenesis is fueled by persistent HBV infection that stealthily maintains a delicate balance between viral replication and evasion of the host immune system. HBV is remarkably adept at using a combination of both its own, as well as host machinery to ensure its own replication and survival. A key tool in its arsenal, is the HBx protein which can manipulate the epigenetic landscape to decrease its own viral load and enhance persistence, as well as manage host genome epigenetic responses to the presence of viral infection. The HBx protein can initiate epigenetic modifications to dysregulate miRNA expression which, in turn, can regulate downstream epigenetic changes in HBV-HCC pathogenesis. We attempt to link the HBx and miRNA induced epigenetic modulations that influence both the HBV and host genome expression in HBV-HCC pathogenesis. In particular, the review investigates the interplay between CHB infection, the silencing role of miRNA, epigenetic change, immune system expression and HBV-HCC pathogenesis. The review demonstrates exactly how HBx-dysregulated miRNA in HBV-HCC pathogenesis influence and are influenced by epigenetic changes to modulate both viral and host genome expression. In particular, the review identifies a specific subset of HBx induced epigenetic miRNA pathways in HBV-HCC pathogenesis demonstrating the complex interplay between HBV infection, epigenetic change, disease and immune response. The wide-ranging influence of epigenetic change and miRNA modulation offers considerable potential as a therapeutic option in HBV-HCC.
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Affiliation(s)
- Kurt Sartorius
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa.,Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban, South Africa.,Department of Surgery, University of KwaZulu-Natal Gastrointestinal Cancer Research Centre, Durban, South Africa
| | - Ping An
- Basic Research Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United States
| | - Cheryl Winkler
- Basic Research Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United States
| | - Anil Chuturgoon
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, Durban, South Africa
| | - Xiaodong Li
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
| | - Julia Makarova
- Faculty of Biology and Biotechnology, National Research University Higher School of Economics, Moscow, Russia.,Higher School of Economics University, Moscow, Russia
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
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14
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MIR17HG polymorphism (rs7318578) is associated with liver cancer risk in the Chinese Han population. Biosci Rep 2021; 40:225971. [PMID: 32748943 PMCID: PMC7457078 DOI: 10.1042/bsr20193312] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 07/27/2020] [Accepted: 07/29/2020] [Indexed: 01/09/2023] Open
Abstract
Numerous evidence has revealed that single-nucleotide polymorphisms (SNPs) are associated with liver cancer risk. To assess whether the MIR17HG polymorphisms are associated with the liver cancer risk in the Chinese Han population, we performed a case–control (432 liver cancer patients and 430 healthy controls) study. Genotyping of four variants of MIR17HG was performed with the Agena MassARRAY platform. We used χ2 test to compare the distribution of SNPs allele and genotypes frequencies of cases and controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression analysis to evaluate the association under genetic models. The results indicated that the rs7318578 was significantly associated with increased the risk of liver cancer in the allele (OR = 1.45, 95% CI: 1.18–1.77, P=3.04E-04), recessive (OR = 3.69, 95% CI: 2.45–5.56, P=4.52E-10) and additive model (OR = 1.35, 95% CI: 1.13–1.62, P=0.001). Moreover, we found that individuals with the genotype CC of rs7318578 presented with an increased risk of liver cancer (OR = 3.03, 95% CI: 1.98–4.65, P=3.83E-07); however, the CA genotype of rs7318578 significantly decreased the risk of liver cancer (OR = 0.61, 95% CI: 0.45–0.83, P=0.001, compared with those with the AA genotype. Our findings indicated that MIR17HG polymorphism (rs7318578) contributes to liver cancer susceptibility to the Chinese Han population. Further studies with larger samples are required to confirm the results, as well as functional studies to determine the role of this SNP in miRNA expression or molecular pathways.
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15
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Ghafouri-Fard S, Honarmand Tamizkar K, Hussen BM, Taheri M. MicroRNA signature in liver cancer. Pathol Res Pract 2021; 219:153369. [PMID: 33626406 DOI: 10.1016/j.prp.2021.153369] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/31/2021] [Accepted: 02/02/2021] [Indexed: 12/24/2022]
Abstract
Liver cancer is the 7th utmost frequent neoplasm and the 4th principal source of cancer deaths. This malignancy is linked with several environmental and lifestyle-related factors emphasizing the role of epigenetics in its pathogenesis. MicroRNAs (miRNAs) have been regarded as potent epigenetic mechanisms partaking in the pathogenesis of liver cancer. Dysregulation of miRNAs has been related with poor outcome of patients with liver cancer. In the current manuscript, we provide a concise review of the results of recent studies about the role of miRNAs in the progression of liver cancer and their diagnostic and prognostic utility.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Bashdar Mahmud Hussen
- Pharmacognosy Department, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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16
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Abstract
Chronic infection of the liver by the hepatitis B virus (HBV) is associated with increased risk for developing hepatocellular carcinoma (HCC). A multitude of studies have investigated the mechanism of liver cancer pathogenesis due to chronic HBV infection. Chronic inflammation, expression of specific viral proteins such as HBx, the integration site of the viral genome into the host genome, and the viral genotype, are key players contributing to HCC pathogenesis. In addition, the genetic background of the host and exposure to environmental carcinogens are also predisposing parameters in hepatocarcinogenesis. Despite the plethora of studies, the molecular mechanism of HCC pathogenesis remains incompletely understood. In this review, the focus is on epigenetic mechanisms involved in the pathogenesis of HBV-associated HCC. Epigenetic mechanisms are dynamic molecular processes that regulate gene expression without altering the host DNA, acting by modifying the host chromatin structure via covalent post-translational histone modifications, changing the DNA methylation status, expression of non-coding RNAs such as microRNAs and long noncoding RNAs, and altering the spatial, 3-D organization of the chromatin of the virus-infected cell. Herein, studies are described that provide evidence in support of deregulation of epigenetic mechanisms in the HBV-infected/-replicating hepatocyte and their contribution to hepatocyte transformation. In contrast to genetic mutations which are permanent, epigenetic alterations are dynamic and reversible. Accordingly, the identification of essential molecular epigenetic targets involved in HBV-mediated HCC pathogenesis offers the opportunity for the design and development of novel epigenetic therapeutic approaches.
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Affiliation(s)
- Ourania Andrisani
- Department of Basic Medical Sciences and Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA
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17
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miR-21 modulates cisplatin resistance of gastric cancer cells by inhibiting autophagy via the PI3K/Akt/mTOR pathway. Anticancer Drugs 2021; 31:385-393. [PMID: 31913198 DOI: 10.1097/cad.0000000000000886] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Resistance to cisplatin (DDP) remains a major obstacle in the control of gastric cancer (GC) progression. A previous study revealed that microRNA-21 (miR-21) contributes to DDP resistance in GC cells via the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway. The aim of the current study was to explore the mechanisms underlying the cytoprotective function of miR-21. In this study, DDP-resistant GC cells were obtained by continuous exposure of human gastric adenocarcinoma cells to increasing concentrations of DDP. Western blot analysis was used to evaluate activation of the PI3K/Akt/mechanistic target of rapamycin kinase (mTOR) pathway. The level of miR-21 was altered by transfection of miR-21 mimic and inhibitor. Autophagy was assessed by detecting autophagosome formation, Beclin-1 and LC3 expression. An Annexin V-propidium iodide assay was performed to estimate the survival and death of GC cells. GC cells became refractory to the growth inhibition and apoptosis induced by DDP treatment, activation of Akt and mTOR were increased in DDP-resistant GC cells. Inhibition of autophagy decreased the sensitivity of GC cells to DDP, and autophagy induction produced the opposite effect. DDP-resistant GC cells expressed higher levels of miR-21 compared with the parent cells. Transfection of GC cells with miR-21 mimics contributed to restored DDP resistance by suppressing autophagy, while miR-21 inhibitor sensitized DDP-resistant GC cells by promoting autophagy. In conclusion, the results demonstrated that miR-21 is associated with DDP resistance in GC cells by inhibiting autophagy via the PI3K/Akt/mTOR pathway, and autophagy inducers could be therapeutic targets for the effective treatment of DDP resistance in GC.
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18
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Liu LQ, Yin F, Lu Y, Yan XL, Wu CC, Li X, Li C. A light-up "G-quadruplex nanostring" for label-free and selective detection of miRNA via duplex-specific nuclease mediated tandem rolling circle amplification. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2021; 32:102339. [PMID: 33227538 DOI: 10.1016/j.nano.2020.102339] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 11/08/2020] [Accepted: 11/11/2020] [Indexed: 12/29/2022]
Abstract
MicroRNA (miRNA) has emerged as a promising genetic marker for cancer diagnosis and therapy because its expression level is closely related to the progression of malignant diseases. Herein, a label-free and selective fluorescence platform was proposed for miRNA based on light-up "G-quadruplex nanostring" via duplex-specific nuclease (DSN) mediated tandem rolling circle amplification (RCA). First, a long DNA generated from upstream RCA was designed with the antisense sequences for miR-21 and downstream RCA primer. Upon recognizing miR-21, the resulting DNA-RNA permitted DSN digestion and triggered downstream two-way RCA, and generation of abundant "G-quadruplex nanostring" binding with ZnPPIX for label-free fluorescent responses. In our strategy, the strong preference of DSN for perfectly matched DNA/RNA ensures its excellent selectivity. The developed method generated wide linear response with LOD of 1.019 fM. Additionally, the miR-21 levels in cell extracts have been evaluated, revealing the utility of this tool for biomedical research and clinical diagnosis.
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Affiliation(s)
- Li-Qi Liu
- Department of Chemistry, Liaocheng University, Liaocheng, China
| | - Fei Yin
- Department of Chemistry, Liaocheng University, Liaocheng, China
| | - Yu Lu
- Department of Chemistry, Liaocheng University, Liaocheng, China
| | - Xi-Luan Yan
- Department of Bio-industrial Mechatronics Engineering, National Chung Hsing University, Taiwan
| | - Ching-Chou Wu
- Department of Bio-industrial Mechatronics Engineering, National Chung Hsing University, Taiwan
| | - Xia Li
- Department of Chemistry, Liaocheng University, Liaocheng, China.
| | - Chenzhong Li
- Department of Bio-industrial Mechatronics Engineering, National Chung Hsing University, Taiwan
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19
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Abstract
Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC). There are approximately 250 million people in the world that are chronically infected by this virus, resulting in nearly 1 million deaths every year. Many of these patients die from severe liver diseases, including HCC. HBV may induce HCC through the induction of chronic liver inflammation, which can cause oxidative stress and DNA damage. However, many studies also indicated that HBV could induce HCC via the alteration of hepatocellular physiology that may involve genetic and epigenetic changes of the host DNA, the alteration of cellular signaling pathways, and the inhibition of DNA repair mechanisms. This alteration of cellular physiology can lead to the accumulation of DNA damages and the promotion of cell cycles and predispose hepatocytes to oncogenic transformation.
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Affiliation(s)
- Jiyoung Lee
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, HMR-401, Los Angeles, CA, 90033, USA
| | - Kuen-Nan Tsai
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, HMR-401, Los Angeles, CA, 90033, USA
| | - Jing-Hsiung James Ou
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, HMR-401, Los Angeles, CA, 90033, USA.
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20
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Quiñones-Díaz BI, Reyes-González JM, Sánchez-Guzmán V, Conde-Del Moral I, Valiyeva F, Santiago-Sánchez GS, Vivas-Mejía PE. MicroRNA-18a-5p Suppresses Tumor Growth via Targeting Matrix Metalloproteinase-3 in Cisplatin-Resistant Ovarian Cancer. Front Oncol 2020; 10:602670. [PMID: 33392094 PMCID: PMC7774672 DOI: 10.3389/fonc.2020.602670] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 11/17/2020] [Indexed: 12/22/2022] Open
Abstract
Cumulating evidence indicates that dysregulation of microRNAs (miRNAs) plays a central role in the initiation, progression, and drug resistance of cancer cells. However, the specific miRNAs contributing to drug resistance in ovarian cancer cells have not been fully elucidated. Aimed to identify potential miRNAs involved in platinum resistance, we performed a miRNA expression profile in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells, and we found several differentially abundant miRNAs in the pair of cell lines. Notably, miR-18a-5p (miR-18a), a member of the oncogenic associated miR-17-92 cluster, was decreased in cisplatin-resistant as compared with cisplatin-sensitive cells. Real-time PCR analysis confirmed these findings. We then studied the biological, molecular, and therapeutic consequences of increasing the miR-18a levels with oligonucleotide microRNA mimics (OMM). Compared with a negative control OMM, transient transfection of a miR-18a-OMM reduced cell growth, cell proliferation, and cell invasion. Intraperitoneal injections of miR-18a-OMM-loaded folate-conjugated liposomes significantly reduced the tumor weight and the number of nodules in ovarian cancer-bearing mice when compared with a control-OMM group. Survival analysis using the Kaplan-Meier plotter database showed that ovarian cancer patients with high miR-18a levels live longer in comparison to patients with lower miR-18a levels. Bioinformatic analyses, real-time-PCR, Western blots, and luciferase reporter assays revealed that Matrix Metalloproteinase-3 (MMP-3) is a direct target of miR-18a. Small-interfering RNA (siRNA)-mediated silencing of MMP-3 reduced cell viability, cell growth, and the invasiveness potential of cisplatin-resistant ovarian cancer cells. Our study suggests that targeting miR-18a is a plausible therapeutic strategy for cisplatin-resistant ovarian cancer.
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Affiliation(s)
| | | | | | | | - Fatma Valiyeva
- Comprehensive Cancer Center, University of Puerto Rico, San Juan, Puerto Rico
| | | | - Pablo E Vivas-Mejía
- Department of Biochemistry, University of Puerto Rico, San Juan, Puerto Rico.,Comprehensive Cancer Center, University of Puerto Rico, San Juan, Puerto Rico
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21
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Raafat N, Zaher TI, Etewa RL, El-gerby KM, Rezk NA. Heat shock protein-27 and MiR-17-5p are novel diagnostic and prognostic biomarkers for hepatocellular carcinoma in Egyptian patients. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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22
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The Relevance of MicroRNAs in the Pathogenesis and Prognosis of HCV-Disease: The Emergent Role of miR-17-92 in Cryoglobulinemic Vasculitis. Viruses 2020; 12:v12121364. [PMID: 33260407 PMCID: PMC7761224 DOI: 10.3390/v12121364] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 11/18/2020] [Accepted: 11/27/2020] [Indexed: 12/26/2022] Open
Abstract
Hepatitis C virus (HCV) is a major public health problem. HCV is a hepatotropic and lymphotropic virus that leads to hepatocellular carcinoma (HCC) and lymphoproliferative disorders such as cryoglobulinemic vasculitis (CV) and non-Hodgkin's lymphoma (NHL). The molecular mechanisms by which HCV induces these diseases are not fully understood. MicroRNAs (miRNAs) are small non-coding molecules that negatively regulate post-transcriptional gene expression by decreasing their target gene expression. We will attempt to summarize the current knowledge on the role of miRNAs in the HCV life cycle, HCV-related HCC, and lymphoproliferative disorders, focusing on both the functional effects of their deregulation as well as on their putative role as biomarkers, based on association analyses. We will also provide original new data regarding the miR 17-92 cluster in chronically infected HCV patients with and without lymphoproliferative disorders who underwent antiviral therapy. All of the cluster members were significantly upregulated in CV patients compared to patients without CV and significantly decreased in those who achieved vasculitis clinical remission after viral eradication. To conclude, miRNAs play an important role in HCV infection and related oncogenic processes, but their molecular pathways are not completely clear. In some cases, they may be potential therapeutic targets or non-invasive biomarkers of tumor progression.
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23
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The miR-21 potential of serving as a biomarker for liver diseases in clinical practice. Biochem Soc Trans 2020; 48:2295-2305. [PMID: 33119045 DOI: 10.1042/bst20200653] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 09/18/2020] [Accepted: 10/05/2020] [Indexed: 12/11/2022]
Abstract
The role of miR-21 in the pathogenesis of various liver diseases, together with the possibility of detecting microRNA in the circulation, makes miR-21 a potential biomarker for noninvasive detection. In this review, we summarize the potential utility of extracellular miR-21 in the clinical management of hepatic disease patients and compared it with the current clinical practice. MiR-21 shows screening and prognostic value for liver cancer. In liver cirrhosis, miR-21 may serve as a biomarker for the differentiating diagnosis and prognosis. MiR-21 is also a potential biomarker for the severity of hepatitis. We elucidate the disease condition under which miR-21 testing can reach the expected performance. Though miR-21 is a key regulator of liver diseases, microRNAs coordinate with each other in the complex regulatory network. As a result, the performance of miR-21 is better when combined with other microRNAs or classical biomarkers under certain clinical circumstances.
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24
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Mani SKK, Yan B, Cui Z, Sun J, Utturkar S, Foca A, Fares N, Durantel D, Lanman N, Merle P, Kazemian M, Andrisani O. Restoration of RNA helicase DDX5 suppresses hepatitis B virus (HBV) biosynthesis and Wnt signaling in HBV-related hepatocellular carcinoma. Theranostics 2020; 10:10957-10972. [PMID: 33042264 PMCID: PMC7532671 DOI: 10.7150/thno.49629] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 08/11/2020] [Indexed: 02/07/2023] Open
Abstract
Rationale: RNA helicase DDX5 is downregulated during hepatitis B virus (HBV) replication, and poor prognosis HBV-related hepatocellular carcinoma (HCC). The aim of this study is to determine the mechanism and significance of DDX5 downregulation for HBV-driven HCC, and identify biologics to prevent DDX5 downregulation. Methods: Molecular approaches including immunoblotting, qRT-PCR, luciferase transfections, hepatosphere assays, Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq), and RNA-seq were used with cellular models of HBV replication, HBV infection, and HBV-related liver tumors, as well as bioinformatic analyses of liver cancer cells from two independent cohorts. Results: We demonstrate that HBV infection induces expression of the proto-oncogenic miR17~92 and miR106b~25 clusters which target the downregulation of DDX5. Increased expression of these miRNAs is also detected in HBV-driven HCCs exhibiting reduced DDX5 mRNA. Stable DDX5 knockdown (DDX5KD) in HBV replicating hepatocytes increased viral replication, and resulted in hepatosphere formation, drug resistance, Wnt activation, and pluripotency gene expression. ATAC-seq of DDX5KD compared to DDX5 wild-type (WT) cells identified accessible chromatin regions enriched in regulation of Wnt signaling genes. RNA-seq analysis comparing WT versus DDX5KD cells identified enhanced expression of multiple genes involved in Wnt pathway. Additionally, expression of Disheveled, DVL1, a key regulator of Wnt pathway activation, was significantly higher in liver cancer cells with low DDX5 expression, from two independent cohorts. Importantly, inhibitors (antagomirs) to miR17~92 and miR106b~25 restored DDX5 levels, reduced DVL1 expression, and suppressed both Wnt activation and viral replication. Conclusion : DDX5 is a negative regulator of Wnt signaling and hepatocyte reprogramming in HCCs. Restoration of DDX5 levels by miR17~92 / miR106b~25 antagomirs in HBV-infected patients can be explored as both antitumor and antiviral strategy.
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25
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Fukada M, Matsuhashi N, Takahashi T, Sugito N, Heishima K, Akao Y, Yoshida K. Tumor Tissue MIR92a and Plasma MIRs21 and 29a as Predictive Biomarkers Associated with Clinicopathological Features and Surgical Resection in a Prospective Study on Colorectal Cancer Patients. J Clin Med 2020; 9:jcm9082509. [PMID: 32759718 PMCID: PMC7465950 DOI: 10.3390/jcm9082509] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 07/15/2020] [Accepted: 07/29/2020] [Indexed: 12/21/2022] Open
Abstract
Cancer-related microRNAs (miRNAs) are emerging as non-invasive biomarkers for colorectal cancer (CRC). This study aimed to analyze the correlation between the levels of tissue and plasma miRNAs and clinicopathological characteristics and surgical resection. This study was a prospective study of CRC patients who underwent surgery. Forty-four sample pairs of tissue and plasma were analyzed. The miRNA levels were evaluated by RT-qPCR. The level of tumor tissue MIR92a showed a significant difference in CRC with lymph node metastasis, stage ≥ III, and high lymphatic invasion. In preoperative plasma, there were significant differences in CRC with stage ≥ III (MIR29a) and perineural invasion (MIR21). In multivariate analysis of lymphatic invasion, the levels of both preoperative plasma MIR29a and tumor tissue MIR92a showed significant differences. Furthermore, in cases with higher plasma miRNA level, the levels of plasma MIRs21 and 29a were significantly decreased after the operation. In this study, there were significant differences in miRNAs levels with respect to the sample type, clinicopathological features, and surgical resection. The levels of tumor tissue MIR92a and preoperative plasma MIR29a may have the potential as a biomarker for prognosis. The plasma MIRs21 and 29a level has the potential to be a predictive biomarker for treatment efficacy.
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Affiliation(s)
- Masahiro Fukada
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu City 501-1194, Japan; (M.F.); (N.M.); (T.T.)
| | - Nobuhisa Matsuhashi
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu City 501-1194, Japan; (M.F.); (N.M.); (T.T.)
| | - Takao Takahashi
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu City 501-1194, Japan; (M.F.); (N.M.); (T.T.)
| | - Nobuhiko Sugito
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu City 501-1194, Japan; (N.S.); (K.H.); (Y.A.)
| | - Kazuki Heishima
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu City 501-1194, Japan; (N.S.); (K.H.); (Y.A.)
| | - Yukihiro Akao
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu City 501-1194, Japan; (N.S.); (K.H.); (Y.A.)
| | - Kazuhiro Yoshida
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu City 501-1194, Japan; (M.F.); (N.M.); (T.T.)
- Correspondence: ; Tel.: +81-058-230-6235
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26
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Xu J, An P, Winkler CA, Yu Y. Dysregulated microRNAs in Hepatitis B Virus-Related Hepatocellular Carcinoma: Potential as Biomarkers and Therapeutic Targets. Front Oncol 2020; 10:1271. [PMID: 32850386 PMCID: PMC7399632 DOI: 10.3389/fonc.2020.01271] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 06/19/2020] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) are non-coding small RNAs that can function as gene regulators and are involved in tumorigenesis. We review the commonly dysregulated miRNAs in liver tumor tissues and plasma/serum of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients. The frequently reported up-regulated miRNAs in liver tumor tissues include miR-18a, miR-21, miR-221, miR-222, and miR-224, whereas down-regulated miRNAs include miR-26a, miR-101, miR-122, miR-125b, miR-145, miR-199a, miR-199b, miR-200a, and miR-223. For a subset of these miRNAs (up-regulated miR-222 and miR-224, down-regulated miR-26a and miR-125b), the pattern of dysregulated circulating miRNAs in plasma/serum is mirrored in tumor tissue based on multiple independent studies. Dysregulated miRNAs target oncogenes or tumor suppressor genes involved in hepatocarcinogenesis. Normalization of dysregulated miRNAs by up- or down-regulation has been shown to inhibit HCC cell proliferation or sensitize liver cancer cells to chemotherapeutic treatment. miRNAs hold as yet unrealized potential as biomarkers for early detection of HCC and as precision therapeutic targets, but further studies in diverse populations and across all stages of HCC are needed.
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Affiliation(s)
- Jinghang Xu
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Peking University, Beijing, China
- Basic Research Laboratory, Molecular Genetic Epidemiology Section, Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Ping An
- Basic Research Laboratory, Molecular Genetic Epidemiology Section, Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Cheryl A. Winkler
- Basic Research Laboratory, Molecular Genetic Epidemiology Section, Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Yanyan Yu
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Peking University, Beijing, China
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Sartorius K, Swadling L, An P, Makarova J, Winkler C, Chuturgoon A, Kramvis A. The Multiple Roles of Hepatitis B Virus X Protein (HBx) Dysregulated MicroRNA in Hepatitis B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) and Immune Pathways. Viruses 2020; 12:v12070746. [PMID: 32664401 PMCID: PMC7412373 DOI: 10.3390/v12070746] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/08/2020] [Accepted: 07/09/2020] [Indexed: 12/11/2022] Open
Abstract
Currently, the treatment of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) [HBV-HCC] relies on blunt tools that are unable to offer effective therapy for later stage pathogenesis. The potential of miRNA to treat HBV-HCC offer a more targeted approach to managing this lethal carcinoma; however, the complexity of miRNA as an ancillary regulator of the immune system remains poorly understood. This review examines the overlapping roles of HBx-dysregulated miRNA in HBV-HCC and immune pathways and seeks to demonstrate that specific miRNA response in immune cells is not independent of their expression in hepatocytes. This interplay between the two pathways may provide us with the possibility of using candidate miRNA to manipulate this interaction as a potential therapeutic option.
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Affiliation(s)
- Kurt Sartorius
- Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg 2050, South Africa
- Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa;
- UKZN Gastrointestinal Cancer Research Centre, Durban 4041, South Africa
- Correspondence:
| | - Leo Swadling
- Division of Infection and Immunity, University College London, London WC1E6BT, UK;
| | - Ping An
- Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc. Frederick Nat. Lab. for Cancer Research, Frederick, MD 20878, USA; (P.A.); (C.W.)
| | - Julia Makarova
- National Research University Higher School of Economics, Faculty of Biology and Biotechnology, 10100 Moscow, Russia;
| | - Cheryl Winkler
- Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc. Frederick Nat. Lab. for Cancer Research, Frederick, MD 20878, USA; (P.A.); (C.W.)
| | - Anil Chuturgoon
- Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa;
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2050, South Africa;
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Bandopadhyay M, Bharadwaj M. Exosomal miRNAs in hepatitis B virus related liver disease: a new hope for biomarker. Gut Pathog 2020; 12:23. [PMID: 32346400 PMCID: PMC7183117 DOI: 10.1186/s13099-020-00353-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 03/31/2020] [Indexed: 02/06/2023] Open
Abstract
The World Health Organisation, in its 2019 progress report on HIV, viral hepatitis and STDs indicates that 257 million people are afflicted with chronic HBV infections, of which, 1 million patients lose their lives every year due to HBV related chronic liver diseases including serious complications such as liver cirrhosis and hepatocellular carcinoma. The course of HBV infection and associated liver injury depend on several host factors, genetic variability of the virus, and the host viral interplay. The challenge of medical science is the early diagnosis/identification of the potential for development of fatal complications like liver cirrhosis and HCC so that timely medical intervention can improve the chances of survival. Currently, neither the vaccination regime nor the diagnostic methods are completely effective as reflected in the high number of annual deaths. It is evident from numerous publications that microRNAs (miRNAs) are the critical regulators of gene expression and various cellular processes like proliferation, development, differentiation, apoptosis and tumorigenesis. Expressions of these diminutive RNAs are significantly affected in cancerous tissues as a result of numerous genomic and epigenetic modifications. Exosomes are membrane-derived vesicles (30–100 nm) secreted by normal as well as malignant cells, and are present in all body fluids. They are recognized as critical molecules in intercellular communication between cells through horizontal transfer of information via their cargo, which includes selective proteins, mRNAs and miRNAs. Exosomal miRNAs are transferred to recipient cells where they can regulate target gene expression. This provides an insight into the elementary biology of cancer progression and therefore the development of therapeutic approaches. This concise review outlines various on-going research on miRNA mediated regulation of HBV pathogenesis with special emphasis on association of exosomal miRNA in advanced stage liver disease like hepatocellular carcinoma. This review also discusses the possible use of exosomal miRNAs as biomarkers in the early detection of HCC and liver cirrhosis.
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Affiliation(s)
- Manikankana Bandopadhyay
- Molecular Genetics and Biochemistry, National Institute of Cancer Prevention and Research (NICPR), Indian Council of Medical Research (ICMR), Noida, Uttar Pradesh 201301 India
| | - Mausumi Bharadwaj
- Molecular Genetics and Biochemistry, National Institute of Cancer Prevention and Research (NICPR), Indian Council of Medical Research (ICMR), Noida, Uttar Pradesh 201301 India
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Chen LB, An Z, Zheng HK, Wang XP, Shan RT, Mao CY, Zhang WQ. MicroRNA-34c suppresses proliferation of vascular smooth muscle cell via modulating high mobility group box protein 1. J Clin Lab Anal 2020; 34:e23293. [PMID: 32157741 PMCID: PMC7370740 DOI: 10.1002/jcla.23293] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/30/2020] [Accepted: 02/05/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Atherosclerosis is the most frequent pathological process that causes cardiovascular diseases. OBJECTIVE The present study aimed to confirm miRNAs associated with atherosclerosis and explore the molecular mechanism of miR-34c and its target high mobility group box protein 1 (HMGB1) in the control of growth of smooth muscle cells in the development of atherosclerosis. METHODS Real-time PCR was firstly performed to confirm miRNA correlation with atherosclerosis, and computational analysis and luciferase assay were performed to explore the target of miR-34c, Western blot, and real-time PCR were also utilized to reveal the effect of whether high glucose (HG) and miR-34c affect miR-34c, HMGB1 levels, NF-κB p65 and TNF-α levels, and the role of miR-34c on vascular smooth muscle cells (VSMCs) viability induced by HG. Students' unpaired t test was performed to compare data between two groups. RESULTS MiR-34c level was associated with atherosclerosis with different expression between VSMCs treated with high glucose or normal VSMCs. Then, HMGB1 is a virtual target of miR-34c with predicted binding site resided in HMGB1 3'UTR and further verified by that miR-34c remarkably reduced luciferase activity of wild HMGB1 3'UTR under a concentration-dependent fashion, and miR-34c cannot influence luciferase activity of mutant HMGB1 3'UTR. CONCLUSIONS The results suggested miR-34c might be a novel therapeutic strategy in the management of atherosclerosis by suppressing the expression of HGMB1 and its downstream effectors.
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Affiliation(s)
- Li-Bo Chen
- Department of Ultrasound, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Zhe An
- Department of Cardiovascular, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Hai-Kuo Zheng
- Department of Cardiovascular, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Xin-Peng Wang
- Department of Cardiovascular, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Rui-Ting Shan
- Department of Cardiovascular, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Cui-Ying Mao
- Department of Cardiovascular, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Wen-Qi Zhang
- Department of Cardiovascular, China-Japan Union Hospital of Jilin University, Changchun, China
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The Regulatory Role of MicroRNA in Hepatitis-B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) Pathogenesis. Cells 2019; 8:cells8121504. [PMID: 31771261 PMCID: PMC6953055 DOI: 10.3390/cells8121504] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 11/11/2019] [Accepted: 11/12/2019] [Indexed: 02/06/2023] Open
Abstract
The incidence and mortality of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) is an intractable public health problem in developing countries that is compounded by limited early detection and therapeutic options. Despite the early promise of utilizing the regulatory role of miRNA in liver cancer, this field remains largely in the work-in-progress phase. This exploratory review paper adopts a broad focus in order to collate evidence of the regulatory role of miRNA in each stage of the HBV-HCC continuum. This includes the regulatory role of miRNA in early HBV infection, chronic inflammation, fibrosis/cirrhosis, and the onset of HCC. The paper specifically investigates HBV dysregulated miRNA that influence the expression of the host/HBV genome in HBV-HCC pathogenesis and fully acknowledges that this does not cover the full spectrum of dysregulated miRNA. The sheer number of dysregulated miRNA in each phase support a hypothesis that future therapeutic interventions will need to consider incorporating multiple miRNA panels.
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31
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Nasr MA, Salah RA, Abd Elkodous M, Elshenawy SE, El-Badri N. Dysregulated MicroRNA Fingerprints and Methylation Patterns in Hepatocellular Carcinoma, Cancer Stem Cells, and Mesenchymal Stem Cells. Front Cell Dev Biol 2019; 7:229. [PMID: 31681762 PMCID: PMC6811506 DOI: 10.3389/fcell.2019.00229] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 09/26/2019] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the top causes of cancer mortality worldwide. Although HCC has been researched extensively, there is still a need for novel and effective therapeutic interventions. There is substantial evidence that initiation of carcinogenesis in liver cirrhosis, a leading cause of HCC, is mediated by cancer stem cells (CSCs). CSCs were also shown to be responsible for relapse and chemoresistance in several cancers, including HCC. MicroRNAs (miRNAs) constitute important epigenetic markers that regulate carcinogenesis by acting post-transcriptionally on mRNAs, contributing to the progression of HCC. We have previously shown that co-culture of cancer cells with mesenchymal stem cells (MSCs) could induce the reprogramming of MSCs into CSC-like cells. In this review, we evaluate the available data concerning the epigenetic regulation of miRNAs through methylation and the possible role of this regulation in stem cell and somatic reprogramming in HCC.
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Affiliation(s)
- Mohamed A Nasr
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - Radwa Ayman Salah
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - M Abd Elkodous
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - Shimaa E Elshenawy
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - Nagwa El-Badri
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
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32
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Wei X, You X, Zhang J, Zhou C. c[RGDyk]-coated liposomes loaded with adriamycin and miR-21 mimics inhibit the growth of hepatoma cell line SMCC-7721 via up-regulating Bax and p53. Transl Cancer Res 2019; 8:1311-1318. [PMID: 35116873 PMCID: PMC8798595 DOI: 10.21037/tcr.2019.07.29] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Accepted: 06/24/2019] [Indexed: 11/06/2022]
Abstract
BACKGROUND This study was conducted to investigate the effects of c[RGDyk]-coated liposomes loaded with Adriamycin (nanodrug) and miR-21 mimics on hepatoma cell line SMCC-7721. METHODS SMCC-7721 cells were divided into five groups: control (receiving no treatment), nanodrug, miR-21 mimics + nanodrug and miR-21 mimics and empty vector. The concentration and duration of treatments were determined using the MTT assay. Cell apoptosis was detected using flow cytometer. The expression of Bax, Bcl-2 and p53 was measured using qPCR and Western blot analysis. RESULTS MTT showed that the nanodrug inhibited cell proliferation. Nanodrug and miR-21 led to cell arrest at S phase and apoptosis. qPCR showed that cells treated with nanodrug and miR-21 increased the expression of Bax and p53. Western blot analysis indicated that Bcl-2 expression was significantly reduced. CONCLUSIONS Our work demonstrates that nanodrug and miR-21 have inhibitory effect on SMCC-7721 cells via up-regulating Bax and p53.
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Affiliation(s)
- Xiaoyong Wei
- Department of General Surgery, The Medical College of Nanchang University, Nanchang 330029, China;,Department of Hepatobiliary Surgery, Jiangxi Cancer Hospital, Nanchang 330029, China
| | - Xiaolong You
- Department of Hepatobiliary Surgery, Jiangxi Cancer Hospital, Nanchang 330029, China
| | - Jianlong Zhang
- Department of Hepatobiliary Surgery, Jiangxi Cancer Hospital, Nanchang 330029, China
| | - Cuncai Zhou
- Department of Hepatobiliary Surgery, Jiangxi Cancer Hospital, Nanchang 330029, China
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Li Y, Hagen DE, Ji T, Bakhtiarizadeh MR, Frederic WM, Traxler EM, Kalish JM, Rivera RM. Altered microRNA expression profiles in large offspring syndrome and Beckwith-Wiedemann syndrome. Epigenetics 2019; 14:850-876. [PMID: 31144574 PMCID: PMC6691986 DOI: 10.1080/15592294.2019.1615357] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The use of assisted reproductive technologies (ART) can induce a congenital overgrowth condition in humans and ruminants, namely Beckwith-Wiedemann syndrome (BWS) and large offspring syndrome (LOS), respectively. Shared phenotypes and epigenotypes have been found between BWS and LOS. We have observed global misregulation of transcripts in bovine foetuses with LOS. microRNAs (miRNAs) are important post-transcriptional gene expression regulators. We hypothesize that there is miRNA misregulation in LOS and that this misregulation is shared with BWS. In this study, small RNA sequencing was conducted to investigate miRNA expression profiles in bovine and human samples. We detected 407 abundant known miRNAs and predicted 196 putative miRNAs from the bovine sequencing results and identified 505 abundant miRNAs in human tongue. Differentially expressed miRNAs (DE-miRNAs) were identified between control and LOS groups in all tissues analysed as well as between BWS and control human samples. DE-miRNAs were detected from several miRNA clusters including DLK1-DIO3 genomic imprinted cluster in LOS and BWS. DNA hypermethylation was associated with downregulation of miRNAs in the DLK1-DIO3. mRNA targets of the DE-miRNAs were predicted and signalling pathways associated with control of organ size (including the Hippo signalling pathway), cell proliferation, apoptosis, cell survival, cell cycle, and cell adhesion were found to be enriched with these genes. Yes associated protein 1 (YAP1) is the core effector of the Hippo signalling pathway, and increased level of active (non-phosphorylated) YAP1 protein was detected in skeletal muscle of LOS foetuses. Overall, our data provide evidence of miRNA misregulation in LOS and BWS.
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Affiliation(s)
- Yahan Li
- a Division of Animal Sciences, University of Missouri , Columbia , MO , USA
| | - Darren Erich Hagen
- b Department of Animal and Food Science, Oklahoma State University , Stillwater , OK , USA
| | - Tieming Ji
- c Department of Statistics, University of Missouri , Columbia , MO , USA
| | | | - Whitney M Frederic
- e Division of Human Genetics, Center for Childhood Cancer Research, The Children's Hospital of Philadelphia , Philadelphia , PA , USA
| | - Emily M Traxler
- e Division of Human Genetics, Center for Childhood Cancer Research, The Children's Hospital of Philadelphia , Philadelphia , PA , USA
| | - Jennifer M Kalish
- e Division of Human Genetics, Center for Childhood Cancer Research, The Children's Hospital of Philadelphia , Philadelphia , PA , USA.,f Perelman School of Medicine, University of Pennsylvania , Philadelphia , PA , USA
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Zhang H, Zhang Y, Zhu X, Chen C, Zhang C, Xia Y, Zhao Y, Andrisani O, Kong L. DEAD Box Protein 5 Inhibits Liver Tumorigenesis by Stimulating Autophagy via Interaction with p62/SQSTM1. Hepatology 2019; 69:1046-1063. [PMID: 30281815 PMCID: PMC6411283 DOI: 10.1002/hep.30300] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 09/13/2018] [Indexed: 12/11/2022]
Abstract
In hepatocellular carcinoma (HCC), dysregulated expression of DDX5 (DEAD box protein 5) and impaired autophagy have been reported separately. However, the relationship between them has not been explored. Here we present evidence to show that, by interacting with autophagic receptor p62, DDX5 promotes autophagy and suppresses tumorigenesis. DDX5 inversely correlated with p62/sequestosome 1 (SQSTM1) expression in hepatitis B virus (HBV)-associated and non-HBV-associated HCCs. Patients with low DDX5 expression showed poor prognosis after tumor resection. We found that DDX5 overexpression induced, while DDX5 knockdown attenuated, autophagic flux in HepG2 and Huh7 cells. DDX5 promoted p62 degradation and markedly reduced the half-life of p62. Moreover, DDX5 overexpression dramatically reduced, while DDX5 knockdown promoted, cancer cell growth and tumorigenesis in vitro and in vivo. We found that DDX5 bound to p62 and interfered with p62/TRAF6 (tumor necrosis factor receptor-associated factor 6) interaction. Further findings revealed that the N-terminal domain of DDX5, involved in the interaction with p62, was sufficient to induce autophagy independent of its RNA binding and helicase activity. DDX5 overexpression decreased p62/TRAF6-mediated lysine 63-linked ubiquitination of mammalian target of rapamycin (mTOR) and subsequently inhibited the mTOR signaling pathway. Knockdown of TRAF6 blocked DDX5-induced autophagy. Furthermore, we showed that miR-17-5p downregulated DDX5 and impaired autophagy. Inhibition of miR-17-5p promoted autophagic flux and suppressed tumor growth in HCC xenograft models. Conclusion: Our findings define a noncanonical pathway that links miR-17-5p, DDX5, p62/TRAF6, autophagy, and HCC. These findings open an avenue for the treatment of HCC.
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Affiliation(s)
- Hao Zhang
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yanqiu Zhang
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xiaoyun Zhu
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Chen Chen
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Chao Zhang
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yuanzheng Xia
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yucheng Zhao
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Ourania Andrisani
- Department of Basic Medical Sciences and Purdue Center for Cancer Research, Purdue University, West Lafayette, IN
| | - Lingyi Kong
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
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Sadri Nahand J, Bokharaei-Salim F, Salmaninejad A, Nesaei A, Mohajeri F, Moshtzan A, Tabibzadeh A, Karimzadeh M, Moghoofei M, Marjani A, Yaghoubi S, Keyvani H. microRNAs: Key players in virus-associated hepatocellular carcinoma. J Cell Physiol 2018; 234:12188-12225. [PMID: 30536673 DOI: 10.1002/jcp.27956] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Accepted: 11/19/2018] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is known as one of the major health problems worldwide. Pathological analysis indicated that a variety of risk factors including genetical (i.e., alteration of tumor suppressors and oncogenes) and environmental factors (i.e., viruses) are involved in beginning and development of HCC. The understanding of these risk factors could guide scientists and clinicians to design effective therapeutic options in HCC treatment. Various viruses such as hepatitis B virus (HBV) and hepatitis C virus (HCV) via targeting several cellular and molecular pathways involved in HCC pathogenesis. Among various cellular and molecular targets, microRNAs (miRNAs) have appeared as key players in HCC progression. miRNAs are short noncoding RNAs which could play important roles as oncogenes or tumor suppressors in several malignancies such as HCC. Deregulation of many miRNAs (i.e., miR-222, miR-25, miR-92a, miR-1, let-7f, and miR-21) could be associated with different stages of HCC. Besides miRNAs, exosomes are other particles which are involved in HCC pathogenesis via targeting different cargos, such as DNAs, RNAs, miRNAs, and proteins. In this review, we summarize the current knowledge of the role of miRNAs and exosomes as important players in HCC pathogenesis. Moreover, we highlighted HCV- and HBV-related miRNAs which led to HCC progression.
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Affiliation(s)
- Javid Sadri Nahand
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | | | - Arash Salmaninejad
- Drug Applied Research Center, Student Research Committee, Tabriz University of Medical Science, Tabriz, Iran.,Department of Medical Genetics, Medical Genetics Research Center, Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abolfazl Nesaei
- Department of Basic Sciences, Faculty of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Fatemeh Mohajeri
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Azadeh Moshtzan
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Alireza Tabibzadeh
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | | | - Mohsen Moghoofei
- Department of Microbiology, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Arezo Marjani
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | - Shoeleh Yaghoubi
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Hossein Keyvani
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
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Huang H, Salavaggione O, Rivera L, Mukherjee S, Brekken R, Tennant B, Iyer R, Adjei A. Woodchuck VEGF (wVEGF) characteristics: Model for angiogenesis and human hepatocellular carcinoma directed therapies. Arch Biochem Biophys 2018; 661:97-106. [PMID: 30439360 DOI: 10.1016/j.abb.2018.11.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 10/21/2018] [Accepted: 11/12/2018] [Indexed: 02/07/2023]
Abstract
Vascular endothelial growth factor (VEGF) stimulates angiogenesis. Human hepatocellular carcinoma (HCC) is a VEGF-driven tumor often associated with chronic hepatitis B or C virus infection. The woodchuck is a well-characterized model of hepatitis B virus related HCC and a valuable tool for translational studies of novel VEGF targeted agents. We cloned the cDNA encoding woodchuck VEGF (wVEGF), transiently expressed it in COS cells and functionally characterized the recombinant protein. The open reading frame of wVEGF contained 645 nucleotides encoding a protein of 214 amino acids. Two protein bands (17 and 25 kDa) were detected in conditioned media of wVEGF expressing COS-1 cells and a single band of 25 kDa was identified in cell lysates. Addition of recombinant wVEGF to COS cells enhanced cell proliferation and stimulated VEGFR2, Akt, ERK1/2, and FAK phosphorylation. Sunitinib, a tyrosine kinase inhibitor, inhibited wVEGF- induced VEGFR2 phosphorylation in a dose-dependent manner. Finally, development of HCC in woodchucks was accompanied by increased laminin and PECAM1 expressing vessels, VEGFR2 expression, increased ligation of VEGF to VEGFR2, and a decrease in collagen IV-positive blood vessels. Our results suggest that woodchuck model can be used further to study angiogenesis and the effect of VEGF directed therapies in human HCC.
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Affiliation(s)
- Huayi Huang
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA; Department of Laboratory Medicine, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China
| | - Oreste Salavaggione
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Lee Rivera
- Department of Surgery and Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA
| | - Sarbajit Mukherjee
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA; Department of Internal Medicine, Hematology-Oncology Division, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Rolf Brekken
- Department of Surgery and Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA
| | - Bud Tennant
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Renuka Iyer
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
| | - Araba Adjei
- Department of Medical Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA
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Sanchez-Mejias A, Kwon J, Chew XH, Siemens A, Sohn HS, Jing G, Zhang B, Yang H, Tay Y. A novel SOCS5/miR-18/miR-25 axis promotes tumorigenesis in liver cancer. Int J Cancer 2018; 144:311-321. [DOI: 10.1002/ijc.31857] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 07/14/2018] [Accepted: 08/15/2018] [Indexed: 12/11/2022]
Affiliation(s)
- Avencia Sanchez-Mejias
- Cancer Science Institute of Singapore, Centre for Translational Medicine; National University of Singapore; Singapore 117599 Singapore
| | - Junsu Kwon
- Cancer Science Institute of Singapore, Centre for Translational Medicine; National University of Singapore; Singapore 117599 Singapore
| | - Xiao Hong Chew
- Cancer Science Institute of Singapore, Centre for Translational Medicine; National University of Singapore; Singapore 117599 Singapore
| | - Angela Siemens
- Cancer Science Institute of Singapore, Centre for Translational Medicine; National University of Singapore; Singapore 117599 Singapore
| | - Hye Seon Sohn
- Cancer Science Institute of Singapore, Centre for Translational Medicine; National University of Singapore; Singapore 117599 Singapore
| | - Guo Jing
- Cancer Science Institute of Singapore, Centre for Translational Medicine; National University of Singapore; Singapore 117599 Singapore
| | - Bin Zhang
- Cancer Science Institute of Singapore, Centre for Translational Medicine; National University of Singapore; Singapore 117599 Singapore
| | - Henry Yang
- Cancer Science Institute of Singapore, Centre for Translational Medicine; National University of Singapore; Singapore 117599 Singapore
| | - Yvonne Tay
- Cancer Science Institute of Singapore, Centre for Translational Medicine; National University of Singapore; Singapore 117599 Singapore
- Department of Biochemistry; Yong Loo Lin School of Medicine, National University of Singapore; Singapore 117597 Singapore
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Espín-Pérez A, Krauskopf J, Chadeau-Hyam M, van Veldhoven K, Chung F, Cullinan P, Piepers J, van Herwijnen M, Kubesch N, Carrasco-Turigas G, Nieuwenhuijsen M, Vineis P, Kleinjans JCS, de Kok TMCM. Short-term transcriptome and microRNAs responses to exposure to different air pollutants in two population studies. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2018; 242:182-190. [PMID: 29980036 DOI: 10.1016/j.envpol.2018.06.051] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 06/17/2018] [Accepted: 06/17/2018] [Indexed: 05/18/2023]
Abstract
Diesel vehicle emissions are the major source of genotoxic compounds in ambient air from urban areas. These pollutants are linked to risks of cardiovascular diseases, lung cancer, respiratory infections and adverse neurological effects. Biological events associated with exposure to some air pollutants are widely unknown but applying omics techniques may help to identify the molecular processes that link exposure to disease risk. Most data on health risks are related to long-term exposure, so the aim of this study is to investigate the impact of short-term exposure (two hours) to air pollutants on the blood transcriptome and microRNA expression levels. We analyzed transcriptomics and microRNA expression using microarray technology on blood samples from volunteers participating in studies in London, the Oxford Street cohort, and, in Barcelona, the TAPAS cohort. Personal exposure levels measurements of particulate matter (PM10, PM2.5), ultrafine particles (UFPC), nitrogen oxides (NO2, NO and NOx), black carbon (BC) and carbon oxides (CO and CO2) were registered for each volunteer. Associations between air pollutant levels and gene/microRNA expression were evaluated using multivariate normal models (MVN). MVN-models identified compound-specific expression of blood cell genes and microRNAs associated with air pollution despite the low exposure levels, the short exposure periods and the relatively small-sized cohorts. Hsa-miR-197-3p, hsa-miR-29a-3p, hsa-miR-15a-5p, hsa-miR-16-5p and hsa-miR-92a-3p are found significantly expressed in association with exposures. These microRNAs target also relevant transcripts, indicating their potential relevance in the research of omics-biomarkers responding to air pollution. Furthermore, these microRNAs are also known to be associated with diseases previously linked to air pollution exposure including several cancers such lung cancer and Alzheimer's disease. In conclusion, we identified in this study promising compound-specific mRNA and microRNA biomarkers after two hours of exposure to low levels of air pollutants during two hours that suggest increased cancer risks.
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Affiliation(s)
- Almudena Espín-Pérez
- Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.
| | - Julian Krauskopf
- Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
| | - Marc Chadeau-Hyam
- MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Karin van Veldhoven
- MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Fan Chung
- MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Paul Cullinan
- MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Jolanda Piepers
- Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
| | - Marcel van Herwijnen
- Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
| | - Nadine Kubesch
- Centre for Epidemiology and Screening, University of Copenhagen, Copenhagen, Denmark
| | | | | | - Paolo Vineis
- MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Jos C S Kleinjans
- Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
| | - Theo M C M de Kok
- Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
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Chen X, Cheng JY, Yin J. Predicting microRNA-disease associations using bipartite local models and hubness-aware regression. RNA Biol 2018; 15:1192-1205. [PMID: 30196756 DOI: 10.1080/15476286.2018.1517010] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
The development and progression of numerous complex human diseases have been confirmed to be associated with microRNAs (miRNAs) by various experimental and clinical studies. Predicting potential miRNA-disease associations can help us understand the underlying molecular and cellular mechanisms of diseases and promote the development of disease treatment and diagnosis. Due to the high cost of conventional experimental verification, proposing a new computational method for miRNA-disease association prediction is an efficient and economical way. Since previous computational models ignored the hubness phenomenon, we presented a novel computational model of Bipartite Local models and Hubness-Aware Regression for MiRNA-Disease Association prediction (BLHARMDA). In this method, we first used known miRNA-disease associations to calculate the Jaccard similarity between miRNAs and between diseases, then utilized a modified kNNs model in the bipartite local model method. As a result, we effectively alleviated the detriments from 'bad' hubs. BLHARMDA obtained AUCs of 0.9141 and 0.8390 in the global and local leave-one-out cross validation, respectively, which outperformed most of the previous models and proved high prediction performance of BLHARMDA. Besides, the standard deviation of 0.0006 in 5-fold cross validation confirmed our model's prediction stability and the averaged prediction accuracy of 0.9120 showed the high precision of our model. In addition, to further evaluate our model's accuracy, we implemented BLHARMDA on three typical human diseases in three different types of case studies. As a result, 49 (Esophageal Neoplasms), 50 (Lung Neoplasms) and 50 (Carcinoma Hepatocellular) out of the top 50 related miRNAs were validated by recent experimental discoveries.
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Affiliation(s)
- Xing Chen
- a School of Information and Control Engineering , China University of Mining and Technology , Xuzhou , China
| | - Jun-Yan Cheng
- b College of Computer Science and Technology , Wuhan University of Science and Technology , Hubei , China
| | - Jun Yin
- a School of Information and Control Engineering , China University of Mining and Technology , Xuzhou , China
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40
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Zhu C, Zhang M, Hu J, Li H, Liu S, Li T, Wu L, Han B. Prognostic effect of IL-6/JAK2/STAT3 signal-induced microRNA-21-5p expression on short term recurrence of hepatocellular carcinoma after hepatectomy. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2018; 11:4169-4178. [PMID: 31949811 PMCID: PMC6962805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 06/29/2018] [Indexed: 06/10/2023]
Abstract
AIM To investigate the putative role of interleukin (IL)-6/Janus Kinase (JAK) 2/Signal transducers and activators of transcription (STAT) 3 signaling pathway in hepatocellular carcinoma (HCC) short term recurrence (STR), and whether the pathway promotes HCC progression through microRNA-21-5p (miRNA-21). METHODS Immunohistochemistry was performed to evaluate the protein expression of IL-6, JAK2 and STAT3. Real-time PCR was used to evaluate the miRNA-21 expression. We also analyzed the correlation of IL-6, JAK2 and STAT3 protein expression with miRNA-21. Clinicopathological variables, including prognosis, were compared between low and high-expressing groups of miRNA-21. RESULTS miRNA-21 expression was significantly increased in the HCC tumor tissue compared to the non-tumor tissue. IL-6 and STAT3 high expression was significantly correlated to high miRNA-21 expression in HCC tumor tissues. Patients with high miRNA-21 expression have more frequent early recurrence. The 6 month overall survival and disease-free survival rate of the miRNA-21 high groups were 72.1% and 30.8%, respectively. Moreover, high miRNA-21 expression was correlated with disease-free survival (DFS) (P < 0.05) and overall survival (OS) (P < 0.05). Multivariate analysis revealed that miRNA-21 and STAT3 high expression were independent prognostic factors of DFS and OS. The area under the ROC curve (AUC) of miRNA-21 and STR, DFS, OS was 0.951 (P < 0.001), 0.847 (P < 0.001), 0.844 (P < 0.001), respectively. CONCLUSIONS miRNA-21 expression, induced by IL-6/JAK2/STAT3 signaling pathway, was increased in the early recurrence of HCC patients and indicated poor prognosis. Expression analysis of miRNA-21 revealed that it may be a valuable prognostic biomarker for HCC.
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Affiliation(s)
- Chengzhan Zhu
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao UniversityQingdao, Shandong, P. R. China
| | - Mao Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao UniversityQingdao, Shandong, P. R. China
| | - Jie Hu
- The Third Xiangya Hospital of Central South UniversityChangsha, Hunan, P. R. China
| | - Haoran Li
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao UniversityQingdao, Shandong, P. R. China
| | - Shihai Liu
- Medical Animal Laboratory, The Affiliated Hospital of Qingdao UniversityQingdao, Shandong, P. R. China
| | - Tianxiang Li
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao UniversityQingdao, Shandong, P. R. China
| | - Liqun Wu
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao UniversityQingdao, Shandong, P. R. China
| | - Bing Han
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao UniversityQingdao, Shandong, P. R. China
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Li L, Jia L, Ding Y. Upregulation of miR-375 inhibits human liver cancer cell growth by modulating cell proliferation and apoptosis via targeting ErbB2. Oncol Lett 2018; 16:3319-3326. [PMID: 30127930 DOI: 10.3892/ol.2018.9011] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 12/06/2017] [Indexed: 12/18/2022] Open
Abstract
microRNAs (miRNA/miRs) are a class of small non-coding RNAs; they serve important biological roles in tumorigenesis through the regulation of oncogene expression, and they may be used for the diagnosis and treatment of human cancer. miR-375 was identified to exhibit abnormal expression levels in a number of types of tumor; however, the biological role of miR-375 in human hepatocellular carcinoma (HCC) remains incompletely characterized. The present study investigated the expression of miR-375 in human HCC tissues and human liver cancer cell lines; results from a reverse transcription quantitative polymerase chain reaction analysis indicated that the expression of miR-375 was significantly decreased in tissues and live cancer cell lines, compared with normal tissues and PHH cells. Additional studies demonstrated that the upregulation of miR-375 inhibited human liver cancer cell growth via regulation of cell apoptosis. It was also revealed that the receptor tyrosine-protein kinase erbB-2 (ErbB2) gene was a direct target gene of miR-375, and that the regulation of ErbB2 was associated with the human liver cancer growth. Therefore, the present study demonstrated that miR-375 was expressed at low levels both in human HCC tissues and cell line, compared with normal tissues and PHH cells, and that the induction of miR-375 expression may regulate human liver cancer cell function through targeting the ErbB2 gene, which may potentially improve the diagnosis and treatment of patients with HCC in the future.
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Affiliation(s)
- Lina Li
- Department of Digestive Diseases, Daqing Longnan Hospital, Daqing, Heilongjiang 163453, P.R. China
| | - Liping Jia
- Department of Digestive Diseases, Daqing Longnan Hospital, Daqing, Heilongjiang 163453, P.R. China
| | - Yan Ding
- The First Department of General Surgery, Daqing Oilfield General Hospital, Daqing, Heilongjiang 163000, P.R. China
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Freitas N, Lukash T, Gunewardena S, Chappell B, Slagle BL, Gudima SO. Relative Abundance of Integrant-Derived Viral RNAs in Infected Tissues Harvested from Chronic Hepatitis B Virus Carriers. J Virol 2018; 92:e02221-17. [PMID: 29491161 PMCID: PMC5923063 DOI: 10.1128/jvi.02221-17] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Accepted: 02/17/2018] [Indexed: 02/07/2023] Open
Abstract
Five matching sets of nonmalignant liver tissues and hepatocellular carcinoma (HCC) samples from individuals chronically infected with hepatitis B virus (HBV) were examined. The HBV genomic sequences were determined by using overlapping PCR amplicons covering the entire viral genome. Four pairs of tissues were infected with HBV genotype C, while one pair was infected with HBV genotype B. HBV replication markers were found in all tissues. In the majority of HCC samples, the levels of pregenomic/precore RNA (pgRNA) and covalently closed circular DNA (cccDNA) were lower than those in liver tissue counterparts. Regardless of the presence of HBV replication markers, (i) integrant-derived HBV RNAs (id-RNAs) were found in all tissues by reverse transcription-PCR (RT-PCR) analysis and were considerably abundant or predominant in 6/10 tissue samples (2 liver and 4 HCC samples), (ii) RNAs that were polyadenylated using the cryptic HBV polyadenylation signal and therefore could be produced by HBV replication or derived from integrated HBV DNA were found in 5/10 samples (3 liver and 2 HCC samples) and were considerably abundant species in 3/10 tissues (2 livers and 1 HCC), and (iii) cccDNA-transcribed RNAs polyadenylated near position 1931 were not abundant in 7/10 tissues (2 liver and 5 HCC samples) and were predominant in only two liver samples. Subsequent RNA sequencing analysis of selected liver/HCC samples also showed relative abundance of id-RNAs in most of the examined tissues. Our findings suggesting that id-RNAs could represent a significant source of HBV envelope proteins, which is independent of viral replication, are discussed in the context of the possible contribution of id-RNAs to the HBV life cycle.IMPORTANCE The relative abundance of integrant-derived HBV RNAs (id-RNAs) in chronically infected tissues suggest that id-RNAs coding for the envelope proteins may facilitate the production of a considerable fraction of surface antigens (HBsAg) in infected cells bearing HBV integrants. If the same cells support HBV replication, then a significant fraction of assembled HBV virions could bear id-RNA-derived HBsAg as a major component of their envelopes. Therefore, the infectivity of these HBV virions and their ability to facilitate virus cell-to-cell spread could be determined mainly by the properties of id-RNA-derived envelope proteins and not by the properties of replication-derived HBsAg. These interpretations suggest that id-RNAs may play a role in the maintenance of chronic HBV infection and therefore contribute to the HBV life cycle. Furthermore, the production of HBsAg from id-RNAs independently of viral replication may explain at least in part why treatment with interferon or nucleos(t)ides in most cases fails to achieve a loss of serum HBsAg.
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Affiliation(s)
- Natalia Freitas
- Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Tetyana Lukash
- Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Sumedha Gunewardena
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Benjamin Chappell
- Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Betty L Slagle
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
| | - Severin O Gudima
- Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, USA
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Yin X, Sun S, Zhao J, Yang J, Lei X, Xu C, Li K. Rs4705342 polymorphism is involved in the tumorigenesis of HBV positive HCC by altering the binding affinity of HBV induced NF‐kB with the promoter region of microRNA‐143. J Cell Biochem 2018; 119:5233-5242. [PMID: 29236306 DOI: 10.1002/jcb.26581] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2017] [Accepted: 12/04/2017] [Indexed: 01/05/2023]
Affiliation(s)
- Xiuli Yin
- Department of Internal MedicineShandong Rongjun HospitalJinanP.R. China
| | - Shiying Sun
- Department of General SurgeryShandong Rongjun HospitalJinanP.R. China
| | - Junyan Zhao
- Department of GastroenterologyShandong Qianfoshan Hospital Affiliated to Shandong UniversityJinanP.R. China
| | - Jing Yang
- Department of GastroenterologyShandong Qianfoshan Hospital Affiliated to Shandong UniversityJinanP.R. China
| | - Xiaofei Lei
- Department of GastroenterologyShandong Qianfoshan Hospital Affiliated to Shandong UniversityJinanP.R. China
| | - Changqing Xu
- Department of GastroenterologyShandong Qianfoshan Hospital Affiliated to Shandong UniversityJinanP.R. China
| | - Kun Li
- Department of GastroenterologyShandong Qianfoshan Hospital Affiliated to Shandong UniversityJinanP.R. China
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Li SG, Shi QW, Yuan LY, Qin LP, Wang Y, Miao YQ, Chen Z, Ling CQ, Qin WX. C-Myc-dependent repression of two oncogenic miRNA clusters contributes to triptolide-induced cell death in hepatocellular carcinoma cells. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018. [PMID: 29523159 PMCID: PMC5845216 DOI: 10.1186/s13046-018-0698-2] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Triptolide is a structurally unique diterpene triepoxide with potent antitumor activity. However,the effect and mechanism of triptolide on hepatocellular carcinoma (HCC) is not well studied. METHODS Cells were treated with triptolide, and the anti-HCC activity of triptolide was evaluated using flow cytometry, western blot, and xenograft studies. MicroRNA microarray and quantitative reverse-transcription polymerase chain reaction was used to identify differential microRNAs induced by triptolide. Chromatin immunoprecipitation assay was employed to study the interaction between c-Myc and genomic regions of miR106b-25. MicroRNAs overexpression and knockdown experiments were performed to determine the role of these microRNAs in triptolide-induced apoptosis. RESULTS Triptolide inhibited cell proliferation and induced marked apoptosis in multiple HCC cell lines with different p53 status. Several signaling molecules involved in different pathways were altered after the treatment of triptolide. Xenograft tumor volume was significantly reduced in triptolide-treated group compared with vehicle control group. Two miRNA clusters, miR-17-92 and miR-106b-25, were significantly suppressed by triptolide, which resulted in the upregulation of their common target genes, including BIM, PTEN, and p21. In HCC samples, high levels of these miRNA clusters correlated with shorter recurrence free survival. Triptolide inhibited the expression of theses miRNAs in a c-Myc-dependent manner, which enhanced triptolide-induced cell death. We further showed that triptolide down-regulated the expression of c-Myc through targeting ERCC3, a newly identified triptolide-binding protein. CONCLUSIONS The triptolide-induced modulation of c-Myc/miRNA clusters/target genes axis enhances its potent antitumor activity, which indicates that triptolide serves as an attractive chemotherapeutic agent against HCC.
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Affiliation(s)
- Shu-Guang Li
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China.,Department of Endocrinology, General Hospital of Wuhan, People's Liberation Army, Wuhan, People's Republic of China
| | - Qian-Wei Shi
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China.,Guang An' men Hospital, China Academy of Chinese Medical Sciences, Beijing, People's Republic of China
| | - Ling-Yan Yuan
- Department of oncology, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Li-Ping Qin
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Yan Wang
- Department of oncology, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Yu-Qing Miao
- Department of oncology, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Zhe Chen
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Chang-Quan Ling
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China.
| | - Wen-Xing Qin
- Department of oncology, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China.
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Sengupta D, Govindaraj V, Kar S. Alteration in microRNA-17-92 dynamics accounts for differential nature of cellular proliferation. FEBS Lett 2018; 592:446-458. [PMID: 29331028 DOI: 10.1002/1873-3468.12974] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2017] [Revised: 12/21/2017] [Accepted: 01/05/2018] [Indexed: 12/19/2022]
Abstract
MicroRNAs associated with the mir-17-92 cluster are crucial regulators of the mammalian cell cycle, as they inhibit transcription factors related to the E2F family that tightly control decision-making events for a cell to commit for active cellular proliferation. Intriguingly, in many solid cancers, these mir-17-92 cluster members are overexpressed, whereas in some hematopoietic cancers they are down-regulated. Our proposed model of the Myc/E2F/mir-17-92 network demonstrates that the differential expression pattern of mir-17-92 in different cell types can be conceived due to having a contrasting E2F dynamics induced by mir-17-92. The model predicts that by explicitly altering the mir-17-92-related part of the network, experimentally it is possible to control cellular proliferation in a cell type-dependent manner for therapeutic intervention.
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Affiliation(s)
| | | | - Sandip Kar
- Department of Chemistry, IIT Bombay, Mumbai, India
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47
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Involvement of inflammation and its related microRNAs in hepatocellular carcinoma. Oncotarget 2017; 8:22145-22165. [PMID: 27888618 PMCID: PMC5400654 DOI: 10.18632/oncotarget.13530] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Accepted: 11/02/2016] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most commonly diagnosed type of cancer. The tumor inflammatory microenvironment regulates almost every step towards liver tumorigenesis and subsequent progression, and regulation of the inflammation-related signaling pathways, cytokines, chemokines and non-coding RNAs influences the proliferation, migration and metastasis of liver tumor cells. Inflammation fine-tunes the cancer microenvironment to favor epithelial-mesenchymal transition, in which cancer stem cells maintain tumorigenic potential. Emerging evidence points to inflammation-related microRNAs as crucial molecules to integrate the complex cellular and molecular crosstalk during HCC progression. Thus understanding the mechanisms by which inflammation regulates microRNAs might provide novel and admissible strategies for preventing, diagnosing and treating HCC. In this review, we will update three hypotheses of hepatocarcinogenesis and elaborate the most predominant inflammation signaling pathways, i.e. IL-6/STAT3 and NF-κB. We also try to summarize the crucial tumor-promoting and tumor-suppressing microRNAs and detail how they regulate HCC initiation and progression and collaborate with other critical modulators in this review.
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Expression Profiling of Cellular MicroRNA in Asymptomatic HBsAg Carriers and Chronic Hepatitis B Patients. BIOMED RESEARCH INTERNATIONAL 2017; 2017:6484835. [PMID: 28913356 PMCID: PMC5587942 DOI: 10.1155/2017/6484835] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Revised: 05/31/2017] [Accepted: 06/22/2017] [Indexed: 12/13/2022]
Abstract
Background MicroRNAs (miRNAs) may serve as potential molecular markers to predict liver injury resulting from chronic hepatitis B (CHB). In the present study, we want to study the expression profile and clinical significance of miRNAs at different stages of CHB virus infection. Methods Using miRNA microarray, we investigated the global expression profiles of cellular miRNA in asymptomatic hepatitis B antigen carriers (ASCs) and CHB patients, compared with healthy controls (HCs). Results We identified 79 and 203 differentially expressed miRNAs in the peripheral blood mononuclear cells of ASCs and CHB patients compared to HCs, respectively. Some of these miRNAs were common to ASCs and CHB patients, but another set of miRNAs that showed differential expression between ASCs and CHB patients was also identified. Gene ontology and pathway enrichment analysis showed that the target genes of the identified miRNAs played a role in important biological functions, such as learning or memory, cell-cell adherens junction, ion channel inhibitor activity, TGF-beta signaling pathway, and p53 signaling pathway. Conclusion We identified some significant differentially expressed miRNA in different phases of HBV infection, which might serve as biomarkers or therapeutic targets in the future.
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Keshavarzi M, Sorayayi S, Jafar Rezaei M, Mohammadi M, Ghaderi A, Rostamzadeh A, Masoudifar A, Mirzaei H. MicroRNAs‐Based Imaging Techniques in Cancer Diagnosis and Therapy. J Cell Biochem 2017; 118:4121-4128. [DOI: 10.1002/jcb.26012] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 03/22/2017] [Indexed: 12/12/2022]
Affiliation(s)
- Maryam Keshavarzi
- Department of Oral and Maxillofacial RadiologySchool of DentistryLorestan University of Medical SciencesKhorramabadIran
| | - Saba Sorayayi
- Faculty of MedicineDepartment of Clinical BiochemistryArdabil University of Medical SciencesArdabilIran
| | - Mohammad Jafar Rezaei
- Cellular and Molecular Research Center, Department of Anatomical Sciences, Faculty of MedicineKurdistan University of Medical SciencesSanandajIran
| | - Mohsen Mohammadi
- Faculty of PharmacyDepartment of Pharmaceutical BiotechnologyLorestan University of Medical SciencesKhorramabadIran
| | - Amir Ghaderi
- Faculty of PharmacyDepartment of Pharmaceutical BiotechnologyTehran University of Medical ScienceTehranIran
| | - Ayoob Rostamzadeh
- Faculty of MedicineDepartment of Anatomy and NeuroscienceShahrekord University of Medical SciencesShahrekordIran
| | - Aria Masoudifar
- Department of Molecular BiotechnologyRoyan Institute for BiotechnologyCell Science Research CenterACECRIsfahanIran
| | - Hamed Mirzaei
- Department of Medical BiotechnologySchool of MedicineMashhad University of Medical SciencesMashhadIran
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Anti-microRNA-21/221 and microRNA-199a transfected by ultrasound microbubbles induces the apoptosis of human hepatoma HepG2 cells. Oncol Lett 2017; 13:3669-3675. [PMID: 28529584 PMCID: PMC5431703 DOI: 10.3892/ol.2017.5910] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Accepted: 02/07/2017] [Indexed: 12/23/2022] Open
Abstract
Gene therapy, particularly microRNA (miRNA), is a promising candidate in the treatment of cancer; however, it is challenging to develop gene delivery systems. Ultrasound microbubbles have been used for gene delivery with excellent results. The present study aimed to investigate the transfection efficiency of HepG2 cells using ultrasound microbubbles. The effects of three miRNAs (miR-21, miR-221 and miR-199a) on HepG2 cells were also determined by performing ultrasound microbubble-mediated gene transfection. Three recombinant plasmids containing anti-miR-21, anti-miR-221 and miR-199a were fused with enhanced green fluorescent protein. For the transfection of genes, the type of contrast agent, the concentration of microbubble contrast agent and the exposure intensity of ultrasound were optimized. The expression of miRNAs was detected using reverse transcription-polymerase chain reaction. To determine the effect of anti-miR-21, anti-miR-221 and miR-199a on HepG2 cells, MTT, cell cycle analysis and Annexin V-PE/7-ADD apoptosis assays were performed. The optimal condition was 10% sulfur hexafluoride microbubbles at an ultrasound frequency of 2.0 MHz and mechanical index of 0.28. When cells were transfected with three recombinant plasmids using ultrasound microbubbles, there was significant downregulation of miR-21 and miR-221 and upregulation of miR-199a (P<0.05). All three treatments inhibited cell proliferation and promoted the apoptosis of cells. The present data indicated that the delivery of anti-miR-21, anti-miR-221 and miR-199a may be mediated by ultrasound microbubble contrast agents. With this approach, cell proliferation may be effectively inhibited and cell apoptosis may be induced. These are novel cancer therapy targets.
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