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Causey A, Constantine M, Oswald J, Dellomo A, Masters B, Omorogbe E, Admon A, Garzino-Demo A, Ehrlich E. Analysis of the ubiquitin-modified proteome identifies novel host factors in Kaposi's sarcoma herpesvirus lytic reactivation. J Virol 2025; 99:e0122424. [PMID: 39636148 PMCID: PMC11784101 DOI: 10.1128/jvi.01224-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Accepted: 11/05/2024] [Indexed: 12/07/2024] Open
Abstract
Kaposi's sarcoma herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma and is associated with primary effusion lymphoma (PEL), multicentric Castleman's disease, and two inflammatory diseases. KSHV-associated cancers are primarily associated with genes expressed during latency, while other pathologies are associated with lytic gene expression. The major lytic switch of the virus, Replication and Transcription Activator (RTA), interacts with cellular machinery to co-opt the host ubiquitin proteasome system to evade the immune response as well as activate the program of lytic replication. Through stable isotope labeling using amino acids in cell culture (SILAC) labeling, ubiquitin remnant enrichment, and mass spectrometry, we have analyzed the RTA-dependent ubiquitin-modified proteome. We identified RTA-dependent changes in the populations of polyubiquitin chains, as well as changes in ubiquitinated proteins in both cells expressing RTA and naturally infected cells following lytic reactivation. We observed an enrichment of proteins that are also reported to be SUMOylated, suggesting that RTA, a small ubiquitin-like modifier (SUMO) targeting ubiquitin ligase, may function to alleviate a SUMO-dependent block to lytic reactivation. RTA targeted substrates directly through a ubiquitin ligase domain-dependent mechanism as well as indirectly through cellular ubiquitin ligase RAUL. Our ubiquitome analysis revealed an RTA-dependent mechanism of immune evasion. We provide evidence of inhibition of transporter associated with antigen processing (TAP)-dependent peptide transport, resulting in decreased human leukocyte antigen (HLA) complex stability. The results of this analysis increase our understanding of mechanisms governing the latent to lytic transition in addition to the identification of a novel RTA-dependent mechanism of immune evasion. IMPORTANCE Kaposi's sarcoma herpesvirus, an AIDS-associated pathogen, is associated with multiple cancers and inflammatory syndromes. This virus has a latent and lytic lifecycle, each associated with pathogenesis and oncogenesis. Here, we identify proteins that display differential abundance in different phases of the lifecycle. We provide evidence supporting a new model of viral immune evasion. These findings increase our understanding of how the virus manipulates the host cell and provides new targets for intervention.
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Affiliation(s)
- Amerria Causey
- Biological Sciences, Towson University, Towson, Maryland, USA
| | | | - Jessica Oswald
- Biological Sciences, Towson University, Towson, Maryland, USA
| | - Anna Dellomo
- Biological Sciences, Towson University, Towson, Maryland, USA
| | - Bronwyn Masters
- Biological Sciences, Towson University, Towson, Maryland, USA
| | - Esosa Omorogbe
- Biological Sciences, Towson University, Towson, Maryland, USA
| | - Arie Admon
- Biology, Technion - Israel Institute of Technology, Haifa, Israel
| | - Alfredo Garzino-Demo
- Department of Microbial Pathogenesis, University of Maryland Baltimore School of Dentistry, Baltimore, Maryland, USA
- Department of Microbiology and Immunology, University of Maryland Baltimore School of Medicine, Baltimore, Maryland, USA
- Department of Molecular Medicine, University of Padua, Padua, Italy
| | - Elana Ehrlich
- Biological Sciences, Towson University, Towson, Maryland, USA
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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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Wang W, Hashimi B, Wang P. Targeting ferroptosis: the role of non-coding RNAs in hepatocellular carcinoma progression and therapy. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-03791-y. [PMID: 39820644 DOI: 10.1007/s00210-025-03791-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 01/06/2025] [Indexed: 01/19/2025]
Abstract
One of the most common tumors is hepatocellular carcinoma (HCC), and the prognosis for late-stage HCC is still not good. It is anticipated that improved outcomes would result from a deeper comprehension of the pathophysiology of HCC. Ferroptosis as a new discovered cell death type is linked to the progression of HCC and may be crucial for its detection, prevention, therapy, and prognosis. Numerous studies suggest that epigenetic alterations mediated by non-coding RNAs (ncRNA) might influence cancer cell susceptibility to ferroptosis. This study elucidates the processes of ferroptosis and delineates the paths by which ncRNAs influence HCC by modulating ferroptosis. Furthermore, it offers significant insights into ferroptosis-associated ncRNAs, intending to discover novel therapeutic approaches for HCC. It also explores innovative concepts for the future use of ncRNA-based ferroptosis-targeted therapeutics.
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Affiliation(s)
- Weijia Wang
- Department of Oncology, Qilu Hospital of Shandong University Dezhou Hospital (Dezhou People's Hospital), Shandong Province, China
| | - Behishta Hashimi
- Department of Midwifery, Jahan Institute of Health Sciences, Kabul, Afghanistan
| | - Ping Wang
- Department of Oncology, Yantaishan Hospital Affiliated to Binzhou Medical University, Yantai, Shandong Province, China.
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Razi S, Khojini JY, Norioun H, Hayati MJ, Naseri N, Tajbaksh A, Gheibihayat SM. MicroRNA-mediated regulation of Ferroptosis: Implications for disease pathogenesis and therapeutic interventions. Cell Signal 2024; 125:111503. [PMID: 39510403 DOI: 10.1016/j.cellsig.2024.111503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 10/05/2024] [Accepted: 10/31/2024] [Indexed: 11/15/2024]
Abstract
Ferroptosis, a form of iron-dependent regulated cell death, is characterized by the accumulation of lipid peroxides and distinctive morphological features. Moreover, the reduction of intracellular antioxidant enzyme expression or activity, specifically glutathione peroxidase 4 (GPX4) results in activation of the endogenous pathway of ferroptosis. In this review, we aimed to explore the intricate interplay between microRNAs (miRNAs) and ferroptosis, shedding light on its implications in various disease pathologies. This review delves into the role of miRNAs in modulating key regulators of ferroptosis, including genes involved in iron metabolism, lipid peroxidation, and antioxidant defenses. Furthermore, the potential of targeting miRNAs for therapeutic interventions in ferroptosis-related diseases, such as cancer, neurodegenerative disorders, and ischemia/reperfusion injury, is highlighted.
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Affiliation(s)
- Shokufeh Razi
- Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany
| | - Javad Yaghmoorian Khojini
- Department of Medical Biotechnology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Hamid Norioun
- Medical Genetics Department, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
| | - Mohammad Javad Hayati
- Department of Medical Biotechnology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Nasim Naseri
- Department of Animal Sciences and Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Amir Tajbaksh
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Mohammad Gheibihayat
- Department of Medical Biotechnology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; Yazd Cardiovascular Research Center, Non-communicable Diseases Research Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
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Chen T, Mahdadi S, Vidal M, Desbène-Finck S. Non-nucleoside inhibitors of DNMT1 and DNMT3 for targeted cancer therapy. Pharmacol Res 2024; 207:107328. [PMID: 39079576 DOI: 10.1016/j.phrs.2024.107328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 07/26/2024] [Accepted: 07/26/2024] [Indexed: 08/02/2024]
Abstract
DNA methylation can deactivate tumor suppressor genes thus causing cancers. Two DNA methylation inhibitors have been approved by the Food and Drug Administration (FDA) and have entered clinical use. However, these inhibitors are nucleoside analogues that can be incorporated into DNA or RNA and induce significant side effects. DNMT1 and DNMT3 are key enzymes involved in DNA methylation. In the acute myeloid leukemia model, a non-nucleoside DNMT1-specific inhibitor has shown lower toxicity and improved pharmacokinetics compared to traditional nucleoside drugs. DNMT3 is also implicated in certain specific cancers. Thus, developing non-nucleoside inhibitors for DNMT1 or DNMT3 can help in understanding their roles in carcinogenesis and provide targeted treatment options in certain cancers. Although no non-nucleoside inhibitors have yet entered clinical trials, in this review, we focus on DNMT1 or DNMT3 selective inhibitors. For DNMT1 selective inhibitors, we have compiled information on the repurposed drugs, derivative compounds and selective inhibitors identified through virtual screening. Additionally, we have outlined potential targets for DNMT1, including protein-protein complex, RNA mimics and aptamers. Compared to DNMT1, research on DNMT3-specific inhibitors has been less extensive. In this context, our exploration has identified a limited number of molecular inhibitors, and we have proposed specific long non-coding RNAs (lncRNAs) as potential contributors to the selective inhibition of DNMT3. This collective effort aims to offer valuable insights into the development of non-nucleoside inhibitors that selectively target DNMT1 or DNMT3.
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Affiliation(s)
- Ting Chen
- UMR 8038 CNRS, U1268 INSERM, UFR de pharmacie, Université Paris cité, 75270, France
| | - Syrine Mahdadi
- UMR 8038 CNRS, U1268 INSERM, UFR de pharmacie, Université Paris cité, 75270, France
| | - Michel Vidal
- UMR 8038 CNRS, U1268 INSERM, UFR de pharmacie, Université Paris cité, 75270, France; Toxicology, Cochin Hospital, HUPC, APHP, Paris 75014, France
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Wu L, Zhang Y, Ren J. Targeting non-coding RNAs and N 6-methyladenosine modification in hepatocellular carcinoma. Biochem Pharmacol 2024; 223:116153. [PMID: 38513741 DOI: 10.1016/j.bcp.2024.116153] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 03/08/2024] [Accepted: 03/18/2024] [Indexed: 03/23/2024]
Abstract
Hepatocellular carcinoma (HCC), the most common form of primary liver cancers, accounts for a significant portion of cancer-related death globally. However, the molecular mechanisms driving the onset and progression of HCC are still not fully understood. Emerging evidence has indicated that non-protein-coding regions of genomes could give rise to transcripts, termed non-coding RNA (ncRNA), forming novel functional driving force for aberrant cellular activity. Over the past decades, overwhelming evidence has denoted involvement of a complex array of molecular function of ncRNAs at different stages of HCC tumorigenesis and progression. In this context, several pre-clinical studies have highlighted the potentials of ncRNAs as novel therapeutic modalities in the management of human HCC. Moreover, N6-methyladenosine (m6A) modification, the most prevalent form of internal mRNA modifications in mammalian cells, is essential for the governance of biological processes within cells. Dysregulation of m6A in ncRNAs has been implicated in human carcinogenesis, including HCC. In this review, we will discuss dysregulation of several hallmark ncRNAs (miRNAs, lncRNAs, and circRNAs) in HCC and address the latest advances for their involvement in the onset and progression of HCC. We also focus on dysregulation of m6A modification and various m6A regulators in the etiology of HCC. In the end, we discussed the contemporary preclinical and clinical application of ncRNA-based and m6A-targeted therapies in HCC.
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Affiliation(s)
- Lin Wu
- Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China
| | - Yingmei Zhang
- Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China
| | - Jun Ren
- Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China.
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7
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Cheng T, Zhou C, Bian S, Sobeck K, Liu Y. Coordinated activation of DNMT3a and TET2 in cancer stem cell-like cells initiates and sustains drug resistance in hepatocellular carcinoma. Cancer Cell Int 2024; 24:110. [PMID: 38528605 PMCID: PMC10962188 DOI: 10.1186/s12935-024-03288-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 02/29/2024] [Indexed: 03/27/2024] Open
Abstract
BACKGROUND Resistance to targeted therapies represents a significant hurdle to successfully treating hepatocellular carcinoma (HCC). While epigenetic abnormalities are critical determinants of HCC relapse and therapeutic resistance, the underlying mechanisms are poorly understood. We aimed to address whether and how dysregulated epigenetic regulators have regulatory and functional communications in establishing and maintaining drug resistance. METHODS HCC-resistant cells were characterized by CCK-8, IncuCyte Live-Cell analysis, flow cytometry and wound-healing assays. Target expression was assessed by qPCR and Western blotting. Global and promoter DNA methylation was measured by dotblotting, methylated-DNA immunoprecipitation and enzymatic digestion. Protein interaction and promoter binding of DNMT3a-TET2 were investigated by co-immunoprecipitation, ChIP-qPCR. The regulatory and functional roles of DNMT3a and TET2 were studied by lentivirus infection and puromycin selection. The association of DNMT and TET expression with drug response and survival of HCC patients was assessed by public datasets, spearman correlation coefficients and online tools. RESULTS We identified the coordination of DNMT3a and TET2 as an actionable mechanism of drug resistance in HCC. The faster growth and migration of resistant HCC cells were attributed to DNMT3a and TET2 upregulation followed by increased 5mC and 5hmC production. HCC patients with higher DNMT3a and TET2 had a shorter survival time with a less favorable response to sorafenib therapy than those with lower expression. Cancer stem cell-like cells (CSCs) displayed DNMT3a and TET2 overexpression, which were insensitive to sorafenib. Either genetic or pharmacological suppression of DNMT3a or/and TET2 impaired resistant cell growth and oncosphere formation, and restored sorafenib sensitivity. Mechanistically, DNMT3a did not establish a regulatory circuit with TET2, but formed a complex with TET2 and HDAC2. This complex bound the promoters of oncogenes (i.e., CDK1, CCNA2, RASEF), and upregulated them without involving promoter DNA methylation. In contrast, DNMT3a-TET2 crosstalk silences tumor suppressors (i.e., P15, SOCS2) through a corepressor complex with HDAC2 along with increased promoter DNA methylation. CONCLUSIONS We demonstrate that DNMT3a and TET2 act coordinately to regulate HCC cell fate in DNA methylation-dependent and -independent manners, representing strong predictors for drug resistance and poor prognosis, and thus are promising therapeutic targets for refractory HCC.
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Affiliation(s)
- Tao Cheng
- Department of Hepatobiliary and Pancreas Surgery, First Hospital of Jilin University, Changchun, Jilin, 130021, P.R. China
- The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA
| | - Changli Zhou
- The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA
- MetroHealth Research Institute, Case Western Reserve University, Cleveland, OH, 44109, USA
| | - Sicheng Bian
- MetroHealth Research Institute, Case Western Reserve University, Cleveland, OH, 44109, USA
| | - Kelsey Sobeck
- The Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Yahui Liu
- Department of Hepatobiliary and Pancreas Surgery, First Hospital of Jilin University, Changchun, Jilin, 130021, P.R. China.
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Peng Y, Xiao S, Zuo W, Xie Y, Xiao Y. Potential diagnostic value of miRNAs in sexually transmitted infections. Gene 2024; 895:147992. [PMID: 37977319 DOI: 10.1016/j.gene.2023.147992] [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: 09/21/2023] [Revised: 11/03/2023] [Accepted: 11/13/2023] [Indexed: 11/19/2023]
Abstract
MiRNAs are small endogenous non-coding RNAs that have been demonstrated to be involved in post-transcriptional gene silencing, regulating a number of metabolic functions in the human body, including immune response, cellular physiology, organ development, angiogenesis, signaling, and other aspects. As popular molecules that have been studied in previous years, given their extensive regulatory functions, miRNAs hold considerable promise as non-invasive biomarkers. Sexually transmitted infections(STIs) are still widespread and have an adverse effect on individuals, communities, and society worldwide. miRNAs in the regulatory networks are generally involved in their molecular processes of formation and development. In this review, we discuss the value of miRNAs for the diagnosis of STIs.
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Affiliation(s)
- Yunchi Peng
- Department of Clinical Laboratory, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China
| | - Shuangwen Xiao
- Department of Clinical Laboratory, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China
| | - Wei Zuo
- Department of Clinical Laboratory, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China
| | - Yafeng Xie
- Department of Clinical Laboratory, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China
| | - Yongjian Xiao
- Department of Clinical Laboratory, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China.
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Shan C, Liang Y, Wang K, Li P. Noncoding RNAs in cancer ferroptosis: From biology to clinical opportunity. Biomed Pharmacother 2023; 165:115053. [PMID: 37379641 DOI: 10.1016/j.biopha.2023.115053] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/16/2023] [Accepted: 06/21/2023] [Indexed: 06/30/2023] Open
Abstract
Ferroptosis is a recently discovered pattern of programmed cell death that is nonapoptotic and irondependent. It is involved in lipid peroxidation dependent on reactive oxygen species. Ferroptosis has been verified to play a crucial regulatory role in a variety of pathological courses of disease, in particularly cancer. Emerging research has highlighted the potential of ferroptosis in tumorigenesis, cancer development and resistance to chemotherapy. However, the regulatory mechanism of ferroptosis remains unclear, which limits the application of ferroptosis in cancer treatment. Noncoding RNAs (ncRNAs) are noncoding transcripts that regulate gene expression in various ways to affect the malignant phenotypes of cancer cells. At present, the biological function and underlying regulatory mechanism of ncRNAs in cancer ferroptosis have been partially elucidated. Herein, we summarize the current knowledge of the central regulatory network of ferroptosis, with a focus on the regulatory functions of ncRNAs in cancer ferroptosis. The clinical application and prospects of ferroptosis-related ncRNAs in cancer diagnosis, prognosis and anticancer therapies are also discussed. Elucidating the function and mechanism of ncRNAs in ferroptosis, along with assessing the clinical significance of ferroptosis-related ncRNAs, provides new perspectives for understanding cancer biology and treatment approaches, which may benefit numerous cancer patients in the future.
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Affiliation(s)
- Chan Shan
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China.
| | - Yan Liang
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266021, China
| | - Kun Wang
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Peifeng Li
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China.
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Zheng P, Dou Y, Wang Q. Immune response and treatment targets of chronic hepatitis B virus infection: innate and adaptive immunity. Front Cell Infect Microbiol 2023; 13:1206720. [PMID: 37424786 PMCID: PMC10324618 DOI: 10.3389/fcimb.2023.1206720] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Accepted: 06/06/2023] [Indexed: 07/11/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a major global public health risk that threatens human life and health, although the number of vaccinated people has increased. The clinical outcome of HBV infection depends on the complex interplay between viral replication and the host immune response. Innate immunity plays an important role in the early stages of the disease but retains no long-term immune memory. However, HBV evades detection by the host innate immune system through stealth. Therefore, adaptive immunity involving T and B cells is crucial for controlling and clearing HBV infections that lead to liver inflammation and damage. The persistence of HBV leads to immune tolerance owing to immune cell dysfunction, T cell exhaustion, and an increase in suppressor cells and cytokines. Although significant progress has been made in HBV treatment in recent years, the balance between immune tolerance, immune activation, inflammation, and fibrosis in chronic hepatitis B remains unknown, making a functional cure difficult to achieve. Therefore, this review focuses on the important cells involved in the innate and adaptive immunity of chronic hepatitis B that target the host immune system and identifies treatment strategies.
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Affiliation(s)
- Peiyu Zheng
- Department of Infectious Diseases, The First Hospital of Shanxi Medical University, Taiyuan, China
- Graduate School of Shanxi Medical University, Taiyuan, China
| | - Yongqing Dou
- Department of Infectious Diseases, The First Hospital of Shanxi Medical University, Taiyuan, China
| | - Qinying Wang
- Department of Infectious Diseases, The First Hospital of Shanxi Medical University, Taiyuan, China
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Lee BB, Kim D, Kim Y, Han J, Shim YM, Kim DH. Metformin regulates expression of DNA methyltransferases through the miR-148/-152 family in non-small lung cancer cells. Clin Epigenetics 2023; 15:48. [PMID: 36959680 PMCID: PMC10037810 DOI: 10.1186/s13148-023-01466-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Accepted: 03/15/2023] [Indexed: 03/25/2023] Open
Abstract
BACKGROUND To understand the molecular mechanisms involved in regulation of DNA methyltransferases (DNMTs) by metformin in non-small cell lung cancer (NSCLC) cells. METHODS Expression levels of DNMTs in response to metformin were analyzed in NSCLC cells. MicroRNAs regulating expression of DNMTs at the post-transcriptional level were searched using miRNA-target databases (miRDB and miRTarBase), TCGA RNASeqV2 lung cancer data, and miRNA-seq. RESULTS Metformin dose-dependently downregulated expression of DNMT1 and DNMT3a at the post-transcriptional level and expression of DNMT3b at the transcriptional level in A549 lung cancer cells. Activity of DNMTs was reduced by about 2.6-fold in A549 cells treated with 10 mM metformin for 72 h. miR-148/-152 family members (miR-148a, miR-148b, and miR-152) targeting the 3'UTR of DNMTs were associated with post-transcriptional regulation of DNMTs by metformin. Metformin upregulated expression of miR-148a, miR-148b, and miR-152 in A549 and H1650 cells. Transfection with an miR-148b plasmid or a mimic suppressed expression of DNMT1 and DNMT3b in A549 cells. Transfection with the miR-148a mimic in A549 and H1650 cells decreased the luciferase activity of DNMT1 3'UTR. A combination of metformin and cisplatin synergistically increased expression levels of miR-148/-152 family members but decreased expression of DNMTs in A549 cells. Low expression of miR-148b was associated with poor overall survival (HR = 2.56, 95% CI 1.09-6.47; P = 0.04) but not with recurrence-free survival. CONCLUSIONS The present study suggests that metformin inhibits expression of DNMTs by upregulating miR-148/-152 family members in NSCLC cells.
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Affiliation(s)
- Bo Bin Lee
- Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 16419, Korea
| | - Dongho Kim
- Yonsei New I1 Han Institute for Integrative Lung Cancer Research, Yonsei University College of Medicine, Seoul, 03772, Korea
| | - Yujin Kim
- Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 16419, Korea
| | - Joungho Han
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea
| | - Young Mog Shim
- Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea
| | - Duk-Hwan Kim
- Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 16419, Korea.
- Samsung Comprehensive Cancer CenterResearch Institute for Future Medicine S139-7, #50 Ilwon-dong, Gangnam-gu, Seoul, 06351, Korea.
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Hu CY, Wu HT, Shan YS, Wang CT, Shieh GS, Wu CL, Ou HY. Evodiamine Exhibits Anti-Bladder Cancer Activity by Suppression of Glutathione Peroxidase 4 and Induction of Ferroptosis. Int J Mol Sci 2023; 24:ijms24076021. [PMID: 37046995 PMCID: PMC10094601 DOI: 10.3390/ijms24076021] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 03/17/2023] [Accepted: 03/21/2023] [Indexed: 04/03/2023] Open
Abstract
Evodiamine (EVO) exhibits anti-cancer activity through the inhibition of cell proliferation; however, little is known about its underlying mechanism. To determine whether ferroptosis is involved in the therapeutic effects of EVO, we investigated critical factors, such as lipid peroxidation levels and glutathione peroxidase 4 (GPX4) expression, under EVO treatment. Our results showed that EVO inhibited the cell proliferation of poorly differentiated, high-grade bladder cancer TCCSUP cells in a dose- and time-dependent manner. Lipid peroxides were detected by fluorescence microscopy after cancer cell exposure to EVO. GPX4, which catalyzes the conversion of lipid peroxides to prevent cells from undergoing ferroptosis, was decreased dose-dependently by EVO treatment. Given the features of iron dependency and lipid-peroxidation-driven death in ferroptosis, the iron chelator deferoxamine (DFO) was used to suppress EVO-induced ferroptosis. The lipid peroxide level significantly decreased when cells were treated with DFO prior to EVO treatment. DFO also attenuated EVO-induced cell death. Co-treatment with a pan-caspase inhibitor or necroptosis inhibitor with EVO did not alleviate cancer cell death. These results indicate that EVO induces ferroptosis rather than apoptosis or necroptosis. Furthermore, EVO suppressed the migratory ability, decreased the expression of mesenchymal markers, and increased epithelial marker expression, determined by a transwell migration assay and Western blotting. The TCCSUP bladder tumor xenograft tumor model confirmed the effects of EVO on the inhibition of tumor growth and EMT. In conclusion, EVO is a novel inducer for activating the ferroptosis of bladder cancer cells and may be a potential therapeutic agent for bladder cancer.
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Affiliation(s)
- Che-Yuan Hu
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; (C.-Y.H.)
- Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Hung-Tsung Wu
- Department of Internal Medicine, School of Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Yan-Shen Shan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; (C.-Y.H.)
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Chung-Teng Wang
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Gia-Shing Shieh
- Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
- Department of Urology, Tainan Hospital, Ministry of Health and Welfare, Executive Yuan, Tainan 70043, Taiwan
| | - Chao-Liang Wu
- Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 600566, Taiwan
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
- Correspondence: (C.-L.W.); (H.-Y.O.); Tel.: +886-920-598-519 (C.-L.W.); +886-6-2353535 (ext. 4577) (H.-Y.O.)
| | - Horng-Yih Ou
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; (C.-Y.H.)
- Department of Internal Medicine, School of Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
- Correspondence: (C.-L.W.); (H.-Y.O.); Tel.: +886-920-598-519 (C.-L.W.); +886-6-2353535 (ext. 4577) (H.-Y.O.)
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13
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Papadimitriou MA, Panoutsopoulou K, Pilala KM, Scorilas A, Avgeris M. Epi-miRNAs: Modern mediators of methylation status in human cancers. WILEY INTERDISCIPLINARY REVIEWS. RNA 2023; 14:e1735. [PMID: 35580998 DOI: 10.1002/wrna.1735] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 04/07/2022] [Accepted: 04/11/2022] [Indexed: 02/01/2023]
Abstract
Methylation of the fundamental macromolecules, DNA/RNA, and proteins, is remarkably abundant, evolutionarily conserved, and functionally significant in cellular homeostasis and normal tissue/organism development. Disrupted methylation imprinting is strongly linked to loss of the physiological equilibrium and numerous human pathologies, and most importantly to carcinogenesis, tumor heterogeneity, and cancer progression. Mounting recent evidence has documented the active implication of miRNAs in the orchestration of the multicomponent cellular methylation machineries and the deregulation of methylation profile in the epigenetic, epitranscriptomic, and epiproteomic levels during cancer onset and progression. The elucidation of such regulatory networks between the miRNome and the cellular methylation machineries has led to the emergence of a novel subclass of miRNAs, namely "epi-miRNAs" or "epi-miRs." Herein, we have summarized the existing knowledge on the functional role of epi-miRs in the methylation dynamic landscape of human cancers and their clinical utility in modern cancer diagnostics and tailored therapeutics. This article is categorized under: RNA in Disease and Development > RNA in Disease.
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Affiliation(s)
- Maria-Alexandra Papadimitriou
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Konstantina Panoutsopoulou
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Katerina-Marina Pilala
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Andreas Scorilas
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Margaritis Avgeris
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.,Laboratory of Clinical Biochemistry - Molecular Diagnostics, Second Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, "P. & A. Kyriakou" Children's Hospital, Athens, Greece
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14
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Dou W, Xie J, Chen J, Zhou J, Xu Z, Wang Z, Zhu Q. Overexpression of adrenomedullin (ADM) alleviates the senescence of human dental pulp stem cells by regulating the miR-152/CCNA2 pathway. Cell Cycle 2023; 22:565-579. [PMID: 36310381 PMCID: PMC9928452 DOI: 10.1080/15384101.2022.2135621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
The limitation of human dental pulp stem cells (DPSCs), which have potential application value in regenerative medicine, is that they are prone to age in vitro. Studies have shown adrenomedullin (ADM) is believed to promote the proliferation of human DPSCs, but whether it can also affect aging remains to be investigated. A lentivirus vector was used to construct human DPSCs overexpressing ADM. Senescence tests were carried out on cells of the 7th and 15th passage. Transcriptome analysis was conducted to analyze microRNA expression regulation changes after human DPSCs overexpressed ADM. H2O2 induced the aging model of human DPSCs, and we examined the mechanism of recovery of aging through transfection experiments with miR-152 mimic, pCDH-CCNA2, and CCNA2 siRNA. Overexpression of ADM significantly upregulated the G2/M phase ratio of human DPSCs in natural passage culture (P = 0.001) and inhibited the expression of p53 (P = 0.014), P21 WAF1 (P = 0.015), and P16 INK4A (P = 0.001). Decreased ROS accumulation was observed in human DPSCs during long-term natural passage (P = 0.022). Transcriptome analysis showed that miR-152 was significantly upregulated during human DPSC senescence (P = 0.001) and could induce cell senescence by directly targeting CCNA2. Transfection with miR-152 mimic significantly reversed the inhibitory effect of ADM overexpression on p53 (P = 0.006), P21 WAF1 (P = 0.012), and P16 INK4A (P = 0.01) proteins in human DPSCs (H2O2-induced). In contrast, pCDH-CCNA2 weakened the effect of the miR-152 mimic, thus promoting cell proliferation and antiaging. ADM-overexpressing human DPSCs promote cell cycle progression and resist cellular senescence through CCNA2 expression promotion by inhibiting miR-152.
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Affiliation(s)
- Wenxue Dou
- Department of Stomatology, The First Affiliated Hospital of Naval Medical University: Changhai Hospital, Shanghai, China
| | - Jiaye Xie
- Department of Stomatology, Tongren Hospital Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jianan Chen
- Department of Stomatology, The First Affiliated Hospital of Naval Medical University: Changhai Hospital, Shanghai, China
| | - Jiajun Zhou
- Department of Stomatology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Zunyue Xu
- Department of Stomatology, Shanghai Songjiang District Central Hospital, Shanghai, China
| | - Zheng Wang
- Department of Stomatology, Tongren Hospital Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Qiang Zhu
- Department of Stomatology, The First Affiliated Hospital of Naval Medical University: Changhai Hospital, Shanghai, China,CONTACT Qiang Zhu Department of Stomatology, The First Affiliated Hospital of Naval Medical University: Changhai Hospital, Shanghai200433, China
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15
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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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16
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Mahmoudi-Lamouki R, Kadkhoda S, Hussen BM, Ghafouri-Fard S. Emerging role of miRNAs in the regulation of ferroptosis. Front Mol Biosci 2023; 10:1115996. [PMID: 36876051 PMCID: PMC9975729 DOI: 10.3389/fmolb.2023.1115996] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 02/06/2023] [Indexed: 02/17/2023] Open
Abstract
Ferroptosis is a kind of cell death which has distinctive features differentiating it from autophagy, necrosis and apoptosis. This iron-dependent form of cell death is described by an increase in lipid reactive oxygen species, shrinkage of mitochondria and decrease in mitochondrial cristae. Ferroptosis is involved in the initiation and progression of many diseases and is regarded as a hotspot of investigations on treatment of disorders. Recent studies have shown that microRNAs partake in the regulation of ferroptosis. The impact of microRNAs on this process has been verified in different cancers as well as intervertebral disc degeneration, acute myocardial infarction, vascular disease, intracerebral hemorrhage, preeclampsia, hemorrhagic stroke, atrial fibrillation, pulmonary fibrosis and atherosclerosis. miR-675, miR-93, miR-27a, miR-34a and miR-141 have been shown to affect iron metabolism, antioxidant metabolism and lipid metabolism, thus influencing all pivotal mechanisms in the ferroptosis process. In the current review, we summarize the role of microRNAs in ferroptosis and their involvement in the pathetiology of malignant and non-malignant disorders.
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Affiliation(s)
| | - Sepideh Kadkhoda
- Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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17
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Bhattacharya A. Epigenetic modifications and regulations in gastrointestinal diseases. EPIGENETICS IN ORGAN SPECIFIC DISORDERS 2023:497-543. [DOI: 10.1016/b978-0-12-823931-5.00005-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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18
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Prinz C, Frese R, Grams M, Fehring L. Emerging Role of microRNA Dysregulation in Diagnosis and Prognosis of Extrahepatic Cholangiocarcinoma. Genes (Basel) 2022; 13:1479. [PMID: 36011390 PMCID: PMC9407895 DOI: 10.3390/genes13081479] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 08/11/2022] [Accepted: 08/12/2022] [Indexed: 12/01/2022] Open
Abstract
Extrahepatic cholangiocarcinomas, also called bile duct carcinomas, represent a special entity in gastrointestinal tumors, and histological specimens of the tumors are often difficult to obtain. A special feature of these tumors is the strong neovascularization, which can often be seen in the endoluminal endoscopic procedure called cholangioscopy, performed alone or in combination with laserscanning techniques. The additional analysis of microRNA expression profiles associated with inflammation and neovascularization in bile duct tumors or just the bile duct fluid of these patients could be of enormous additional importance. In particular, the dysregulation of microRNA in these cholangiocarcinomas (CCA) was previously reported to affect epigenetics (reported for miR-148, miR-152), inflammation (determined for miR-200, miR-125, and miR-605), and chemoresistance (miR-200b, 204) in patients with cholangiocarcinoma. More importantly, in the context of malignant neovascularization, well-defined microRNAs including miR-141, miR-181, miR-191, and miR-200b have been found to be dysregulated in cholangiocarcinoma and have been associated with an increased proliferation and vascularization in CCA. Thus, a panel of these microRNA molecules together with the clinical aspects of these tumors might facilitate tumor diagnosis and early treatment. To our knowledge, this is the first review that outlines the unique potential of combining macroscopic findings from cholangioscopy with microRNA expression.
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Affiliation(s)
- Christian Prinz
- Medizinische Klinik 2, Helios Universitätsklinikum, 42283 Wuppertal, Germany
- Lehrstuhl für Innere Medizin 1 der, University of Witten gGmbH, 42283 Wuppertal, Germany
| | - Robin Frese
- Medizinische Klinik 2, Helios Universitätsklinikum, 42283 Wuppertal, Germany
- Lehrstuhl für Innere Medizin 1 der, University of Witten gGmbH, 42283 Wuppertal, Germany
| | - Mashiba Grams
- Medizinische Klinik 2, Helios Universitätsklinikum, 42283 Wuppertal, Germany
- Lehrstuhl für Innere Medizin 1 der, University of Witten gGmbH, 42283 Wuppertal, Germany
| | - Leonard Fehring
- Medizinische Klinik 2, Helios Universitätsklinikum, 42283 Wuppertal, Germany
- Lehrstuhl für Innere Medizin 1 der, University of Witten gGmbH, 42283 Wuppertal, Germany
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19
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Mofed D, Sabet S, Baiomy AA, Salem TZ. The Transgene Expression of the Immature Form of the HCV Core Protein (C191) and the LncRNA MEG3 Increases Apoptosis in HepG2 Cells. Curr Issues Mol Biol 2022; 44:3632-3647. [PMID: 36005145 PMCID: PMC9406719 DOI: 10.3390/cimb44080249] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/20/2022] [Accepted: 07/21/2022] [Indexed: 11/16/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) are regulated in cancer cells, including lncRNA MEG3, which is downregulated in Hepatocellular Carcinoma (HCC). In addition, hepatitis C virus (HCV) core proteins are known to dysregulate important cellular pathways that are linked to HCC development. In this study, we were interested in evaluating the overexpression of lncRNA MEG3, either alone or in combination with two forms of HCV core protein (C173 and C191) in HepG2 cells. Cell viability was assessed by MTT assay. Transcripts' levels of key genes known to be regulated in HCC, such as p53, DNMT1, miRNA152, TGF-b, and BCL-2, were measured by qRT-PCR. Protein expression levels of caspase-3 and MKI67 were determined by immunocytochemistry and apoptosis assays. The co-expression of lncRNA MEG3 and C191 resulted in a marked increase and accumulation of dead cells and a reduction in cell viability. In addition, a marked increase in the expression of tumor suppressor genes (p53 and miRNA152), as well as a marked decrease in the expression of oncogenes (DNMT1, BCL2, and TGF-b), were detected. Moreover, apoptosis assay results revealed a significant increase in total apoptosis (early and late). Finally, immunocytochemistry results detected a significant increase in apoptotic marker caspase-3 and a decrease in tumor marker MKI67. In this study, transgene expression of C191 and lncRNA MEG3 showed induction in apoptosis in HepG2 cells greater than the expression of each one alone. These results suggest potential anticancer characteristics.
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Affiliation(s)
- Dina Mofed
- Molecular Biology and Virology Lab, Biomedical Sciences Program, Zewail City of Science and Technology, October Gardens, 6th of October City, Giza 12578, Egypt
- Zoology Graduate Program, Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Salwa Sabet
- Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Ahmed A. Baiomy
- Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Tamer Z. Salem
- Molecular Biology and Virology Lab, Biomedical Sciences Program, Zewail City of Science and Technology, October Gardens, 6th of October City, Giza 12578, Egypt
- Department of Microbial Genetics, Agricultural Genetic Engineering Research Institute (AGERl), Agricultural Research Center (ARC), Giza 12619, Egypt
- National Biotechnology Network of Expertise (NBNE), Academy of Science Research and Technology (ASRT), Cairo 11334, Egypt
- Correspondence: ; Tel.: +20-1014114122
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20
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Xiong X, Yang M, Yu H, Hu Y, Yang L, Zhu Y, Fei X, Pan B, Xiong Y, Fu W, Li J. MicroRNA‐342‐3p regulates yak oocyte meiotic maturation by targeting DNA methyltransferase 1. Reprod Domest Anim 2022; 57:761-770. [DOI: 10.1111/rda.14119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 03/24/2022] [Accepted: 03/27/2022] [Indexed: 11/30/2022]
Affiliation(s)
- Xianrong Xiong
- Key Laboratory of Qinghai‐Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education Southwest Minzu University Chengdu Sichuan 610041 P.R. China
| | - Manzhen Yang
- Key Laboratory for Animal Science of National Ethnic Affairs Commission Southwest Minzu University Chengdu Sichuan 610041 P.R. China
| | - Hailing Yu
- Key Laboratory for Animal Science of National Ethnic Affairs Commission Southwest Minzu University Chengdu Sichuan 610041 P.R. China
| | - Yulei Hu
- Key Laboratory of Qinghai‐Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education Southwest Minzu University Chengdu Sichuan 610041 P.R. China
| | - Luyu Yang
- Key Laboratory for Animal Science of National Ethnic Affairs Commission Southwest Minzu University Chengdu Sichuan 610041 P.R. China
| | - Yanjin Zhu
- Key Laboratory of Qinghai‐Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education Southwest Minzu University Chengdu Sichuan 610041 P.R. China
| | - Xixi Fei
- Key Laboratory of Qinghai‐Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education Southwest Minzu University Chengdu Sichuan 610041 P.R. China
| | - Bangting Pan
- Key Laboratory of Qinghai‐Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education Southwest Minzu University Chengdu Sichuan 610041 P.R. China
| | - Yan Xiong
- Key Laboratory for Animal Science of National Ethnic Affairs Commission Southwest Minzu University Chengdu Sichuan 610041 P.R. China
| | - Wei Fu
- Key Laboratory of Qinghai‐Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education Southwest Minzu University Chengdu Sichuan 610041 P.R. China
| | - Jian Li
- Key Laboratory of Qinghai‐Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education Southwest Minzu University Chengdu Sichuan 610041 P.R. China
- Key Laboratory for Animal Science of National Ethnic Affairs Commission Southwest Minzu University Chengdu Sichuan 610041 P.R. China
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21
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Zhao S, Zheng W, Yu C, Xu G, Zhang X, Pan C, Feng Y, Yang K, Zhou J, Ma Y. The Role of Ferroptosis in the Treatment and Drug Resistance of Hepatocellular Carcinoma. Front Cell Dev Biol 2022; 10:845232. [PMID: 35309918 PMCID: PMC8927068 DOI: 10.3389/fcell.2022.845232] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 02/04/2022] [Indexed: 01/11/2023] Open
Abstract
Cell death is a fundamental feature of multicellular organisms’ development and a key driver of degenerative diseases. Ferroptosis is a new regulatory cell death mediated by iron-dependent lipid peroxidation, which is different from apoptosis and necrosis in morphology, pathophysiology and mechanism. Recent studies have found that ferroptosis is involved in the development of many diseases including hepatocellular carcinoma (HCC). As further research progresses, specific mechanisms of ferroptosis in HCC are being revealed. In this review, we summarize these recent advances about the treatment of drug-resistance in HCC and the latest ferroptosis-related treatment for HCC.
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Affiliation(s)
| | | | | | | | | | | | | | - Kunxing Yang
- *Correspondence: Kunxing Yang, ; Jin Zhou, ; Yong Ma,
| | - Jin Zhou
- *Correspondence: Kunxing Yang, ; Jin Zhou, ; Yong Ma,
| | - Yong Ma
- *Correspondence: Kunxing Yang, ; Jin Zhou, ; Yong Ma,
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22
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Zhang G, Zheng D, Chen X, Li L, Yu J. miR-152-mediated MKK7 downregulation is attenuated by MYCNOS in ovarian adenocarcinoma. Oncol Lett 2021; 22:841. [PMID: 34733360 PMCID: PMC8561216 DOI: 10.3892/ol.2021.13102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 09/07/2021] [Indexed: 12/09/2022] Open
Abstract
MYCN opposite strand (MYCNOS) acts as an oncogenic long non-coding RNA in liver cancer. However, its role in other cancer types is unknown. The aim of the present study was to investigate the function of MYCNOS in ovarian adenocarcinoma (OA). MYCNOS expression in OA was determined using reverse transcription-quantitative PCR (RT-qPCR), and its prognostic value for OA was evaluated in a 5-year follow-up study. The predicted interaction between MYCNOS and microRNA (miR)-152 was confirmed using a dual luciferase reporter assay. The association between MYCNOS and miR-152 was also analyzed in overexpression experiments. The effects of MYCNOS and miR-152 on mitogen-activated protein kinase kinase 7 (MKK7) expression were explored using RT-qPCR and western blotting. Cell proliferation was analyzed using a Cell Counting Kit-8 assay. MYCNOS expression was found to be upregulated in OA and predicted poor survival. In addition, MYCNOS was predicted to interact with miR-152, and a dual luciferase assay confirmed this interaction. However, MYCNOS and miR-152 overexpression did not affect their mutual expression levels. MYCNOS overexpression upregulated MKK7, a target of miR-152. Cell proliferation increased following simultaneous MYCNOS and MKK7 overexpression, but was reduced following miR-152 overexpression. Moreover, MYCNOS overexpression attenuated the effects of miR-152 overexpression. In conclusion, MYCNOS may act by sponging miR-152 to upregulate MKK7 expression in OA, thereby promoting cell proliferation.
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Affiliation(s)
- Guifang Zhang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China
| | - Dan Zheng
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China
| | - Xiaoqing Chen
- Day Operation Center, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi 330003, P.R. China
| | - Li Li
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China
| | - Jingrong Yu
- Department of Oncology, The Fourth Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330003, P.R. China
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23
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Wu S, Li T, Liu W, Huang Y. Ferroptosis and Cancer: Complex Relationship and Potential Application of Exosomes. Front Cell Dev Biol 2021; 9:733751. [PMID: 34568341 PMCID: PMC8455874 DOI: 10.3389/fcell.2021.733751] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 08/13/2021] [Indexed: 12/15/2022] Open
Abstract
Cell death induction has become popular as a novel cancer treatment. Ferroptosis, a newly discovered form of cell death, features regulated, iron-dependent accumulation of lipid hydroperoxides. Since this word “ferroptosis” was coined, numerous studies have examined the complex relationship between ferroptosis and cancer. Here, starting from the intrinsic hallmarks of cancer and cell death, we discuss the theoretical basis of cell death induction as a cancer treatment. We review various aspects of the relationship between ferroptosis and cancer, including the genetic basis, epigenetic modification, cancer stem cells, and the tumor microenvironment, to provide information and support for further research on ferroptosis. We also note that exosomes can be applied in ferroptosis-based therapy. These extracellular vesicles can deliver different molecules to modulate cancer cells and cell death pathways. Using exosomes to control ferroptosis occurring in targeted cells is promising for cancer therapy.
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Affiliation(s)
- Shuang Wu
- College of Life and Health Sciences, Northeastern University, Shenyang, China
| | - Tianye Li
- College of Life and Health Sciences, Northeastern University, Shenyang, China
| | - Weiwei Liu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China.,Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Changchun, China
| | - Yongye Huang
- College of Life and Health Sciences, Northeastern University, Shenyang, China
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24
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Zhang D, Guo S, Schrodi SJ. Mechanisms of DNA Methylation in Virus-Host Interaction in Hepatitis B Infection: Pathogenesis and Oncogenetic Properties. Int J Mol Sci 2021; 22:9858. [PMID: 34576022 PMCID: PMC8466338 DOI: 10.3390/ijms22189858] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 09/10/2021] [Accepted: 09/10/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatitis B virus (HBV), the well-studied oncovirus that contributes to the majority of hepatocellular carcinomas (HCC) worldwide, can cause a severe inflammatory microenvironment leading to genetic and epigenetic changes in hepatocyte clones. HBV replication contributes to the regulation of DNA methyltransferase gene expression, particularly by X protein (HBx), and subsequent methylation changes may lead to abnormal transcription activation of adjacent genes and genomic instability. Undoubtedly, the altered expression of these genes has been known to cause diverse aspects of infected hepatocytes, including apoptosis, proliferation, reactive oxygen species (ROS) accumulation, and immune responses. Additionally, pollutant-induced DNA methylation changes and aberrant methylation of imprinted genes in hepatocytes also complicate the process of tumorigenesis. Meanwhile, hepatocytes also contribute to epigenetic modification of the viral genome to affect HBV replication or viral protein production. Meanwhile, methylation levels of HBV integrants and surrounding host regions also play crucial roles in their ability to produce viral proteins in affected hepatocytes. Both host and viral changes can provide novel insights into tumorigenesis, individualized responses to therapeutic intervention, disease progress, and early diagnosis. As such, DNA methylation-mediated epigenetic silencing of cancer-related genes and viral replication is a compelling therapeutic goal to reduce morbidity and mortality from liver cancer caused by chronic HBV infection. In this review, we summarize the most recent research on aberrant DNA methylation associated with HBV infection, which is involved in HCC development, and provide an outlook on the future direction of the research.
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Affiliation(s)
- Dake Zhang
- Key Laboratory of Biomechanics and Mechanobiology, Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China
| | - Shicheng Guo
- Department of Medical Genetics, University of Wisconsin-Madison, Madison, WI 53706, USA;
| | - Steven J. Schrodi
- Department of Medical Genetics, University of Wisconsin-Madison, Madison, WI 53706, USA;
- Computation and Informatics in Biology and Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA
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25
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Pietropaolo V, Prezioso C, Moens U. Role of Virus-Induced Host Cell Epigenetic Changes in Cancer. Int J Mol Sci 2021; 22:ijms22158346. [PMID: 34361112 PMCID: PMC8346956 DOI: 10.3390/ijms22158346] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 07/30/2021] [Accepted: 08/02/2021] [Indexed: 12/12/2022] Open
Abstract
The tumor viruses human T-lymphotropic virus 1 (HTLV-1), hepatitis C virus (HCV), Merkel cell polyomavirus (MCPyV), high-risk human papillomaviruses (HR-HPVs), Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpes virus (KSHV) and hepatitis B virus (HBV) account for approximately 15% of all human cancers. Although the oncoproteins of these tumor viruses display no sequence similarity to one another, they use the same mechanisms to convey cancer hallmarks on the infected cell. Perturbed gene expression is one of the underlying mechanisms to induce cancer hallmarks. Epigenetic processes, including DNA methylation, histone modification and chromatin remodeling, microRNA, long noncoding RNA, and circular RNA affect gene expression without introducing changes in the DNA sequence. Increasing evidence demonstrates that oncoviruses cause epigenetic modifications, which play a pivotal role in carcinogenesis. In this review, recent advances in the role of host cell epigenetic changes in virus-induced cancers are summarized.
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Affiliation(s)
- Valeria Pietropaolo
- Department of Public Health and Infectious Diseases, “Sapienza” University, 00185 Rome, Italy;
- Correspondence: (V.P.); (U.M.)
| | - Carla Prezioso
- Department of Public Health and Infectious Diseases, “Sapienza” University, 00185 Rome, Italy;
- IRCSS San Raffaele Roma, Microbiology of Chronic Neuro-Degenerative Pathologies, 00161 Rome, Italy
| | - Ugo Moens
- Molecular Inflammation Research Group, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø—The Arctic University of Norway, 9037 Tromsø, Norway
- Correspondence: (V.P.); (U.M.)
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26
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Li F, Ou Q, Lai Z, Pu L, Chen X, Wang L, Sun L, Liang X, Wang Y, Xu H, Wei J, Wu F, Zhu H, Wang L. The Co-occurrence of Chronic Hepatitis B and Fibrosis Is Associated With a Decrease in Hepatic Global DNA Methylation Levels in Patients With Non-alcoholic Fatty Liver Disease. Front Genet 2021; 12:671552. [PMID: 34335686 PMCID: PMC8318039 DOI: 10.3389/fgene.2021.671552] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 06/01/2021] [Indexed: 01/23/2023] Open
Abstract
Global DNA hypomethylation has been reported in patients with chronic hepatitis B (CHB) and non-alcoholic fatty-liver disease (NAFLD). However, the global DNA methylation profile of patients with concurrent NAFLD and CHB (NAFLD + CHB) is still unclear. We aimed to detect the hepatic global DNA methylation levels of NAFLD + CHB patients and assess the associated risk factors. Liver biopsies were collected from 55 NAFLD patients with or without CHB. The histological characteristics of the biopsy were then assessed. Hepatic global DNA methylation levels were quantified by fluorometric method. The hepatic global DNA methylation levels in NAFLD + CHB group were significantly lower than that in NAFLD group. Participants with fibrosis showed lower levels of hepatic global DNA methylation than those without fibrosis. Participants with both CHB and fibrosis had lower levels of hepatic global DNA methylation than those without either CHB or fibrosis. The co-occurrence of CHB and fibrosis was significantly associated with a reduction in global DNA methylation levels compared to the absence of both CHB and fibrosis. Our study suggests that patients with NAFLD + CHB exhibited lower levels of global DNA methylation than patients who had NAFLD alone. The co-occurrence of CHB and liver fibrosis in NAFLD patients was associated with a decrease in global DNA methylation levels.
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Affiliation(s)
- FangYuan Li
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - Qian Ou
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - ZhiWei Lai
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - LiuZhen Pu
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - XingYi Chen
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - LiRong Wang
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - LiuQiao Sun
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - XiaoPing Liang
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - YaoYao Wang
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - Hang Xu
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - Jun Wei
- Department of Science and Technology, Guangzhou Customs, Guangzhou, China
| | - Feng Wu
- Department of Science and Technology, Guangzhou Customs, Guangzhou, China
| | - HuiLian Zhu
- Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - LiJun Wang
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
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27
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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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28
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Singh AK, Rooge SB, Varshney A, Vasudevan M, Kumar M, Geffers R, Kumar V, Sarin SK. Identification of miRNAs associated with dendritic cell dysfunction during acute and chronic hepatitis B virus infection. J Med Virol 2021; 93:3697-3706. [PMID: 33107616 DOI: 10.1002/jmv.26629] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 10/08/2020] [Accepted: 10/25/2020] [Indexed: 12/14/2022]
Abstract
The uptake or expression of hepatitis B virus (HBV) proteins by dendritic cells (DCs) is considered important for disease outcome. Differential expression of microRNA (miRNA) may have a role in viral persistence and hepatocellular injury. The miRNA expression was investigated by microarray in DCs from different stages of HBV infection and liver disease namely, immune active (IA; n = 20); low replicative (LR; n = 20); HBeAg negative (n = 20); acute viral hepatitis (AVH, n = 20) and healthy controls (n = 20). miRNA levels were analyzed by unsupervised hierarchical clustering and principal component analyses and validated by quantitative polymerase Chain Reaction (qPCR). The miRNA-messenger RNA (mRNA)regulatory networks identified 19 miRNAs and 12 target gene interactions in major histocompatibility complex and other immune pathways. miR-2278, miR-615-3p, and miR-3681-3p were downregulated in the IA group compared to healthy control, miR-152-3p and miR-3613-3p in the LR group compared to IA group and miR-152-3p and miR-503-3p in HBe negative compared to LR group. However, miR-7-1-1-3p, miR-192-5p, miR-195-5p, and miR-32-5p in LR, miR-342-3p, and miR-940 in HBe negative, and miR-34a-5p, miR-130b-3p, miR-221-3p, miR-320a, miR-324-5p, and miR-484 in AVH were upregulated. Further, qPCR confirmed changes in miRNA levels and their target genes associated with antigen processing and presentation. Thus, a deregulated network of miRNAs-mRNAs in DCs seems responsible for an impaired immune response during HBV pathogenesis.
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Affiliation(s)
- Avishek Kumar Singh
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
- Vascular and Interventional Translational Laboratory, Departments of Radiology, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Aditi Varshney
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | | | - Manoj Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Robert Geffers
- Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Vijay Kumar
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv Kumar Sarin
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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29
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Hu X, Tian K. [A Review of Epigenetic Modifications Regulate MicroRNA Expression in Lung Cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2021; 23:582-588. [PMID: 32702792 PMCID: PMC7406441 DOI: 10.3779/j.issn.1009-3419.2020.102.29] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
肺癌是全世界癌症引起死亡中较常见的一种。近年来，参与肺癌发病的分子机制被逐步揭开，但是其发生发展的确切机制并未完全阐明。其中微小RNAs（microRNAs, miRNAs）是一种短小并且广泛存在于植物、病毒及人类等各种生物中的内源性单链的非编码RNA。miRNAs在正常肺组织中发挥着多种功能，它参与细胞生长、代谢、增殖和分化等众多生物学过程。而miRNAs的异常表达与肺肿瘤的发生、发展、侵袭、转移相关。因此，miRNAs可被视为一种新的生物标志物。与编码蛋白质的基因类似，miRNA的表达和功能受多种因素以及表观遗传网络（包括DNA甲基化和组蛋白修饰机制）的调控。此外，miRNAs本身也能调控那些表观遗传修饰的关键酶来影响表观修饰。miRNA与表观基因学之间的相互联系将有助于我们研发以miRNA为导向的肺癌诊断、治疗和预后的方案。
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Affiliation(s)
- Xilin Hu
- Department of Thoracic Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266071, China
| | - Kaihua Tian
- Department of Thoracic Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266071, China
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30
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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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31
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Tao B, Xiang W, Li X, He C, Chen L, Xia X, Peng T, Peng L, Yang X, Zhong C. Regulation of Toll-like receptor-mediated inflammatory response by microRNA-152-3p-mediated demethylation of MyD88 in systemic lupus erythematosus. Inflamm Res 2021; 70:285-296. [PMID: 33507312 DOI: 10.1007/s00011-020-01433-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 12/09/2020] [Accepted: 12/19/2020] [Indexed: 11/29/2022] Open
Abstract
OBJECTIVE microRNAs (miRNAs) play critical roles in embryogenesis, cell differentiation and the pathogenesis of several human diseases, including systemic lupus erythematosus (SLE). Toll-like receptors (TLRs) are also known to exert crucial functions in the immune response activation occurring in the pathogenesis of autoimmune diseases like SLE. Herein, the current study aimed to explore the potential role of miR-152-3p in TLR-mediated inflammatory response in SLE. METHODS We determined the miR-152-3p expression profiles in CD4+ T cells and peripheral blood mononuclear cells (PBMCs) harvested from patients with SLE and healthy controls, and analyzed the correlation between miR-152-3p expression and clinicopathological parameters. CD70 and CD40L expression patterns in CD4+ T cells were assessed by RT-qPCR and flow cytometry. ChIP was adopted to determine the enrichment of DNA methyltransferase 1 (DNMT1) in the promoter region of myeloid differentiation factor 88 (MyD88). RESULTS The obtained findings revealed that miR-152-3p was highly-expressed in CD4+ T cells and PBMCs of patients with SLE, and this high expression was associated with facial erythema, joint pain, double-stranded DNA, and IgG antibody. DNMT1 could be enriched in the MyD88 promoter, and miR-152-3p inhibited the methylation of MyD88 by targeting DNMT1. We also found that silencing miR-152-3p inhibited MyD88 expression not only to repress the autoreactivity of CD4+ T cells and but also to restrain their cellular inflammation, which were also validated in vivo. CONCLUSION Our study suggests that miR-152-3p promotes TLR-mediated inflammatory response in CD4+ T cells by regulating the DNMT1/MyD88 signaling pathway, which highlights novel anti-inflammatory target for SLE treatment.
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Affiliation(s)
- Bei Tao
- Department of Rheumatology and Immunology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People's Republic of China
| | - Wei Xiang
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Street, Luzhou, 646000, Sichuan Province, People's Republic of China
- Neurosurgery Clinical Medical Research Center of Sichuan Province, Luzhou, 646000, People's Republic of China
| | - Xianglong Li
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Street, Luzhou, 646000, Sichuan Province, People's Republic of China
- Neurosurgery Clinical Medical Research Center of Sichuan Province, Luzhou, 646000, People's Republic of China
| | - Chengsong He
- Department of Rheumatology and Immunology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People's Republic of China
| | - Ligang Chen
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Street, Luzhou, 646000, Sichuan Province, People's Republic of China
- Neurosurgery Clinical Medical Research Center of Sichuan Province, Luzhou, 646000, People's Republic of China
| | - Xiangguo Xia
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Street, Luzhou, 646000, Sichuan Province, People's Republic of China
- Neurosurgery Clinical Medical Research Center of Sichuan Province, Luzhou, 646000, People's Republic of China
| | - Tangming Peng
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Street, Luzhou, 646000, Sichuan Province, People's Republic of China
- Neurosurgery Clinical Medical Research Center of Sichuan Province, Luzhou, 646000, People's Republic of China
| | - Lilei Peng
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Street, Luzhou, 646000, Sichuan Province, People's Republic of China
- Neurosurgery Clinical Medical Research Center of Sichuan Province, Luzhou, 646000, People's Republic of China
| | - Xiaobo Yang
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Street, Luzhou, 646000, Sichuan Province, People's Republic of China
- Neurosurgery Clinical Medical Research Center of Sichuan Province, Luzhou, 646000, People's Republic of China
| | - Chuanhong Zhong
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Street, Luzhou, 646000, Sichuan Province, People's Republic of China.
- Neurosurgery Clinical Medical Research Center of Sichuan Province, Luzhou, 646000, People's Republic of China.
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32
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Fernández-Ponce C, Navarro Quiroz R, Díaz Perez A, Aroca Martinez G, Cadena Bonfanti A, Acosta Hoyos A, Gómez Escorcia L, Hernández Agudelo S, Orozco Sánchez C, Villarreal Camacho J, Atencio Ibarra L, Consuegra Machado J, Espinoza Garavito A, García-Cózar F, Navarro Quiroz E. MicroRNAs overexpressed in Crohn's disease and their interactions with mechanisms of epigenetic regulation explain novel aspects of Crohn's disease pathogenesis. Clin Epigenetics 2021; 13:39. [PMID: 33602320 PMCID: PMC7890887 DOI: 10.1186/s13148-021-01022-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 02/02/2021] [Indexed: 12/14/2022] Open
Abstract
Background In this review, we were interested to identify the wide universe of enzymes associated with epigenetic modifications, whose gene expression is regulated by miRNAs with a high relative abundance in Crohn's disease (CD) affected tissues, with the aim to determine their impact in the pathogenesis and evolution of the disease. Methods We used HMDD and Bibliometrix R-package in order to identify the miRNAs overexpressed in CD. The identified enzymes associated with epigenetic mechanisms and post-translational modifications, regulated by miRNAs upregulated in CD, were analyzed using String v11 database. Results We found 190 miRNAs with great abundance in patients with CD, of which 26 miRNAs regulate the gene expression of enzymes known to catalyze epigenetic modifications involved in essentials pathophysiological processes, such as chromatin architecture reorganization, immune response regulation including CD4+ T cells polarization, integrity of gut mucosa, gut microbiota composition and tumorigenesis. Conclusion The integrated analysis of miRNAs with a high relative abundance in patients with CD showed a combined and superimposed gene expression regulation of enzymes associated with relevant epigenetic mechanisms and that could explain, in part, the pathogenesis of CD. Supplementary Information The online version contains supplementary material available at 10.1186/s13148-021-01022-8.
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Affiliation(s)
- Cecilia Fernández-Ponce
- Department of Biomedicine, Biotechnology and Public Health, University of Cadiz, Cadiz, Spain
| | - Roberto Navarro Quiroz
- CMCC-Centro de Matemática, Computação E Cognição, Laboratório do Biología Computacional e Bioinformática-LBCB, Universidade Federal Do ABC, Sao Paulo, 01023, Brazil
| | - Anderson Díaz Perez
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia.,Universidad Rafael Nuñez, 130001, Cartagena, Colombia
| | - Gustavo Aroca Martinez
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia.,Department of Nephrology, Clinica de La Costa, 080001, Barranquilla, Colombia
| | - Andrés Cadena Bonfanti
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia.,Department of Nephrology, Clinica de La Costa, 080001, Barranquilla, Colombia
| | - Antonio Acosta Hoyos
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia
| | - Lorena Gómez Escorcia
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia.,Universidad Rafael Nuñez, 130001, Cartagena, Colombia
| | - Sandra Hernández Agudelo
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia.,Department of Nephrology, Clinica de La Costa, 080001, Barranquilla, Colombia
| | - Christian Orozco Sánchez
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia
| | | | | | | | - Alberto Espinoza Garavito
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia
| | - Francisco García-Cózar
- Department of Biomedicine, Biotechnology and Public Health, University of Cadiz, Cadiz, Spain
| | - Elkin Navarro Quiroz
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia. .,Centro de Investigación E Innovación en Biomoléculas, C4U S.A.S, 080001, Barranquilla, Colombia.
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Morishita A, Oura K, Tadokoro T, Fujita K, Tani J, Masaki T. MicroRNAs in the Pathogenesis of Hepatocellular Carcinoma: A Review. Cancers (Basel) 2021; 13:cancers13030514. [PMID: 33572780 PMCID: PMC7866004 DOI: 10.3390/cancers13030514] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/22/2021] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is one of the most frequently occurring cancers, and the prognosis for late-stage HCC remains poor. A better understanding of the pathogenesis of HCC is expected to improve outcomes. MicroRNAs (miRNAs) are small, noncoding, single-stranded RNAs that regulate the expression of various target genes, including those in cancer-associated genomic regions or fragile sites in various human cancers. We summarize the central roles of miRNAs in the pathogenesis of HCC and discuss their potential utility as valuable biomarkers and new therapeutic agents for HCC. Abstract Hepatocellular carcinoma (HCC) is the seventh most frequent cancer and the fourth leading cause of cancer mortality worldwide. Despite substantial advances in therapeutic strategies, the prognosis of late-stage HCC remains dismal because of the high recurrence rate. A better understanding of the etiology of HCC is therefore necessary to improve outcomes. MicroRNAs (miRNAs) are small, endogenous, noncoding, single-stranded RNAs that modulate the expression of their target genes at the posttranscriptional and translational levels. Aberrant expression of miRNAs has frequently been detected in cancer-associated genomic regions or fragile sites in various human cancers and has been observed in both HCC cells and tissues. The precise patterns of aberrant miRNA expression differ depending on disease etiology, including various causes of hepatocarcinogenesis, such as viral hepatitis, alcoholic liver disease, or nonalcoholic steatohepatitis. However, little is known about the underlying mechanisms and the association of miRNAs with the pathogenesis of HCC of various etiologies. In the present review, we summarize the key mechanisms of miRNAs in the pathogenesis of HCC and emphasize their potential utility as valuable diagnostic and prognostic biomarkers, as well as innovative therapeutic targets, in HCC diagnosis and treatment.
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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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Loaeza-Loaeza J, Beltran AS, Hernández-Sotelo D. DNMTs and Impact of CpG Content, Transcription Factors, Consensus Motifs, lncRNAs, and Histone Marks on DNA Methylation. Genes (Basel) 2020; 11:genes11111336. [PMID: 33198240 PMCID: PMC7696963 DOI: 10.3390/genes11111336] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 11/06/2020] [Accepted: 11/10/2020] [Indexed: 12/15/2022] Open
Abstract
DNA methyltransferases (DNMTs) play an essential role in DNA methylation and transcriptional regulation in the genome. DNMTs, along with other poorly studied elements, modulate the dynamic DNA methylation patterns of embryonic and adult cells. We summarize the current knowledge on the molecular mechanism of DNMTs’ functional targeting to maintain genome-wide DNA methylation patterns. We focus on DNMTs’ intrinsic characteristics, transcriptional regulation, and post-transcriptional modifications. Furthermore, we focus special attention on the DNMTs’ specificity for target sites, including key cis-regulatory factors such as CpG content, common motifs, transcription factors (TF) binding sites, lncRNAs, and histone marks to regulate DNA methylation. We also review how complexes of DNMTs/TFs or DNMTs/lncRNAs are involved in DNA methylation in specific genome regions. Understanding these processes is essential because the spatiotemporal regulation of DNA methylation modulates gene expression in health and disease.
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Affiliation(s)
- Jaqueline Loaeza-Loaeza
- Laboratorio de Epigenética del Cáncer, Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Guerrero, NC 39087 Chilpancingo, Mexico;
| | - Adriana S. Beltran
- Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA;
| | - Daniel Hernández-Sotelo
- Laboratorio de Epigenética del Cáncer, Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Guerrero, NC 39087 Chilpancingo, Mexico;
- Correspondence:
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Zhang MY, Calin GA, Yuen KS, Jin DY, Chim CS. Epigenetic silencing of miR-342-3p in B cell lymphoma and its impact on autophagy. Clin Epigenetics 2020; 12:150. [PMID: 33076962 PMCID: PMC7574348 DOI: 10.1186/s13148-020-00926-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Accepted: 08/25/2020] [Indexed: 12/24/2022] Open
Abstract
Background miR-342-3p, localized to 14q32, is a tumor suppressor miRNA implicated in carcinogenesis. Given the presence of a promotor-associated CpG island for its host gene, EVL, we hypothesized that intronic miR-342-3p is a tumor suppressor co-regulated with host gene by promoter DNA methylation in B cell lymphoma. Results By bisulfite pyrosequencing-verified methylation-specific PCR (MSP), EVL/MIR342 methylation was detected in five (50%) lymphoma cell lines but not normal peripheral blood and tonsils. EVL/MIR342 methylation correlated with repression of both miR-342-3p and EVL in cell lines. In completely methylated SU-DHL-16 cells, 5-AzadC treatment resulted in promoter demethylation and re-expression of miR-342-3p and EVL. In 132 primary lymphoma samples, EVL/MIR342 was preferentially methylated in B cell lymphomas (N = 68; 68.7%) than T cell lymphoma (N = 8; 24.2%) by MSP (P < 0.0001). Moreover, EVL/MIR342 methylation was associated with lower miR-342-3p expression in 79 primary NHL (P = 0.0443). In SU-DHL-16 cells, the tumor suppressor function of miR-342-3p was demonstrated by the inhibition of cellular proliferation and increase of cell death upon over-expression of miR-342-3p. Mechanistically, overexpression of miR-342-3p resulted in a decrease of LC3-II, a biomarker of autophagy, which was pro-survival for SU-DHL-16. Pre-treatment with 3-methyladenine, an autophagy inhibitor, abrogated tumor suppression associated with miR-342-3p overexpression. By luciferase assay, MAP1LC3B, a precursor of LC3-II, was confirmed as a direct target of miR-342-3p. Finally, in SU-DHL-16 cells, overexpression of miR-342-3p downregulated the known target DNMT1, with promoter demethylation and re-expression of tumor suppressor E-cadherin. Conclusions Intronic miR-342-3p is co-regulated with its host gene EVL by tumor-specific promoter DNA methylation in B cell lymphoma. The tumor suppressor function of miR-342-3p was mediated via inhibition of pro-survival autophagy by targeting MAP1LC3B and downregulation of DNMT1 with demethylation and re-expression of tumor suppressor genes.
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Affiliation(s)
- Min Yue Zhang
- Division of Hematology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.,Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam Road, Pokfulam, Hong Kong
| | - George A Calin
- Translational Molecular Pathology Department, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kit San Yuen
- School of Biomedical Sciences, The University of Hong Kong, Pokfulam Road, Pokfulam, Hong Kong
| | - Dong Yan Jin
- School of Biomedical Sciences, The University of Hong Kong, Pokfulam Road, Pokfulam, Hong Kong
| | - Chor Sang Chim
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam Road, Pokfulam, Hong Kong.
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Regulatory Mechanisms of Epigenetic miRNA Relationships in Human Cancer and Potential as Therapeutic Targets. Cancers (Basel) 2020; 12:cancers12102922. [PMID: 33050637 PMCID: PMC7600069 DOI: 10.3390/cancers12102922] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 10/03/2020] [Accepted: 10/07/2020] [Indexed: 12/15/2022] Open
Abstract
Simple Summary By the virtue of targeting multiple genes, a microRNA (miRNA) can infer variable consequences on tumorigenesis by appearing as both a tumour suppressor and oncogene. miRNAs can regulate gene expression by modulating genome-wide epigenetic status of genes that are involved in various cancers. These miRNAs perform direct inhibition of key mediators of the epigenetic machinery, such as DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) genes. Along with miRNAs gene expression, similar to other protein-coding genes, miRNAs are also controlled by epigenetic mechanisms. Overall, this reciprocal interaction between the miRNAs and the epigenetic architecture is significantly implicated in the aberrant expression of miRNAs detected in various human cancers. Comprehensive knowledge of the miRNA-epigenetic dynamics in cancer is essential for the discovery of novel anticancer therapeutics. Abstract Initiation and progression of cancer are under both genetic and epigenetic regulation. Epigenetic modifications including alterations in DNA methylation, RNA and histone modifications can lead to microRNA (miRNA) gene dysregulation and malignant cellular transformation and are hereditary and reversible. miRNAs are small non-coding RNAs which regulate the expression of specific target genes through degradation or inhibition of translation of the target mRNA. miRNAs can target epigenetic modifier enzymes involved in epigenetic modulation, establishing a trilateral regulatory “epi–miR–epi” feedback circuit. The intricate association between miRNAs and the epigenetic architecture is an important feature through which to monitor gene expression profiles in cancer. This review summarises the involvement of epigenetically regulated miRNAs and miRNA-mediated epigenetic modulations in various cancers. In addition, the application of bioinformatics tools to study these networks and the use of therapeutic miRNAs for the treatment of cancer are also reviewed. A comprehensive interpretation of these mechanisms and the interwoven bond between miRNAs and epigenetics is crucial for understanding how the human epigenome is maintained, how aberrant miRNA expression can contribute to tumorigenesis and how knowledge of these factors can be translated into diagnostic and therapeutic tool development.
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Zhang X, Wang L, Li H, Zhang L, Zheng X, Cheng W. Crosstalk between noncoding RNAs and ferroptosis: new dawn for overcoming cancer progression. Cell Death Dis 2020; 11:580. [PMID: 32709863 PMCID: PMC7381619 DOI: 10.1038/s41419-020-02772-8] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 07/06/2020] [Accepted: 07/10/2020] [Indexed: 02/06/2023]
Abstract
Cancer progression including proliferation, metastasis, and chemoresistance has become a serious hindrance to cancer therapy. This phenomenon mainly derives from the innate insensitive or acquired resistance of cancer cells to apoptosis. Ferroptosis is a newly discovered mechanism of programmed cell death characterized by peroxidation of the lipid membrane induced by reactive oxygen species. Ferroptosis has been confirmed to eliminate cancer cells in an apoptosis-independent manner, however, the specific regulatory mechanism of ferroptosis is still unknown. The use of ferroptosis for overcoming cancer progression is limited. Noncoding RNAs have been found to play an important roles in cancer. They regulate gene expression to affect biological processes of cancer cells such as proliferation, cell cycle, and cell death. Thus far, the functions of ncRNAs in ferroptosis of cancer cells have been examined, and the specific mechanisms by which noncoding RNAs regulate ferroptosis have been partially discovered. However, there is no summary of ferroptosis associated noncoding RNAs and their functions in different cancer types. In this review, we discuss the roles of ferroptosis-associated noncoding RNAs in detail. Moreover, future work regarding the interaction between noncoding RNAs and ferroptosis is proposed, the possible obstacles are predicted and associated solutions are put forward. This review will deepen our understanding of the relationship between noncoding RNAs and ferroptosis, and provide new insights in targeting noncoding RNAs in ferroptosis associated therapeutic strategies.
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Affiliation(s)
- Xuefei Zhang
- Department of Ultrasonography, Harbin Medical University Cancer Hospital, 150 Haping Road, 150040, Harbin, China
| | - Lingling Wang
- Department of Ultrasonography, Harbin Medical University Cancer Hospital, 150 Haping Road, 150040, Harbin, China
| | - Haixia Li
- Department of Ultrasonography, Harbin Medical University Cancer Hospital, 150 Haping Road, 150040, Harbin, China
| | - Lei Zhang
- Department of Ultrasonography, Harbin Medical University Cancer Hospital, 150 Haping Road, 150040, Harbin, China.
| | - Xiulan Zheng
- Department of Ultrasonography, Harbin Medical University Cancer Hospital, 150 Haping Road, 150040, Harbin, China.
| | - Wen Cheng
- Department of Ultrasonography, Harbin Medical University Cancer Hospital, 150 Haping Road, 150040, Harbin, 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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Fei X, Zhang P, Pan Y, Liu Y. MicroRNA-98-5p Inhibits Tumorigenesis of Hepatitis B Virus-Related Hepatocellular Carcinoma by Targeting NF-κB-Inducing Kinase. Yonsei Med J 2020; 61:460-470. [PMID: 32469170 PMCID: PMC7256008 DOI: 10.3349/ymj.2020.61.6.460] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 03/23/2020] [Accepted: 04/03/2020] [Indexed: 01/01/2023] Open
Abstract
PURPOSE MicroRNAs play key regulatory roles in the tumorigenesis of hepatitis B virus-related hepatocellular carcinoma (HBV-HCC). This study aimed to explore the regulatory effects of microRNA-98-5p (miR-98-5p) on the proliferation, migration, invasion, and apoptosis of HBV-HCC cells, as well as the underlying mechanisms involving nuclear factor-κB-inducing kinase (NIK). MATERIALS AND METHODS The expressions of miR-98-5p and NIK in HBV-HCC tissues and cells, and the level of HBV DNA in HBV-HCC cells were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The proliferation, migration, invasion, and apoptosis of HBV-HCC cells were analyzed by cell counting kit-8, wound healing, transwell, and flow cytometry assay, respectively. The targeting relationship between miR-98-5p and NIK was predicted by StarBase3.0 and verified by dual-luciferase reporter assay. HBV-HCC xenograft tumor model was constructed in mice to observe the tumor growth in vivo. RESULTS The expression of miR-98-5p was declined in HBV-HCC tissues and cells. Overexpression of miR-98-5p markedly reduced the level of HBV DNA; inhibited the proliferation, migration, and invasion; and promoted the apoptosis of HBV-HCC cells. NIK was a target of miR-98-5p. Overexpression of miR-98-5p markedly decreased the protein expression of NIK in MHCC97H-HBV cells. NIK reversed the tumor-suppressing effect of miR-98-5p on HBV-HCC cells. Furthermore, overexpression of miR-98-5p significantly inhibited the xenograft tumor growth and decreased the expression of NIK in mice. CONCLUSION MiR-98-5p inhibits the secretion of HBV, proliferation, migration, and invasion of HBV-HCC cells by targeting NIK.
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Affiliation(s)
- Xiukun Fei
- Department of Infectious Diseases, Zaozhuang Maternal and Child Health Care Hospital, Zaozhuang, China
| | - Peipei Zhang
- Department of Liver Disease, Zaozhuang Traditional Chinese Medicine Hospital, Zaozhuang, China
| | - Yu Pan
- Department of Infectious Diseases, Zaozhuang Maternal and Child Health Care Hospital, Zaozhuang, China
| | - Yuanyuan Liu
- Department of Infectious Diseases, Zaozhuang Maternal and Child Health Care Hospital, Zaozhuang, China.
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Frazier S, McBride MW, Mulvana H, Graham D. From animal models to patients: the role of placental microRNAs, miR-210, miR-126, and miR-148a/152 in preeclampsia. Clin Sci (Lond) 2020; 134:1001-1025. [PMID: 32337535 PMCID: PMC7239341 DOI: 10.1042/cs20200023] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 03/23/2020] [Accepted: 04/14/2020] [Indexed: 12/12/2022]
Abstract
Placental microRNAs (miRNAs) regulate the placental transcriptome and play a pathological role in preeclampsia (PE), a hypertensive disorder of pregnancy. Three PE rodent model studies explored the role of placental miRNAs, miR-210, miR-126, and miR-148/152 respectively, by examining expression of the miRNAs, their inducers, and potential gene targets. This review evaluates the role of miR-210, miR-126, and miR-148/152 in PE by comparing findings from the three rodent model studies with in vitro studies, other animal models, and preeclamptic patients to provide comprehensive insight into genetic components and pathological processes in the placenta contributing to PE. The majority of studies demonstrate miR-210 is upregulated in PE in part driven by HIF-1α and NF-κBp50, stimulated by hypoxia and/or immune-mediated processes. Elevated miR-210 may contribute to PE via inhibiting anti-inflammatory Th2-cytokines. Studies report an up- and downregulation of miR-126, arguably reflecting differences in expression between cell types and its multifunctional capacity. MiR-126 may play a pro-angiogenic role by mediating the PI3K-Akt pathway. Most studies report miR-148/152 family members are upregulated in PE. Evidence suggests they may inhibit DNA methylation of genes involved in metabolic and inflammatory pathways. Given the genetic heterogeneity of PE, it is unlikely that a single placental miRNA is a suitable therapeutic target for all patients. Investigating miRNAs in PE subtypes in patients and animal models may represent a more appropriate approach going forward. Developing methods for targeting placental miRNAs and specific placental cell types remains crucial for research seeking to target placental miRNAs as a novel treatment for PE.
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Affiliation(s)
- Sonya Frazier
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, U.K
| | - Martin W. McBride
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, U.K
| | - Helen Mulvana
- Biomedical Engineering, University of Strathclyde, Glasgow, U.K
| | - Delyth Graham
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, U.K
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Li K, Tang M, Tong S, Wang C, Sun Q, Lv M, Sun X, Wang T, Jin S. BRAFi induced demethylation of miR-152-5p regulates phenotype switching by targeting TXNIP in cutaneous melanoma. Apoptosis 2020; 25:179-191. [PMID: 32056038 DOI: 10.1007/s10495-019-01586-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Treatment of advanced BRAFV600-mutant melanoma using BRAF inhibitors (BRAFi) eventually leads to drug resistance and selects for highly metastatic tumor cells. We compared the most differentially dysregulated miRNA expression profiles of vemurafenib-resistant and highly-metastatic melanoma cell lines obtained from GEO DataSets. We discovered miR-152-5p was a potential regulator mediating melanoma drug resistance and metastasis. Functionally, knockdown of miR-152-5p significantly compromised the metastatic ability of BRAFi-resistant melanoma cells and overexpression of miR-152-5p promoted the formation of slow-cycling phenotype. Furthermore, we explored the cause of how and why miR-152-5p affected metastasis in depth. Mechanistically, miR-152-5p targeted TXNIP which affected metastasis and BRAFi altered the methylation status of MIR152 promoter. Our study highlights the crucial role of miR-152-5p on melanoma metastasis after BRAFi treatment and holds significant implying that discontinuous dosing strategy may improve the benefit of advanced BRAFV600-mutant melanoma patients.
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Affiliation(s)
- Kezhu Li
- Department of Plastic Surgery, the First Affiliated Hospital of China Medical University, No.155, Nanjing North Street, Shenyang City, 110001, Liaoning, China
| | - Mingrui Tang
- Department of Plastic Surgery, the First Affiliated Hospital of China Medical University, No.155, Nanjing North Street, Shenyang City, 110001, Liaoning, China
| | - Shuang Tong
- Department of Plastic Surgery, the First Affiliated Hospital of China Medical University, No.155, Nanjing North Street, Shenyang City, 110001, Liaoning, China
| | - Chenchao Wang
- Department of Plastic Surgery, the First Affiliated Hospital of China Medical University, No.155, Nanjing North Street, Shenyang City, 110001, Liaoning, China
| | - Qiang Sun
- Department of Plastic Surgery, the First Affiliated Hospital of China Medical University, No.155, Nanjing North Street, Shenyang City, 110001, Liaoning, China
| | - Mengzhu Lv
- Department of Plastic Surgery, the First Affiliated Hospital of China Medical University, No.155, Nanjing North Street, Shenyang City, 110001, Liaoning, China
| | - Xu Sun
- Department of Plastic Surgery, the First Affiliated Hospital of China Medical University, No.155, Nanjing North Street, Shenyang City, 110001, Liaoning, China
| | - Ting Wang
- Department of Plastic Surgery, the First Affiliated Hospital of China Medical University, No.155, Nanjing North Street, Shenyang City, 110001, Liaoning, China
| | - Shifeng Jin
- Department of Plastic Surgery, the First Affiliated Hospital of China Medical University, No.155, Nanjing North Street, Shenyang City, 110001, Liaoning, China.
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Zhao X, Dou J, Cao J, Wang Y, Gao Q, Zeng Q, Liu W, Liu B, Cui Z, Teng L, Zhang J, Zhao C. Uncovering the potential differentially expressed miRNAs as diagnostic biomarkers for hepatocellular carcinoma based on machine learning in The Cancer Genome Atlas database. Oncol Rep 2020; 43:1771-1784. [PMID: 32236623 PMCID: PMC7160538 DOI: 10.3892/or.2020.7551] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 01/22/2020] [Indexed: 02/07/2023] Open
Abstract
The present study aimed to identify novel diagnostic differentially expressed microRNAs (miRNAs/miRs) in order to understand the molecular mechanisms underlying hepatocellular carcinoma. The expression data of miRNA and mRNA were downloaded for differential expression analysis. Optimal diagnostic differentially expressed miRNA biomarkers were identified via a random forest algorithm. Classification models were established to distinguish patients with hepatocellular carcinoma and normal individuals. A regulatory network between optimal diagnostic differentially expressed miRNA and differentially expressed mRNAs was then constructed. The GSE63046 dataset and in vitro experiments were used to validate the expression of the optimal diagnostic differentially expressed miRNAs identified. In addition, diagnostic and prognostic analyses of optimal diagnostic differentially expressed miRNAs were performed. In total, 14 differentially expressed miRNAs (all upregulated) and 2,982 differentially expressed mRNAs (1,989 upregulated and 993 downregulated) were identified. hsa-miR-10b-5p, hsa-miR-10b-3p, hsa-miR-224-5p, hsa-miR-183-5p and hsa-miR-182-5p were considered as the optimal diagnostic biomarkers for hepatocellular carcinoma. The mRNAs targeted by these five miRNAs included secreted frizzled related protein 1 (SFRP1), endothelin receptor type B (EDNRB), nuclear receptor subfamily 4 group A member 3 (NR4A3), four and a half LIM domains 2 (FHL2), NK3 homeobox 1 (NKX3-1), interleukin 6 signal transducer (IL6ST) and forkhead box O1 (FOXO1). ‘Bile acid biosynthesis and cholesterol’ was the most enriched signaling pathways of these target mRNAs. The expression validation of the five miRNAs was consistent with the present bioinformatics analysis. Notably, hsa-miR-10b-5p and hsa-miR-10b-3p had a significant prognosis value for patients with hepatocellular carcinoma. In conclusion, the five differentially expressed miRNAs may be considered as diagnostic biomarkers for patients with hepatocellular carcinoma. In addition, the differential expression levels of the targets of these five mRNAs, including SFRP1, EDNRB, NR4A3, FHL2, NKX3−1, IL6ST and FOXO1, may be involved in hepatocellular carcinoma tumorigenesis.
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Affiliation(s)
- Xin Zhao
- Department of Hepatobiliary Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Jian Dou
- Department of Hepatobiliary Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Jinglin Cao
- Department of Hepatobiliary Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Yang Wang
- Department of Hepatobiliary Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Qingjun Gao
- Department of Hepatobiliary Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Qiang Zeng
- Department of Hepatobiliary Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Wenpeng Liu
- Department of Hepatobiliary Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Baowang Liu
- Department of Hepatobiliary Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Ziqiang Cui
- Department of Hepatobiliary Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Liang Teng
- Department of Hepatobiliary Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Junhong Zhang
- Department of Hepatobiliary Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Caiyan Zhao
- Department of Infection, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
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Vyas HS, Upadhyay KK, Devkar RV. miRNAs Signatures In Patients With Acute Liver Injury: Clinical Concerns and Correlations. Curr Mol Med 2019; 20:325-335. [PMID: 31823701 DOI: 10.2174/1566524020666191211153546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 11/25/2019] [Accepted: 11/27/2019] [Indexed: 11/22/2022]
Abstract
Non-coding RNAs can be highly exploited for their biological significance in living systems. miRNAs are in the upstream position of cellular regulation cascade and hold merit in its state. A plethora of information is available on a wide variety of miRNAs that undergo alterations in experimentally induced models of liver injuries. The underlying mechanisms governed by these miRNAs have been inferred through cellbased experiments but the scientific knowledge on miRNA signatures in patients with liver injury are primordial and lack scientific clarity. Hence, it is crucial to get insight into the status and synergy of miRNAs in patients, with varying degrees of acute toxic manifestations in the liver. Though some miRNAs are being investigated in clinical trials, a major research lacuna exists with regard to the functional role of other miRNAs in liver diseases. This review article is a meticulous compilation of disease based or drug/alcohol based acute liver injuries in patients and resultant alteration in their miRNA profile. Investigative reports on underlying miRNA-liver crosstalk in cell-based or murine models are also discussed herein to draw a correlation with clinical findings.
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Affiliation(s)
- Hitarthi S Vyas
- Division of Metabolic Endocrinology, Department of Zoology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat 390002, India
| | - Kapil K Upadhyay
- Division of Metabolic Endocrinology, Department of Zoology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat 390002, India
| | - Ranjitsinh V Devkar
- Division of Metabolic Endocrinology, Department of Zoology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat 390002, India
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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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Role of Non-Coding RNAs in the Progression of Liver Cancer: Evidence from Experimental Models. Cancers (Basel) 2019; 11:cancers11111652. [PMID: 31731549 PMCID: PMC6896146 DOI: 10.3390/cancers11111652] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 10/18/2019] [Accepted: 10/21/2019] [Indexed: 12/12/2022] Open
Abstract
Liver cancer is a devastating cancer that ranges from relatively rare (around 2% of all cancers in the United States) to commonplace (up to 50% of cancers in underdeveloped countries). Depending upon the stage of pathogenesis, prognosis, or functional liver tissue present, transplantation or partial hepatectomy may be the only available treatment option. However, due to the rise in metabolic syndrome and the increasing demand for livers, patients often wait months or years for available organs. Due to this shortage, doctors must have other treatment options available. One promising area of cancer research lies in understanding the role of regulatory non-coding RNAs (ncRNAs) as oncogenic drivers and potential targets for prospective therapies. While the role of these ncRNAs was not initially clear, many of them have since been recognized to function as important players in the regulation of gene expression, epigenetic modification, and signal transduction in both normal and cancer cell cycles. Dysregulation of these different ncRNA subtypes has been implicated in the pathogenesis and progression of many major cancers including hepatocellular carcinoma. This review summarizes current findings on the roles noncoding RNAs play in the progression of liver cancer and the various animal models used in current research to elucidate those data.
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Fan X, Jin S, Li Y, Khadaroo PA, Dai Y, He L, Zhou D, Lin H. Genetic And Epigenetic Regulation Of E-Cadherin Signaling In Human Hepatocellular Carcinoma. Cancer Manag Res 2019; 11:8947-8963. [PMID: 31802937 PMCID: PMC6801489 DOI: 10.2147/cmar.s225606] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 09/27/2019] [Indexed: 12/24/2022] Open
Abstract
E-cadherin is well known as a growth and invasion suppressor and belongs to the large cadherin family. Loss of E-cadherin is widely known as the hallmark of epithelial-to-mesenchymal transition (EMT) with the involvement of transcription factors such as Snail, Slug, Twist and Zeb1/2. Tumor cells undergoing EMT could migrate to distant sites and become metastases. Recently, numerous studies have revealed how the expression of E-cadherin is regulated by different kinds of genetic and epigenetic alteration, which are implicated in several crucial transcription factors and pathways. E-cadherin signaling plays an important role in hepatocellular carcinoma (HCC) initiation and progression considering the highly mutated frequency of CTNNB1 (27%). Combining the data from The Cancer Genome Atlas (TCGA) database and previous studies, we have summarized the roles of gene mutations, chromosome instability, DNA methylation, histone modifications and non-coding RNA in E-cadherin in HCC. In this review, we discuss the current understanding of the relationship between these modifications and HCC. Perspectives on E-cadherin-related research in HCC are provided.
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Affiliation(s)
- Xiaoxiao Fan
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
| | - Shengxi Jin
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
- School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
| | - Yirun Li
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
| | - Parikshit Asutosh Khadaroo
- School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
| | - Yili Dai
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
- School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
| | - Lifeng He
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
| | - Daizhan Zhou
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
| | - Hui Lin
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
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MicroRNA-802 induces hepatitis B virus replication and replication through regulating SMARCE1 expression in hepatocellular carcinoma. Cell Death Dis 2019; 10:783. [PMID: 31611549 PMCID: PMC6791889 DOI: 10.1038/s41419-019-1999-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Revised: 08/22/2019] [Accepted: 08/26/2019] [Indexed: 12/17/2022]
Abstract
Growing evidences have indicated that microRNAs (miRNAs) can regulate hepatitis B virus (HBV) expression and replication, playing crucial roles in the development of HBV infection. Until now, the functional role and mechanism of miR-802 in HBV replication and expression remain unknown. We indicated that miR-802 expression was upregulated in the HBV-associated hepatocellular carcinoma (HCC) tissues compared with the adjacent noncancerous samples. In addition, we showed that the SMARCE1 expression level was downregulated in the HBV-associated HCC tissues compared with the adjacent noncancerous samples. miR-802 expression was negatively related with MARCE1 expression in HBV-associated HCC tissues. Moreover, miR-802 expression was upregulated, and SMARCE1 expression was downregulated in the HBV-infected HepG2.2.15 cells. Ectopic expression of miR-802 significantly enhanced HBV DNA replication, while knockdown of miR-802 significantly decreased HBV DNA replication. We showed that overexpression of miR-802 promoted HbsAg and HbeAg expression, while inhibition of miR-802 decreased HbsAg and HbeAg expression. Furthermore, we indicated that ectopic expression of SMARCE1 suppressed HBV DNA replication and decreased the expression level of HbsAg and HbeAg. Finally, we showed that overexpression of miR-802 promoted HBV DNA replication through regulating SMARCE1 expression. These results suggested the important roles of miR-802 on HBV expression and replication, which may shed new light on the development of treatment for HBV.
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microRNA-17 functions as an oncogene by downregulating Smad3 expression in hepatocellular carcinoma. Cell Death Dis 2019; 10:723. [PMID: 31558704 PMCID: PMC6763424 DOI: 10.1038/s41419-019-1960-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Revised: 08/06/2019] [Accepted: 09/04/2019] [Indexed: 02/06/2023]
Abstract
The sekelsky mothers against dpp3 (Smad3) functions as a transcriptional modulator activated by transforming growth factor-β (TGF-β). Accumulated evidences indicated that Smad3 played the important roles in carcinogenesis and progression of hepatocellular carcinoma (HCC). Up to now, the regulatory mechanism of Smad3 in HCC still remains unclear. It has been known that some particular microRNAs (miRNAs) involve in carcinogenesis through the regulation of gene expressions with targeting mRNAs. In our study, the unknown candidates of miRNAs that target Smad3 mRNA were searched by using a newly established in vivo approach, the miRNA in vivo precipitation (miRIP). Using a loss-of-function assay, we demonstrated that miR-17 directly targeted Smad3 in HCC cells and inhibition on miR-17 increased Smad3 expression. Furthermore, we found that downregulation on Smad3 expression was consistent with high level of miR-17 in HCC tissues of patients when compared with around normal liver tissues. The manipulated miR-17 silence in HCC cells suppressed their growth of both in vitro and in vivo. Such suppression on cell growth could be recovered through downregulating Smad3. In addition, miR-17 affected cell proliferation through arresting cell cycle in G1 phase. The negative correlation between levels of miR-17 and protein levels of Smad3 was supported by the results of analysis with HCC tissue chip. In summary, for the first time, we confirmed that miR-17 directly targeted Smad3 mRNA and downregulated Smad3 protein expression in HCC. Our results indicated that the increased expression of miR-17 promoted carcinogenesis of HCC through down-regulations of Smad3, suggesting miR-17 might serve as the potential diagnostic and therapeutic targets for clinical HCC.
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Fan Y, Gan M, Tan Y, Chen L, Shen L, Niu L, Liu Y, Tang G, Jiang Y, Li X, Zhang S, Bai L, Zhu L. Mir-152 Regulates 3T3-L1 Preadipocyte Proliferation and Differentiation. Molecules 2019; 24:molecules24183379. [PMID: 31533306 PMCID: PMC6766927 DOI: 10.3390/molecules24183379] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 09/12/2019] [Accepted: 09/16/2019] [Indexed: 01/14/2023] Open
Abstract
Adipogenesis is a complex biological process and the main cause of obesity. Recently, microRNAs (miRNAs), a class of small endogenous non-coding RNAs, have been proven to play an important role in adipogenesis by the post-transcriptional regulation of target genes. In this current study, we observed an increment of miR-152 expression during the process of 3T3-L1 cell audiogenic differentiation. A functional analysis indicated that the overexpression of miR-152 inhibited pre-adipocyte proliferation and suppressed the expression of some cell cycle-related genes. Moreover, the overexpression of miR-152 promoted lipid accumulation in 3T3-L1 preadipocytes accompanied by increase of the expression of some pro-audiogenic genes. Additionally, a dual-luciferase reporter assay demonstrated lipoprotein lipase (LPL) was a direct target gene of miR-152 during preadipocyte differentiation. Further analysis showed that miR-152 was positively correlated with adipogenesis and intramuscular fat formation in vivo. Taken together, our findings suggest that miR-152 could suppress 3T3-L1 preadipocyte proliferation, whereas it could promote 3T3-L1 preadipocyte differentiation by negatively regulating LPL. The findings indicate that miR-152 might have a therapeutic significance for obesity and obesity-related metabolic syndrome.
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Affiliation(s)
- Yuan Fan
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
| | - Mailin Gan
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
| | - Ya Tan
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
- Institute of Animal Husbandry and Veterinary, Guizhou Academy of Agricultural Science, Guiyang 550005, Guizhou, China.
| | - Lei Chen
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
| | - Linyuan Shen
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
| | - Lili Niu
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
| | - Yihui Liu
- Sichuan Province General Station of Animal Husbandry, Chengdu 611130, Sichuan, China.
| | - Guoqing Tang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
| | - Yanzhi Jiang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
| | - Xuewei Li
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
| | - Shunhua Zhang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
| | - Lin Bai
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
| | - Li Zhu
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
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