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Yuan J, Yan K, Guo Y, Li Y. MicroRNAs: emerging biomarkers and therapeutic targets in pancreatic cancer. Front Mol Biosci 2024; 11:1457875. [PMID: 39290995 PMCID: PMC11406015 DOI: 10.3389/fmolb.2024.1457875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 08/23/2024] [Indexed: 09/19/2024] Open
Abstract
Pancreatic cancer (PC) is a highly malignant disease with high aggressiveness and a dismal prognosis, which is challenging to diagnose clinically early and gains low benefit from standard therapies. MicroRNAs (miRNAs) have become a hot topic in oncology research. Current evidence indicates that miRNAs are regulators involved in the entire process of PC, providing new diagnostic and therapeutic strategies for this fatal disease. Related research has been rapidly updated, making it necessary to review it to propose new directions and ideas and provide guidance for the development of precision medicine for PC. We reviewed the relevant literature through Pubmed, Embase, Web of Science and Medline, showing that abnormally expressed miRNAs in PC patients have the potential to be used as biomarkers for diagnosis and prognosis, highlighting the excellent prospect of combining miRNAs with traditional therapies, and the effective application of these factors for PC, especially miRNA mimics and inhibitors. MiRNAs participate in the entire process of PC and play important roles in diagnosis, treatment and prognosis. They are potential factors in conquering PC in the future.
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Affiliation(s)
- Jiaqian Yuan
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Kaiqi Yan
- Department of Materials Engineering and Science, Ningbo University of Technology, Ningbo, China
| | - Yong Guo
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Yan Li
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
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Butler T, Davey MG, Kerin MJ. Molecular Morbidity Score-Can MicroRNAs Assess the Burden of Disease? Int J Mol Sci 2024; 25:8042. [PMID: 39125612 PMCID: PMC11312210 DOI: 10.3390/ijms25158042] [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: 06/21/2024] [Revised: 07/17/2024] [Accepted: 07/18/2024] [Indexed: 08/12/2024] Open
Abstract
Multimorbidity refers to the presence of two or more chronic diseases and is associated with adverse outcomes for patients. Factors such as an ageing population have contributed to a rise in prevalence of multimorbidity globally; however, multimorbidity is often neglected in clinical guidelines. This is largely because patients with multimorbidity are systematically excluded from clinical trials. Accordingly, there is an urgent need to develop novel biomarkers and methods of prognostication for this cohort of patients. The hallmarks of ageing are now thought to potentiate the pathogenesis of multimorbidity. MicroRNAs are small, regulatory, noncoding RNAs which have been implicated in the pathogenesis and prognostication of numerous chronic diseases; there is a substantial body of evidence now implicating microRNA dysregulation with the different hallmarks of ageing in the aetiology of chronic diseases. This article proposes using the hallmarks of ageing as a framework to develop a panel of microRNAs to assess the prognostic burden of multimorbidity. This putative molecular morbidity score would have many potential applications, including assessing the efficacy of clinical interventions, informing clinical decision making and facilitating wider inclusion of patients with multimorbidity in clinical trials.
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Affiliation(s)
- Thomas Butler
- Department of Surgery, Lambe Institute for Translational Research, University of Galway, H91 TK33 Galway, Ireland; (M.G.D.); (M.J.K.)
| | - Matthew G. Davey
- Department of Surgery, Lambe Institute for Translational Research, University of Galway, H91 TK33 Galway, Ireland; (M.G.D.); (M.J.K.)
| | - Michael J. Kerin
- Department of Surgery, Lambe Institute for Translational Research, University of Galway, H91 TK33 Galway, Ireland; (M.G.D.); (M.J.K.)
- Department of Surgery, University Hospital Galway, Newcastle Road, H91 YR71 Galway, Ireland
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Popov A, Hrudka J, Szabó A, Oliverius M, Šubrt Z, Vránová J, Ciprová V, Moravcová J, Mandys V. Expression of Selected miRNAs in Undifferentiated Carcinoma with Osteoclast-like Giant Cells (UCOGC) of the Pancreas: Comparison with Poorly Differentiated Pancreatic Ductal Adenocarcinoma. Biomedicines 2024; 12:962. [PMID: 38790924 PMCID: PMC11117927 DOI: 10.3390/biomedicines12050962] [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: 02/23/2024] [Revised: 04/18/2024] [Accepted: 04/23/2024] [Indexed: 05/26/2024] Open
Abstract
Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC) of the pancreas represents a rare subtype of pancreatic ductal adenocarcinoma (PDAC). Despite a distinct morphology and specific clinical behavior, UCOGCs exhibit unexpected similarities in regard to DNA mutational profiles with conventional PDAC. Treating pancreatic ductal adenocarcinoma is particularly challenging, with limited prospects for cure. As with many other malignant neoplasms, the exploration of microRNAs (miRNAs, miRs) in regulating the biological characteristics of pancreatic cancer is undergoing extensive investigation to enhance tumor diagnostics and unveil the therapeutic possibilities. Herein, we evaluated the expression of miR-21, -96, -148a, -155, -196a, -210, and -217 in UCOGCs and poorly differentiated (grade 3, G3) PDACs. The expression of miR-21, miR-155, and miR-210 in both UCOGCs and G3 PDACs was significantly upregulated compared to the levels in normal tissue, while the levels of miR-148a and miR-217 were downregulated. We did not find any significant differences between cancerous and normal tissues for the expression of miR-96 and miR-196a in G3 PDACs, whereas miR-196a was slightly, but significantly, downregulated in UCOGCs. On the other hand, we have not observed significant differences in the expression of the majority of miRNAs between UCOGC and G3 PDAC, with the exception of miR-155. UCOGC samples demonstrated lower mean levels of miR-155 in comparison with those in G3 PDACs.
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Affiliation(s)
- Alexey Popov
- Department of Pathology, 3rd Faculty of Medicine, Charles University, University Hospital Královské Vinohrady, 100 00 Prague, Czech Republic; (A.P.); (A.S.)
| | - Jan Hrudka
- Department of Pathology, 3rd Faculty of Medicine, Charles University, University Hospital Královské Vinohrady, 100 00 Prague, Czech Republic; (A.P.); (A.S.)
| | - Arpád Szabó
- Department of Pathology, 3rd Faculty of Medicine, Charles University, University Hospital Královské Vinohrady, 100 00 Prague, Czech Republic; (A.P.); (A.S.)
| | - Martin Oliverius
- Department of Surgery, 3rd Faculty of Medicine, Charles University, University Hospital Královské Vinohrady, 100 00 Prague, Czech Republic; (M.O.); (Z.Š.)
| | - Zdeněk Šubrt
- Department of Surgery, 3rd Faculty of Medicine, Charles University, University Hospital Královské Vinohrady, 100 00 Prague, Czech Republic; (M.O.); (Z.Š.)
| | - Jana Vránová
- Department of Medical Biophysics and Medical Informatics, 3rd Faculty of Medicine, Charles University, 100 00 Prague, Czech Republic;
| | - Vanda Ciprová
- Institute of Pathology, 1st Faculty of Medicine, Charles University, General University Hospital, 100 00 Prague, Czech Republic
| | - Jana Moravcová
- Department of Pathology, 3rd Faculty of Medicine, Charles University, University Hospital Královské Vinohrady, 100 00 Prague, Czech Republic; (A.P.); (A.S.)
- Clinical and Transplant Pathology Centre, Institute for Clinical and Experimental Medicine, 140 00 Prague, Czech Republic
| | - Václav Mandys
- Department of Pathology, 3rd Faculty of Medicine, Charles University, University Hospital Královské Vinohrady, 100 00 Prague, Czech Republic; (A.P.); (A.S.)
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Qadir Nanakali NM, Maleki Dana P, Sadoughi F, Asemi Z, Sharifi M, Asemi R, Yousefi B. The role of dietary polyphenols in alternating DNA methylation in cancer. Crit Rev Food Sci Nutr 2023; 63:12256-12269. [PMID: 35848113 DOI: 10.1080/10408398.2022.2100313] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Natural products such as curcumin, quercetin, and resveratrol have been shown to have antitumor effectsand several studies have examined their role in treating cancer, either alone or in combination with other chemotherapeutic drugs. These compounds are capable of affecting different cancer-related mechanisms, such as proliferation, inflammation, invasion, and metastasis. Along with all of the benefits of these agents, affecting epigenetic processes is one of the most important aspects of their impact. Epigenetic modifications can be categorized into three main processes that include DNA methylation, histone modification, and regulation of small non-coding RNAs. Therefore, targeting DNA methylation can be used as a cancer treatment strategy by identifying or developing methylation modulators. Herein, we take a look into the studies investigating the role of natural products (e.g. curcumin, resveratrol, epigallocatechin gallate (EGCG), and quercetin) in alternating the DNA methylation status of various cancer cells. We discuss how these compounds reduce the expression of enzymes mediating the methylation of tumor suppressor genes and thereby, increasing the expression of tumor suppressors while reactivating antitumor signaling pathways.
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Affiliation(s)
- Nadir Mustafa Qadir Nanakali
- Department of Biomedical Science, College of Science, Cihan University-Erbil, Kurdistan Region, Erbil, Iraq
- Department of Biology, College of Education, Salahaddin University-Erbil, Kurdistan Region, Erbil, Iraq
| | - Parisa Maleki Dana
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, I.R. Iran
| | - Fatemeh Sadoughi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, I.R. Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, I.R. Iran
| | - Mehran Sharifi
- Department of Internal Medicine, School of Medicine, Cancer Prevention Research Center, Seyyed Al-Shohada Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Reza Asemi
- Department of Internal Medicine, School of Medicine, Cancer Prevention Research Center, Seyyed Al-Shohada Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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Dobre M, Poenaru RC, Niculae AM, Vladut C, Herlea V, Milanesi E, Hinescu ME. Increased Levels of miR-15b-5p and miR-20b-5p in Pancreatic Ductal Adenocarcinoma with Hepatic Metastases. Genes (Basel) 2023; 14:1577. [PMID: 37628628 PMCID: PMC10454474 DOI: 10.3390/genes14081577] [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: 06/16/2023] [Revised: 07/27/2023] [Accepted: 07/28/2023] [Indexed: 08/27/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal forms of cancer. The symptoms appear in advanced stages, and diagnostic and prognostic tests for the early detection of PDAC and disease evolution are not available. The dysregulation of microRNAs (miRNAs) has been associated with cancer development and progression, and some miRNAs have been reported to promote specific metastasis. In this study we aimed to identify the miRNAs dysregulated in PDAC tumoral tissues and a subset of miRNAs associated with tumoral characteristics, mainly metastasis presence and site. For this, the expression of 84 miRNAs was evaluated by qPCR in 30 tumoral tissues and 16 samples of non-tumoral pancreatic tissues. The comparison revealed 32 dysregulated miRNAs (19 upregulated and 13 downregulated) in the PDAC group. Reactome pathway over-representation analysis revealed that these miRNAs are involved in several biological pathways, including "ESR-mediated signaling", "PIP3 activates AKT signaling", and "Regulation of PTEN", among others. Moreover, our study identified an upregulation of miR-15b-5p and miR-20b-5p in the tumoral tissues of patients with hepatic metastasis, outlining these miRNAs as potential markers for hepatic metastasis. No significant difference in miRNA expression was observed in relation to anatomic location, lymphovascular invasion, lung metastasis, and the presence of diabetes.
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Affiliation(s)
- Maria Dobre
- Victor Babes National Institute of Pathology, 050096 Bucharest, Romania; (M.D.); (A.M.N.); (M.E.H.)
| | - Radu Cristian Poenaru
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (R.C.P.); (C.V.)
| | - Andrei Marian Niculae
- Victor Babes National Institute of Pathology, 050096 Bucharest, Romania; (M.D.); (A.M.N.); (M.E.H.)
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (R.C.P.); (C.V.)
| | - Catalina Vladut
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (R.C.P.); (C.V.)
- Department of Gastroenterology, “Prof. Dr. Agrippa Ionescu” Clinical Emergency Hospital, 011356 Bucharest, Romania
| | - Vlad Herlea
- Fundeni Clinical Institute, 022328 Bucharest, Romania;
| | - Elena Milanesi
- Victor Babes National Institute of Pathology, 050096 Bucharest, Romania; (M.D.); (A.M.N.); (M.E.H.)
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (R.C.P.); (C.V.)
| | - Mihail Eugen Hinescu
- Victor Babes National Institute of Pathology, 050096 Bucharest, Romania; (M.D.); (A.M.N.); (M.E.H.)
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (R.C.P.); (C.V.)
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Saviana M, Le P, Micalo L, Del Valle-Morales D, Romano G, Acunzo M, Li H, Nana-Sinkam P. Crosstalk between miRNAs and DNA Methylation in Cancer. Genes (Basel) 2023; 14:1075. [PMID: 37239435 PMCID: PMC10217889 DOI: 10.3390/genes14051075] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 05/04/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
miRNAs are some of the most well-characterized regulators of gene expression. Integral to several physiological processes, their aberrant expression often drives the pathogenesis of both benign and malignant diseases. Similarly, DNA methylation represents an epigenetic modification influencing transcription and playing a critical role in silencing numerous genes. The silencing of tumor suppressor genes through DNA methylation has been reported in many types of cancer and is associated with tumor development and progression. A growing body of literature has described the crosstalk between DNA methylation and miRNAs as an additional layer in the regulation of gene expression. Methylation in miRNA promoter regions inhibits its transcription, while miRNAs can target transcripts and subsequently regulate the proteins responsible for DNA methylation. Such relationships between miRNA and DNA methylation serve an important regulatory role in several tumor types and highlight a novel avenue for potential therapeutic targets. In this review, we discuss the crosstalk between DNA methylation and miRNA expression in the pathogenesis of cancer and describe how miRNAs influence DNA methylation and, conversely, how methylation impacts the expression of miRNAs. Finally, we address how these epigenetic modifications may be leveraged as biomarkers in cancer.
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Affiliation(s)
| | | | | | | | | | | | | | - Patrick Nana-Sinkam
- Department of Internal Medicine, Division of Pulmonary Diseases and Critical Care Medicine, Virginia Commonwealth University, 1250 E. Marshall Street, Richmond, VA 23298, USA
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O’Neill F, Allen-Coyle TJ, Roche S, Meiller J, Conlon NT, Swan N, Straubinger RM, Geoghegan J, Straubinger NL, Conlon K, McDermott R, O’Sullivan F, Henry M, Meleady P, McVey G, O’Connor R, Moriarty M, Clynes M. Alteration in Levels of Specific miRNAs and Their Potential Protein Targets between Human Pancreatic Cancer Samples, Adjacent Normal Tissue, and Xenografts Derived from These Tumors. Life (Basel) 2023; 13:608. [PMID: 36983764 PMCID: PMC10057657 DOI: 10.3390/life13030608] [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: 12/09/2022] [Revised: 02/10/2023] [Accepted: 02/15/2023] [Indexed: 02/24/2023] Open
Abstract
Herein, we describe the global comparison of miRNAs in human pancreatic cancer tumors, adjacent normal tissue, and matched patient-derived xenograft models using microarray screening. RNA was extracted from seven tumor, five adjacent normal, and eight FI PDX tumor samples and analyzed by Affymetrix GeneChip miRNA 4.0 array. A transcriptome analysis console (TAC) was used to generate comparative lists of up- and downregulated miRNAs for the comparisons, tumor vs. normal and F1 PDX vs. tumor. Particular attention was paid to miRNAs that were changed in the same direction in both comparisons. We identified the involvement in pancreatic tumor tissue of several miRNAs, including miR4534, miR3154, and miR4742, not previously highlighted as being involved in this type of cancer. Investigation in the parallel mRNA and protein lists from the same samples allowed the elimination of proteins where altered expression correlated with corresponding mRNA levels and was thus less likely to be miRNA regulated. Using the remaining differential expression protein lists for proteins predicted to be targeted for differentially expressed miRNA on our list, we were able to tentatively ascribe specific protein changes to individual miRNA. Particularly interesting target proteins for miRs 615-3p, 2467-3p, 4742-5p, 509-5p, and 605-3p were identified. Prominent among the protein targets are enzymes involved in aldehyde metabolism and membrane transport and trafficking. These results may help to uncover vulnerabilities that could enable novel approaches to treating pancreatic cancer.
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Affiliation(s)
- Fiona O’Neill
- National Institute for Cellular Biotechnology, Dublin City University, D09 NR58 Dublin, Ireland
| | - Taylor-Jade Allen-Coyle
- National Institute for Cellular Biotechnology, Dublin City University, D09 NR58 Dublin, Ireland
- SSPC, The Science Foundation Ireland Research Centre for Pharmaceuticals, V94 T9PX Limerick, Ireland
| | - Sandra Roche
- National Institute for Cellular Biotechnology, Dublin City University, D09 NR58 Dublin, Ireland
| | - Justine Meiller
- National Institute for Cellular Biotechnology, Dublin City University, D09 NR58 Dublin, Ireland
| | - Neil T. Conlon
- National Institute for Cellular Biotechnology, Dublin City University, D09 NR58 Dublin, Ireland
| | - Niall Swan
- St. Vincent’s University Hospital, D04 T6F4 Dublin, Ireland
| | - Robert M. Straubinger
- Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY 14214, USA
| | | | - Ninfa L. Straubinger
- Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY 14214, USA
| | - Kevin Conlon
- St. Vincent’s University Hospital, D04 T6F4 Dublin, Ireland
| | - Ray McDermott
- St. Vincent’s University Hospital, D04 T6F4 Dublin, Ireland
| | - Finbarr O’Sullivan
- National Institute for Cellular Biotechnology, Dublin City University, D09 NR58 Dublin, Ireland
- SSPC, The Science Foundation Ireland Research Centre for Pharmaceuticals, V94 T9PX Limerick, Ireland
| | - Michael Henry
- National Institute for Cellular Biotechnology, Dublin City University, D09 NR58 Dublin, Ireland
| | - Paula Meleady
- National Institute for Cellular Biotechnology, Dublin City University, D09 NR58 Dublin, Ireland
- SSPC, The Science Foundation Ireland Research Centre for Pharmaceuticals, V94 T9PX Limerick, Ireland
- School of Biotechnology, Dublin City University, D09 K2OV Dublin, Ireland
| | - Gerard McVey
- St. Luke’s Hospital, Rathgar, D06 HH36 Dublin, Ireland
| | - Robert O’Connor
- National Institute for Cellular Biotechnology, Dublin City University, D09 NR58 Dublin, Ireland
| | - Michael Moriarty
- National Institute for Cellular Biotechnology, Dublin City University, D09 NR58 Dublin, Ireland
- St. Luke’s Hospital, Rathgar, D06 HH36 Dublin, Ireland
| | - Martin Clynes
- National Institute for Cellular Biotechnology, Dublin City University, D09 NR58 Dublin, Ireland
- SSPC, The Science Foundation Ireland Research Centre for Pharmaceuticals, V94 T9PX Limerick, Ireland
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Gallo Cantafio ME, Torcasio R, Viglietto G, Amodio N. Non-Coding RNA-Dependent Regulation of Mitochondrial Dynamics in Cancer Pathophysiology. Noncoding RNA 2023; 9:ncrna9010016. [PMID: 36827549 PMCID: PMC9964195 DOI: 10.3390/ncrna9010016] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 02/07/2023] [Accepted: 02/18/2023] [Indexed: 02/22/2023] Open
Abstract
Mitochondria are essential organelles which dynamically change their shape and number to adapt to various environmental signals in diverse physio-pathological contexts. Mitochondrial dynamics refers to the delicate balance between mitochondrial fission (or fragmentation) and fusion, that plays a pivotal role in maintaining mitochondrial homeostasis and quality control, impinging on other mitochondrial processes such as metabolism, apoptosis, mitophagy, and autophagy. In this review, we will discuss how dysregulated mitochondrial dynamics can affect different cancer hallmarks, significantly impacting tumor growth, survival, invasion, and chemoresistance. Special emphasis will be given to emerging non-coding RNA molecules targeting the main fusion/fission effectors, acting as novel relevant upstream regulators of the mitochondrial dynamics rheostat in a wide range of tumors.
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Affiliation(s)
| | - Roberta Torcasio
- Department of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
- Laboratory of Cellular and Molecular Cardiovascular Pathophysiology, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, Arcavacata di Rende, 87036 Cosenza, Italy
| | - Giuseppe Viglietto
- Department of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Nicola Amodio
- Department of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
- Correspondence:
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Pancreatic Cancer in Chronic Pancreatitis: Pathogenesis and Diagnostic Approach. Cancers (Basel) 2023; 15:cancers15030761. [PMID: 36765725 PMCID: PMC9913572 DOI: 10.3390/cancers15030761] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/20/2023] [Accepted: 01/24/2023] [Indexed: 01/28/2023] Open
Abstract
Chronic pancreatitis is one of the main risk factors for pancreatic cancer, but it is a rare event. Inflammation and oncogenes work hand in hand as key promoters of this disease. Tobacco is another co-factor. During alcoholic chronic pancreatitis, the cumulative risk of cancer is estimated at 4% after 15 to 20 years. This cumulative risk is higher in hereditary pancreatitis: 19 and 12% in the case of PRSS1 and SPINK1 mutations, respectively, at an age of 60 years. The diagnosis is difficult due to: (i) clinical symptoms of cancer shared with those of chronic pancreatitis; (ii) the parenchymal and ductal remodeling of chronic pancreatitis rendering imaging analysis difficult; and (iii) differential diagnoses, such as pseudo-tumorous chronic pancreatitis and paraduodenal pancreatitis. Nevertheless, the occurrence of cancer during chronic pancreatitis must be suspected in the case of back pain, weight loss, unbalanced diabetes, and jaundice, despite alcohol withdrawal. Imaging must be systematically reviewed. Endoscopic ultrasound-guided fine-needle biopsy can contribute by targeting suspicious tissue areas with the help of molecular biology (search for KRAS, TP53, CDKN2A, DPC4 mutations). Short-term follow-up of patients is necessary at the clinical and paraclinical levels to try to diagnose cancer at a surgically curable stage. Pancreatic surgery is sometimes necessary if there is any doubt.
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Zhang W, Jiang T, Xie K. Epigenetic reprogramming in pancreatic premalignancy and clinical implications. Front Oncol 2023; 13:1024151. [PMID: 36874143 PMCID: PMC9978013 DOI: 10.3389/fonc.2023.1024151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Accepted: 02/01/2023] [Indexed: 02/18/2023] Open
Abstract
Pancreatic cancer (PC) is the most lethal human cancer, with less than 10% 5-year survival. Pancreatic premalignancy is a genetic and epigenomic disease and is linked to PC initiation. Pancreatic premalignant lesions include pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasm (MCN), with pancreatic acinar-to-ductal metaplasia (ADM) as the major source of pancreatic premalignant lesions. Emerging evidence reveals that an epigenetic dysregulation is an early event in pancreatic tumorigenesis. The molecular mechanisms of epigenetic inheritance include chromatin remodeling; modifications in histone, DNA, and RNA; non-coding RNA expression; and alternative splicing of RNA. Changes in those epigenetic modifications contribute to the most notable alterations in chromatin structure and promoter accessibility, thus leading to the silence of tumor suppressor genes and/or activation of oncogenes. The expression profiles of various epigenetic molecules provide a promising opportunity for biomarker development for early diagnosis of PC and novel targeted treatment strategies. However, how the alterations in epigenetic regulatory machinery regulate epigenetic reprogramming in pancreatic premalignant lesions and the different stages of their initiation needs further investigation. This review will summarize the current knowledge of epigenetic reprogramming in pancreatic premalignant initiation and progression, and its clinical applications as detection and diagnostic biomarkers and therapeutic targets in PC.
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Affiliation(s)
- Wei Zhang
- Center for Pancreatic Cancer Research, School of Medicine, The South China University of Technology, Guangzhou, China.,Department of Pathology, School of Medicine, The South China University of Technology, Guangzhou, China
| | - Tingting Jiang
- Center for Pancreatic Cancer Research, School of Medicine, The South China University of Technology, Guangzhou, China.,Department of Pathology, School of Medicine, The South China University of Technology, Guangzhou, China
| | - Keping Xie
- Center for Pancreatic Cancer Research, School of Medicine, The South China University of Technology, Guangzhou, China.,Department of Pathology, School of Medicine, The South China University of Technology, Guangzhou, China
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11
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Yang P, Zhang D, Zhou F, Chen W, Hu C, Xiao D, Cai S. miR-203a-3p-DNMT3B feedback loop facilitates non-small cell lung cancer progression. Hum Cell 2022; 35:1219-1233. [PMID: 35670956 DOI: 10.1007/s13577-022-00728-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 05/17/2022] [Indexed: 11/04/2022]
Abstract
It has been reported that microRNA-203a-3p (miR-203a-3p) modulates cell proliferation, migration and invasion in a variety of cancer cell types. However, little is known about its role in lung cancer progression. The present study found that miR-203a-3p was downregulated in non-small cell lung cancer (NSCLC) cell lines and tissues. Overexpression of miR-203a-3p inhibits NSCLC cell proliferation, migration and invasion, and promotes cellular apoptosis in vitro. Restoration of miR-203a-3p expression in A549 and NCI-H520 cells enhances their chemosensitivity. Further experiments showed that DNA methyltransferase 3B (DNMT3B) was a direct target of miR-203a-3p. In addition, the present results revealed that promoter hypermethylation was the potential mechanism responsible for low miR-203a-3p expression in NSCLC. Notably, feedback regulation between miR-203a-3p and DNMT3B was observed in NSCLC. Moreover, Overexpression of miR-203a-3p reduces tumor growth in vivo. In summary, the present study has identified an miR-203a-3p-DNMT3B feedback loop that facilitates NSCLC progression.
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Affiliation(s)
- Pingshan Yang
- Department of Thoracic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, Guangdong, People's Republic of China
| | - Dongdong Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, Guangdong, People's Republic of China
| | - Fengli Zhou
- Departments of General Practice, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, Guangdong, People's Republic of China
| | - Wenyou Chen
- Department of Thoracic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, Guangdong, People's Republic of China
| | - Chuang Hu
- Department of Thoracic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, Guangdong, People's Republic of China
| | - Duqing Xiao
- Department of Thoracic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, Guangdong, People's Republic of China
| | - Songwang Cai
- Department of Thoracic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, Guangdong, People's Republic of China.
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12
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Emirzeoglu L, Olmez O, Mustafayev F, Berber U, Yilmaz I, Celik S, Oven B, Ozgun M. Prognostic value of expression levels of miR‑148a, miR‑152 and HLA‑G in colon cancer. Oncol Lett 2022; 24:226. [PMID: 35720471 PMCID: PMC9185158 DOI: 10.3892/ol.2022.13347] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 04/26/2022] [Indexed: 11/05/2022] Open
Affiliation(s)
- Levent Emirzeoglu
- Department of Medical Oncology, University of Health Sciences, Sultan II. Abdulhamid Khan Educational and Research Hospital, 34660 Istanbul, Turkey
| | - Ozgur Olmez
- Department of Medical Oncology, University of Health Sciences, Sultan II. Abdulhamid Khan Educational and Research Hospital, 34660 Istanbul, Turkey
| | - Fatma Mustafayev
- Department of Medical Oncology, University of Health Sciences, Sultan II. Abdulhamid Khan Educational and Research Hospital, 34660 Istanbul, Turkey
| | - Ufuk Berber
- Department of Pathology, University of Health Sciences, Sultan II. Abdulhamid Khan Educational and Research Hospital, 34660 Istanbul, Turkey
| | - Ismail Yilmaz
- Department of Pathology, University of Health Sciences, Sultan II. Abdulhamid Khan Educational and Research Hospital, 34660 Istanbul, Turkey
| | - Serkan Celik
- Department of Medical Oncology, Yeditepe University Koşuyolu Hospital, 34718 Istanbul, Turkey
| | - Bala Oven
- Department of Medical Oncology, Yeditepe University Koşuyolu Hospital, 34718 Istanbul, Turkey
| | - Mehmet Ozgun
- Department of Medical Oncology, University of Health Sciences, Sultan II. Abdulhamid Khan Educational and Research Hospital, 34660 Istanbul, Turkey
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13
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Zamberlan M, Boeckx A, Muller F, Vinelli F, Ek O, Vianello C, Coart E, Shibata K, Christian A, Grespi F, Giacomello M, Struman I, Scorrano L, Herkenne S. Inhibition of the mitochondrial protein Opa1 curtails breast cancer growth. J Exp Clin Cancer Res 2022; 41:95. [PMID: 35279198 PMCID: PMC8917763 DOI: 10.1186/s13046-022-02304-6] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 02/26/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Mitochondrial fusion and fission proteins have been nominated as druggable targets in cancer. Whether their inhibition is efficacious in triple negative breast cancer (TNBC) that almost invariably develops chemoresistance is unknown. METHODS We used a combination of bioinformatics analyses of cancer genomic databases, genetic and pharmacological Optic Atrophy 1 (OPA1) inhibition, mitochondrial function and morphology measurements, micro-RNA (miRNA) profiling and formal epistatic analyses to address the role of OPA1 in TNBC proliferation, migration, and invasion in vitro and in vivo. RESULTS We identified a signature of OPA1 upregulation in breast cancer that correlates with worse prognosis. Accordingly, OPA1 inhibition could reduce breast cancer cells proliferation, migration, and invasion in vitro and in vivo. Mechanistically, while OPA1 silencing did not reduce mitochondrial respiration, it increased levels of miRNAs of the 148/152 family known to inhibit tumor growth and invasiveness. Indeed, these miRNAs were epistatic to OPA1 in the regulation of TNBC cells growth and invasiveness. CONCLUSIONS Our data show that targeted inhibition of the mitochondrial fusion protein OPA1 curtails TNBC growth and nominate OPA1 as a druggable target in TNBC.
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Affiliation(s)
- Margherita Zamberlan
- Department of Biology, University of Padova, Via U. Bassi 58B, 35121, Padova, Italy
- Veneto Institute of Molecular Medicine, Via Orus 2, 35129, Padova, Italy
| | - Amandine Boeckx
- Laboratory of molecular angiogenesis, GIGA-Research, Avenue de l'Hôpital, 1, 4020, Liège, Belgium
| | - Florian Muller
- Laboratory of molecular angiogenesis, GIGA-Research, Avenue de l'Hôpital, 1, 4020, Liège, Belgium
| | - Federica Vinelli
- Department of Biology, University of Padova, Via U. Bassi 58B, 35121, Padova, Italy
- Veneto Institute of Molecular Medicine, Via Orus 2, 35129, Padova, Italy
| | - Olivier Ek
- Department of Biology, University of Padova, Via U. Bassi 58B, 35121, Padova, Italy
| | - Caterina Vianello
- Department of Biology, University of Padova, Via U. Bassi 58B, 35121, Padova, Italy
| | - Emeline Coart
- Laboratory of molecular angiogenesis, GIGA-Research, Avenue de l'Hôpital, 1, 4020, Liège, Belgium
| | - Keitaro Shibata
- Department of Biology, University of Padova, Via U. Bassi 58B, 35121, Padova, Italy
- Veneto Institute of Molecular Medicine, Via Orus 2, 35129, Padova, Italy
| | - Aurélie Christian
- Laboratory of molecular angiogenesis, GIGA-Research, Avenue de l'Hôpital, 1, 4020, Liège, Belgium
| | - Francesca Grespi
- Department of Biology, University of Padova, Via U. Bassi 58B, 35121, Padova, Italy
- Veneto Institute of Molecular Medicine, Via Orus 2, 35129, Padova, Italy
| | - Marta Giacomello
- Department of Biology, University of Padova, Via U. Bassi 58B, 35121, Padova, Italy
| | - Ingrid Struman
- Laboratory of molecular angiogenesis, GIGA-Research, Avenue de l'Hôpital, 1, 4020, Liège, Belgium
| | - Luca Scorrano
- Department of Biology, University of Padova, Via U. Bassi 58B, 35121, Padova, Italy.
- Veneto Institute of Molecular Medicine, Via Orus 2, 35129, Padova, Italy.
| | - Stéphanie Herkenne
- Laboratory of molecular angiogenesis, GIGA-Research, Avenue de l'Hôpital, 1, 4020, Liège, Belgium.
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14
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Rimini M, Puzzoni M, Pedica F, Silvestris N, Fornaro L, Aprile G, Loi E, Brunetti O, Vivaldi C, Simionato F, Zavattari P, Scartozzi M, Burgio V, Ratti F, Aldrighetti L, Cascinu S, Casadei-Gardini A. Cholangiocarcinoma: new perspectives for new horizons. Expert Rev Gastroenterol Hepatol 2021; 15:1367-1383. [PMID: 34669536 DOI: 10.1080/17474124.2021.1991313] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Biliary tract cancer represents a heterogeneous group of malignancies characterized by dismal prognosis and scarce therapeutic options. AREA COVERED In the last years, a growing interest in BTC pathology has emerged, thus highlighting a significant heterogeneity of the pathways underlying the carcinogenesis process, from both a molecular and genomic point of view. A better understanding of these differences is mandatory to deepen the behavior of this complex disease, as well as to identify new targetable target mutations, with the aim to improve the survival outcomes. The authors decided to provide a comprehensive overview of the recent highlights on BTCs, with a special focus on the genetic, epigenetic and molecular alterations, which may have an interesting clinical application in the next future. EXPERT OPINION In the last years, the efforts resulted from international collaborations have led to the identification of new promising targets for precision medicine approaches in the BTC setting. Further investigations and prospective trials are needed, but the hope is that these new knowledge in cooperation with the new technologies and procedures, including bio-molecular and genomic analysis as well radiomic studies, will enrich the therapeutic armamentarium thus improving the survival outcomes in a such lethal and complex disease.
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Affiliation(s)
- Margherita Rimini
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Marco Puzzoni
- Medical Oncology, University and University Hospital of Cagliari, Italy
| | - Federica Pedica
- Department of Pathology, San Raffaele Scientific Institute, Milan, Italy
| | - Nicola Silvestris
- Department of oncology, Instituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Istituto Tumori "Giovanni Paolo Ii" of Bari, Bari, Italy.,Department of Biomedical Sciences and Human Oncology, Aldo Moro University of Bari, Bari, Italy
| | - Lorenzo Fornaro
- Department of medical oncology, U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Giuseppe Aprile
- Department of Oncology, San Bortolo General Hospital, Azienda ULSS8 Berica, Vicenza, Italy
| | - Eleonora Loi
- Department of Biomedical Sciences, Unit of Biology and Genetics, University of Cagliari, Cagliari, Italy
| | - Oronzo Brunetti
- Department of oncology, Instituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Istituto Tumori "Giovanni Paolo Ii" of Bari, Bari, Italy
| | - Caterina Vivaldi
- Department of medical oncology, U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Francesca Simionato
- Department of Oncology, San Bortolo General Hospital, Azienda ULSS8 Berica, Vicenza, Italy
| | - Patrizia Zavattari
- Department of Biomedical Sciences, Unit of Biology and Genetics, University of Cagliari, Cagliari, Italy
| | - Mario Scartozzi
- Medical Oncology, University and University Hospital of Cagliari, Italy
| | - Valentina Burgio
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Francesca Ratti
- Hepatobiliary Surgery Division, IRCCS San Raffaele and Vita-Salute University, Italy
| | - Luca Aldrighetti
- Hepatobiliary Surgery Division, IRCCS San Raffaele and Vita-Salute University, Italy
| | - Stefano Cascinu
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
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15
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You H, Wang L, Bu F, Meng H, Pan X, Li J, Zhang Y, Wang A, Yin N, Huang C, Li J. The miR-455-3p/HDAC2 axis plays a pivotal role in the progression and reversal of liver fibrosis and is regulated by epigenetics. FASEB J 2021; 35:e21700. [PMID: 34105828 DOI: 10.1096/fj.202002319rrr] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 01/29/2021] [Accepted: 05/11/2021] [Indexed: 12/29/2022]
Abstract
Histone deacetylases (HDACs), especially HDAC2, play a role in alleviating liver fibrosis; however, the specific upstream regulation mechanism is unknown. Herein, TargetScan was used to predict the potential upstream targets of HDAC2, and the role of miR-455-3p was explored. The dual luciferase reporter assay showed that miR-455-3p binds to the 3' UTR of HDAC2 mRNA. Additionally, miR-455-3p was downregulated in the liver tissues of patients with cirrhosis and mice with liver fibrosis, as well as in primary HSCs isolated from fibrotic mouse livers and TGF-β-treated LX-2 cells. In contrast, it is highly expressed in the reversal stage of hepatic fibrosis and MDI-cultured LX-2 cells. Our functional analyses showed that miR-455-3p overexpression facilitated apoptosis and reduced the expression of pro-fibrotic markers and the proliferation of activated LX-2 cells. On the contrary, miR-455-3p inhibition converted inactivated LX-2 cells into activated, proliferative, fibrogenic cells. Interestingly, restoration of HDAC2 expression partially blocked the function of miR-455-3p. Downregulated miR-455-3p expression can be restored by DNA methyltransferases in activated LX-2 cells. Methylation-specific PCR, bisulfite sequencing PCR, and chromatin immunoprecipitation assays indicated that the methylation level of miR-455-3p promoter CpG islands was elevated in TGF-β-treated LX-2 cells and that miR-455-3p was downregulated in activated LX-2 cells by DNA hypermethylation, which is mediated by DNMT3b and DNMT1. In conclusion, miR-455-3p acts as a liver fibrosis suppressor by targeting HDAC2, and its deficiency further aggravates the reversal phase of fibrosis. Thus, the epigenetics mediated miR-455-3p/HDAC2 axis may serve as a novel potential therapeutic target for clinical treatment of hepatic fibrosis.
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Affiliation(s)
- Hongmei You
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Ling Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Fangtian Bu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Hongwu Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Xueyin Pan
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Juanjuan Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Yafei Zhang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Ao Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Nana Yin
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
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16
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Singh HM, Leber MF, Bossow S, Engeland CE, Dessila J, Grossardt C, Zaoui K, Bell JC, Jäger D, von Kalle C, Ungerechts G. MicroRNA-sensitive oncolytic measles virus for chemovirotherapy of pancreatic cancer. MOLECULAR THERAPY-ONCOLYTICS 2021; 21:340-355. [PMID: 34141871 PMCID: PMC8182383 DOI: 10.1016/j.omto.2021.04.015] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 04/28/2021] [Indexed: 02/07/2023]
Abstract
Advanced pancreatic cancer is characterized by few treatment options and poor outcomes. Oncolytic virotherapy and chemotherapy involve complementary pharmacodynamics and could synergize to improve therapeutic efficacy. Likewise, multimodality treatment may cause additional toxicity, and new agents have to be safe. Balancing both aims, we generated an oncolytic measles virus for 5-fluorouracil-based chemovirotherapy of pancreatic cancer with enhanced tumor specificity through microRNA-regulated vector tropism. The resulting vector encodes a bacterial prodrug convertase, cytosine deaminase-uracil phosphoribosyl transferase, and carries synthetic miR-148a target sites in the viral F gene. Combination of the armed and targeted virus with 5-fluorocytosine, a prodrug of 5-fluorouracil, resulted in cytotoxicity toward both infected and bystander pancreatic cancer cells. In pancreatic cancer xenografts, a single intratumoral injection of the virus induced robust in vivo expression of prodrug convertase. Based on intratumoral transgene expression kinetics, we devised a chemovirotherapy regimen to assess treatment efficacy. Concerted multimodality treatment with intratumoral virus and systemic prodrug administration delayed tumor growth and prolonged survival of xenograft-bearing mice. Our results demonstrate that 5-fluorouracil-based chemovirotherapy with microRNA-sensitive measles virus is an effective strategy against pancreatic cancer at a favorable therapeutic index that warrants future clinical translation.
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Affiliation(s)
- Hans Martin Singh
- Clinical Cooperation Unit Virotherapy, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.,Department of Medical Oncology, National Center for Tumor Diseases (NCT) and Heidelberg University Hospital, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany
| | - Mathias Felix Leber
- Clinical Cooperation Unit Virotherapy, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.,Department of Medical Oncology, National Center for Tumor Diseases (NCT) and Heidelberg University Hospital, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.,Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ONT, Canada
| | - Sascha Bossow
- Clinical Cooperation Unit Virotherapy, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Christine E Engeland
- Clinical Cooperation Unit Virotherapy, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.,Department of Medical Oncology, National Center for Tumor Diseases (NCT) and Heidelberg University Hospital, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.,Clinical Cooperation Unit Virotherapy, Research Group Mechanisms of Oncolytic Immunotherapy, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.,Faculty of Health/School of Medicine, Institute of Virology and Microbiology, Witten/Herdecke University, Stockumer Straße 10, 58453 Witten, Germany
| | - Jan Dessila
- Clinical Cooperation Unit Virotherapy, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Christian Grossardt
- Clinical Cooperation Unit Virotherapy, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Karim Zaoui
- Clinical Cooperation Unit Virotherapy, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.,Department of Otorhinolaryngology and Head and Neck Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany
| | - John C Bell
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ONT, Canada
| | - Dirk Jäger
- Department of Medical Oncology, National Center for Tumor Diseases (NCT) and Heidelberg University Hospital, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany
| | - Christof von Kalle
- Berlin Institute of Health and Charité Universitätsmedizin, Anna-Louisa-Karsch-Straße 2, 10178 Berlin, Germany.,Sidra Medical and Research Center, Al Luqta Street, Education City, North Campus, P.O. Box 26999, Doha, Qatar
| | - Guy Ungerechts
- Clinical Cooperation Unit Virotherapy, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.,Department of Medical Oncology, National Center for Tumor Diseases (NCT) and Heidelberg University Hospital, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.,Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ONT, Canada
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17
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Non-coding RNA biomarkers in pancreatic ductal adenocarcinoma. Semin Cancer Biol 2020; 75:153-168. [PMID: 33049362 DOI: 10.1016/j.semcancer.2020.10.001] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/20/2020] [Accepted: 10/02/2020] [Indexed: 12/13/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, which is usually diagnosed at an advanced stage. The late disease diagnosis, the limited availability of effective therapeutic interventions and lack of robust diagnostic biomarkers, are some of the primary reasons for the dismal 5-year survival rates (∼8%) in patients with PDAC. The pancreatic cancer develops through accumulation of a series of genomic and epigenomic alterations which lead to the transformation of normal pancreatic epithelium into an invasive carcinoma - a process that can take up to 15-20 years to develop, from the occurrence of first initiating mutational event. These facts highlight a unique window of opportunity for the earlier detection of PDAC, which could allow timely disease interception and improvement in the overall survival outcomes in patients suffering from this fatal malignancy. Non-coding RNAs (ncRNAs) have been recognized to play a central role in PDAC pathogenesis and are emerging as attractive candidates for biomarker development in various cancers, including PDAC. More specifically, the ncRNAs play a pivotal role in PDAC biology as they affect tumor growth, migration, and invasion by regulating cellular processes including cell cycle, apoptosis, and epithelial-mesenchymal transition. In this review, we focus on three types of well-established ncRNAs - microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) - and discuss their potential as diagnostic, prognostic and predictive biomarkers in PDAC.
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18
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Karimzadeh MR, Pourdavoud P, Ehtesham N, Qadbeigi M, Asl MM, Alani B, Mosallaei M, Pakzad B. Regulation of DNA methylation machinery by epi-miRNAs in human cancer: emerging new targets in cancer therapy. Cancer Gene Ther 2020; 28:157-174. [PMID: 32773776 DOI: 10.1038/s41417-020-00210-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Revised: 07/24/2020] [Accepted: 07/29/2020] [Indexed: 12/13/2022]
Abstract
Disruption in DNA methylation processes can lead to alteration in gene expression and function that would ultimately result in malignant transformation. In this way, studies have shown that, in cancers, methylation-associated silencing inactivates tumor suppressor genes, as effectively as mutations. DNA methylation machinery is composed of several genes, including those with DNA methyltransferases activity, proteins that bind to methylated cytosine in the promoter region, and enzymes with demethylase activity. Based on a prominent body of evidence, DNA methylation machinery could be regulated by microRNAs (miRNAs) called epi-miRNAs. Numerous studies demonstrated that dysregulation in DNA methylation regulators like upstream epi-miRNAs is indispensable for carcinogenesis; consequently, the malignant capacity of these cells could be reversed by restoring of this regulatory system in cancer. Conceivably, recognition of these epi-miRNAs in cancer cells could not only reveal novel molecular entities in carcinogenesis, but also render promising targets for cancer therapy. In this review, at first, we have an overview of the methylation alteration in cancers, and the effect of this phenomenon in miRNAs expression and after that, we conduct an in-depth discussion about the regulation of DNA methylation regulators by epi-miRNAs in cancer cells.
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Affiliation(s)
- Mohammad Reza Karimzadeh
- Department of medical Genetics, School of Medicine, Bam University of Medical Sciences, Bam, Iran
| | | | - Naeim Ehtesham
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Masood Movahedi Asl
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Behrang Alani
- Department of Applied Cell Sciences, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Meysam Mosallaei
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Bahram Pakzad
- Department of Internal Medicine, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran.
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19
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Mahdi MR, Georges RB, Ali DM, Bedeer RF, Eltahry HM, Gabr AEHZ, Berger MR. Modulation of the Endothelin System in Colorectal Cancer Liver Metastasis: Influence of Epigenetic Mechanisms? Front Pharmacol 2020; 11:180. [PMID: 32194414 PMCID: PMC7063057 DOI: 10.3389/fphar.2020.00180] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 02/10/2020] [Indexed: 12/13/2022] Open
Abstract
Targeting of endothelin system genes is a promising strategy in cancer therapy. The modulation of these genes was explored in a model of colorectal cancer (CRC) liver metastasis and in a panel of CRC tumor cell lines that were exposed to the demethylating agent decitabine. The CC531 rat model mimicking CRC liver metastasis was used for tumor cell re-isolation and analysis of the endothelin system genes and DNA methyltransferases (DNMTs) by microarray. To mimic the effects caused by methylation changes, a panel of seven CRC cell lines was treated with the demethylating agent decitabine. Three genes of the endothelin system were potently modulated at messenger RNA (mRNA) level in rat CC531 cells during liver colonization. The concomitant decrease of two DNMTs suggested an influence from altered methylation. Changes in gene expression were also accomplished by exposure of CRC cells to the demethylating agent decitabine, when using daily low concentrations for 3 days, with minimal cytotoxic effects. Sensitive human SW480 cells showed an almost 100fold upregulation of endothelin-1 mRNA compared to untreated cells. This, however, was different in LS174T cells, which showed no significant increase in gene expression although the methylation levels were significantly decreased at a variety of corresponding loci. We suggest that the mechanism induced by methylation on gene expression in metastatic CRC cells can be compromised. The results question the overall success of treating metastatic CRC by methylation inhibitors.
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Affiliation(s)
- Mohamed R. Mahdi
- Toxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Human Anatomy & Embryology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Rania B. Georges
- Toxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Doaa M. Ali
- Toxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Raouf F. Bedeer
- Department of Human Anatomy & Embryology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Huda M. Eltahry
- Department of Human Anatomy & Embryology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Abd-El Hakiem Z. Gabr
- Department of Human Anatomy & Embryology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Martin R. Berger
- Toxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
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20
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Cacheux J, Bancaud A, Leichlé T, Cordelier P. Technological Challenges and Future Issues for the Detection of Circulating MicroRNAs in Patients With Cancer. Front Chem 2019; 7:815. [PMID: 31850308 PMCID: PMC6894013 DOI: 10.3389/fchem.2019.00815] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 11/11/2019] [Indexed: 12/21/2022] Open
Abstract
In the era of precision medicine, the success of clinical trials, notably for patients diagnosed with cancer, strongly relies on biomarkers with pristine clinical value but also on robust and versatile analytical technologies to ensure proper patients' stratification and treatment. In this review, we will first address whether plasmatic and salivary microRNAs can be considered as a reliable source of biomarkers for cancer diagnosis and prognosis. We will then discuss the pre-analytical steps preceding miRNA quantification (from isolation to purification), and how such process could be biased and time-consuming. Next, we will review the most recent tools derived from micro- and nano-technologies for microRNA detection available to date and how they may compete with current standards. This review will prioritize publications using relevant biological samples. The significance of various physical transduction schemes (mechanical, optical, electrical, etc.) for biological detection will be compared, and pros and cons of each method will be widely discussed. Finally, we will debate on how micro and nanotechnologies could widespread the use of biomarkers in modern medicine, to help manage patients with serious diseases such as cancer.
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Affiliation(s)
- Jean Cacheux
- LAAS-CNRS, Université de Toulouse, CNRS, Toulouse, France.,Université Fédérale de Toulouse Midi-Pyrénées, Université Toulouse III Paul Sabatier, CRCT, Toulouse, France
| | | | | | - Pierre Cordelier
- Université Fédérale de Toulouse Midi-Pyrénées, Université Toulouse III Paul Sabatier, CRCT, Toulouse, France
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21
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Castillejo-Lopez C, Pjanic M, Pirona AC, Hetty S, Wabitsch M, Wadelius C, Quertermous T, Arner E, Ingelsson E. Detailed Functional Characterization of a Waist-Hip Ratio Locus in 7p15.2 Defines an Enhancer Controlling Adipocyte Differentiation. iScience 2019; 20:42-59. [PMID: 31557715 PMCID: PMC6817687 DOI: 10.1016/j.isci.2019.09.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 07/10/2019] [Accepted: 09/05/2019] [Indexed: 12/22/2022] Open
Abstract
We combined CAGE sequencing in human adipocytes during differentiation with data from genome-wide association studies to identify an enhancer in the SNX10 locus on chromosome 7, presumably involved in body fat distribution. Using reporter assays and CRISPR-Cas9 gene editing in human cell lines, we characterized the role of the enhancer in adipogenesis. The enhancer was active during adipogenesis and responded strongly to insulin and isoprenaline. The allele associated with increased waist-hip ratio in human genetic studies was associated with higher enhancer activity. Mutations of the enhancer resulted in less adipocyte differentiation. RNA sequencing of cells with disrupted enhancer showed reduced expression of established adipocyte markers, such as ADIPOQ and LPL, and identified CHI3L1 on chromosome 1 as a potential gene involved in adipocyte differentiation. In conclusion, we identified and characterized an enhancer in the SNX10 locus and outlined its plausible mechanisms of action and downstream targets.
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Affiliation(s)
- Casimiro Castillejo-Lopez
- Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Milos Pjanic
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Anna Chiara Pirona
- Department of Medical Sciences and Science for Life Laboratory, Uppsala University, Uppsala, Sweden; German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Susanne Hetty
- Department of Medical Sciences and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Martin Wabitsch
- Department of Pediatrics and Adolescent Medicine, Division of Pediatric Endocrinology and Diabetes, University of Ulm, Ulm, Germany
| | - Claes Wadelius
- Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Thomas Quertermous
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cardiovascular Institute, Stanford University, Stanford, CA 94305, USA
| | - Erik Arner
- Laboratory for Applied Regulatory Genomics Network Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045 Japan
| | - Erik Ingelsson
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medical Sciences and Science for Life Laboratory, Uppsala University, Uppsala, Sweden; Stanford Cardiovascular Institute, Stanford University, Stanford, CA 94305, USA; Stanford Diabetes Research Center, Stanford University, Stanford, CA 94305, USA.
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22
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Curcuminoid Analogs Differentially Modulate Nuclear Factor Kappa-Light-Chain-Enhancer, P65 Serine276, Mitogen- and Stress-activated Protein Kinase 1 And MicroRNA 148a Status. PROGRESS IN PREVENTIVE MEDICINE 2019. [DOI: 10.1097/pp9.0000000000000024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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23
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Juiz NA, Iovanna J, Dusetti N. Pancreatic Cancer Heterogeneity Can Be Explained Beyond the Genome. Front Oncol 2019; 9:246. [PMID: 31024848 PMCID: PMC6460948 DOI: 10.3389/fonc.2019.00246] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Accepted: 03/18/2019] [Indexed: 12/23/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a major health problem because it induces almost systematic mortality. Carcinogenesis begins with genetic aberrations which trigger epigenetic modifications. While genetic mutations initiate tumorigenesis, they are unable to explain the vast heterogeneity observed among PDAC patients. Instead, epigenetic changes drive transcriptomic alterations that can regulate the malignant phenotype. The contribution of factors from the environment and tumor microenvironment defines different epigenetic landscapes that outline two clinical subtypes: basal, with the worst prognosis, and classical. The epigenetic nature of PDAC, as a reversible phenomenon, encouraged several studies to test epidrugs. However, these drugs lack specificity and although there are epigenetic patterns shared by all PDAC tumors, there are others that are specific to each subtype. Molecular characterization of the epigenetic mechanisms underlying PDAC heterogeneity could be an invaluable tool to predict personalized therapies, stratify patients and search for novel therapies with more specific phenotype-based targets. Novel therapeutic strategies using current anticancer compounds or existing drugs used in other pathologies, alone or in combination, could be used to kill tumor cells or convert aggressive tumors into a more benign phenotype.
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Affiliation(s)
- Natalia Anahi Juiz
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université, Marseille, France
| | - Juan Iovanna
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université, Marseille, France
| | - Nelson Dusetti
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université, Marseille, France
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24
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Zubair H, Azim S, Khan MA, Patel GK, Ahmad A, Pai S, Singh S, Singh AP. Epigenetic Control of Pancreatic Carcinogenesis and Its Regulation by Natural Products. EPIGENETICS OF CANCER PREVENTION 2019:251-270. [DOI: 10.1016/b978-0-12-812494-9.00012-3] [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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25
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Mungamuri SK. Targeting the epigenome as a therapeutic strategy for pancreatic tumors. THERANOSTIC APPROACH FOR PANCREATIC CANCER 2019:211-244. [DOI: 10.1016/b978-0-12-819457-7.00011-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
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26
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Kunovsky L, Tesarikova P, Kala Z, Kroupa R, Kysela P, Dolina J, Trna J. The Use of Biomarkers in Early Diagnostics of Pancreatic Cancer. Can J Gastroenterol Hepatol 2018; 2018:5389820. [PMID: 30186820 PMCID: PMC6112218 DOI: 10.1155/2018/5389820] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 07/27/2018] [Accepted: 08/06/2018] [Indexed: 12/14/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies with increasing incidence. The poor prognosis is due to the aggressive nature of the tumor, late detection, and the resistance to chemotherapy and radiotherapy. A radical surgery procedure is the only treatment that has been shown to improve the 5-year survival rate to 20-25%. However, the majority of patients (80-85%) are diagnosed with locally advanced or metastatic disease and just 15-20% patients are diagnosed in an early stage allowing them to undergo the potentially curative surgical resection. The early detection of PDAC without the use of invasive methods is challenging and discovery of a cost-effective biomarker with high specificity and sensitivity could significantly improve the treatment and survival in these patients. In this review, we summarize current and newly examined biomarkers in early PDAC detection.
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Affiliation(s)
- Lumir Kunovsky
- Department of Gastroenterology, University Hospital Brno Bohunice, Faculty of Medicine, Masaryk University, Czech Republic
- Department of Surgery, University Hospital Brno Bohunice, Faculty of Medicine, Masaryk University, Czech Republic
| | - Pavla Tesarikova
- Department of Internal Medicine, Hospital Boskovice, Czech Republic
| | - Zdenek Kala
- Department of Surgery, University Hospital Brno Bohunice, Faculty of Medicine, Masaryk University, Czech Republic
| | - Radek Kroupa
- Department of Gastroenterology, University Hospital Brno Bohunice, Faculty of Medicine, Masaryk University, Czech Republic
| | - Petr Kysela
- Department of Surgery, University Hospital Brno Bohunice, Faculty of Medicine, Masaryk University, Czech Republic
| | - Jiri Dolina
- Department of Gastroenterology, University Hospital Brno Bohunice, Faculty of Medicine, Masaryk University, Czech Republic
| | - Jan Trna
- Department of Gastroenterology, University Hospital Brno Bohunice, Faculty of Medicine, Masaryk University, Czech Republic
- Department of Internal Medicine, Hospital Boskovice, Czech Republic
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Somatostatin Analogue Treatment Primarily Induce miRNA Expression Changes and Up-Regulates Growth Inhibitory miR-7 and miR-148a in Neuroendocrine Cells. Genes (Basel) 2018; 9:genes9070337. [PMID: 29973528 PMCID: PMC6070923 DOI: 10.3390/genes9070337] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 06/29/2018] [Accepted: 07/02/2018] [Indexed: 01/16/2023] Open
Abstract
Somatostatin (SST) analogues are used to control the proliferation and symptoms of neuroendocrine tumors (NETs). MicroRNAs (miRNA) are small non-coding RNAs that modulate posttranscriptional gene expression. We wanted to characterize the miRNAs operating under the control of SST to elucidate to what extent they mediate STT actions. NCI-H727 carcinoid cell line was treated with either a chimeric SST/dopamine analogue; a SST or dopamine analogue for proliferation assays and for identifying differentially expressed miRNAs using miRNA microarray. The miRNAs induced by SST analogue treatment are investigated in carcinoid cell lines NCI-H727 and CNDT2 using in situ hybridization, qPCR and proliferation assays. SST analogues inhibited the growth of carcinoid cells more potently compared to the dopamine analogue. Principal Component Analysis (PCA) of the samples based on miRNA expression clearly separated the samples based on treatment. Two miRNAs which were highly induced by SST analogues, miR-7 and miR-148a, were shown to inhibit the proliferation of NCI-H727 and CNDT2 cells. SST analogues also produced a general up-regulation of the let-7 family members. SST analogues control and induce distinct miRNA expression patterns among which miR-7 and miR-148a both have growth inhibitory properties.
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28
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Sensitization of prostate cancer to radiation therapy: Molecules and pathways to target. Radiother Oncol 2018; 128:283-300. [PMID: 29929859 DOI: 10.1016/j.radonc.2018.05.021] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 05/01/2018] [Accepted: 05/17/2018] [Indexed: 12/11/2022]
Abstract
Radiation therapy is used to treat cancer by radiation-induced DNA damage. Despite the best efforts to eliminate cancer, some cancer cells survive irradiation, resulting in cancer progression or recurrence. Alteration in DNA damage repair pathways is common in cancers, resulting in modulation of their response to radiation. This article focuses on the recent findings about molecules and pathways that potentially can be targeted to sensitize prostate cancer cells to ionizing radiation, thereby achieving an improved therapeutic outcome.
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29
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Idichi T, Seki N, Kurahara H, Fukuhisa H, Toda H, Shimonosono M, Okato A, Arai T, Kita Y, Mataki Y, Kijima Y, Maemura K, Natsugoe S. Molecular pathogenesis of pancreatic ductal adenocarcinoma: Impact of passenger strand of pre-miR-148a on gene regulation. Cancer Sci 2018; 109:2013-2026. [PMID: 29660218 PMCID: PMC5989856 DOI: 10.1111/cas.13610] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 04/05/2018] [Accepted: 04/06/2018] [Indexed: 01/05/2023] Open
Abstract
We previously used RNA sequencing to establish the microRNA (miRNA) expression signature of pancreatic ductal adenocarcinoma (PDAC). We found that both strands of pre-miR-148a (miR-148a-5p: the passenger strand and miR-148a-3p: the guide strand) were downregulated in cancer tissues. Ectopic expression of miR-148a-5p and miR-148a-3p significantly inhibited cancer cell migration and invasion, indicating that both strands of pre-miR-148a had tumor-suppressive roles in PDAC cells. In silico database and genome-wide gene expression analyses identified a total of 15 genes that were putative targets regulated by these miRNAs. High expression of miR-148a-5p targets (PHLDA2, LPCAT2 and AP1S3) and miR-148a-3p targets (SMA, ENDOD1 and UHMK1) was associated with poor prognosis of patients with PDAC. Moreover, knockdown of PHLDA2 expression inhibited cancer cell aggressiveness, suggesting PHLDA2 acted as an oncogene in PDAC cells. Involvement of the passenger strand of pre-miR-148a (miR-148-5p) is a new concept in cancer research. Novel approaches that identify tumor-suppressive miRNA regulatory networks in lethal PDAC might provide new prognostic markers and therapeutic targets for this disease.
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Affiliation(s)
- Tetsuya Idichi
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Naohiko Seki
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Hiroshi Kurahara
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Haruhi Fukuhisa
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Hiroko Toda
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Masataka Shimonosono
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Atsushi Okato
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Takayuki Arai
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yoshiaki Kita
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Yuko Mataki
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Yuko Kijima
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Kosei Maemura
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
| | - Shoji Natsugoe
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan
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Systematic Review and Meta-Analysis of Diagnostic Accuracy of miRNAs in Patients with Pancreatic Cancer. DISEASE MARKERS 2018; 2018:6292396. [PMID: 29887920 PMCID: PMC5977035 DOI: 10.1155/2018/6292396] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 04/23/2018] [Indexed: 12/19/2022]
Abstract
Background It is reported that miRNAs are aberrantly expressed in patients with pancreatic cancer. However, the diagnostic value of miRNAs in pancreatic cancer remains controversial. The meta-analysis was to access diagnostic accuracy of miRNAs in pancreatic cancer. Methods PubMed, Scopus, Web of Science, Chinese National Knowledge Infrastructure (CNKI), WANFANG Data, China Biomedical Literature Database (CBM), and VIP databases were retrieved up to June 30, 2016, to collect articles concerning the diagnosis of miRNAs in pancreatic cancer. The methodological quality of each study was assessed by the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). This meta-analysis was conducted using RevMan5.0, MetaDiSc 1.4, and Stata 12.0 software. Results There are 40 articles including 109 studies. The pooled SEN was 0.81 (95% CI, 0.80–0.82), the pooled SPE was 0.78 (95% CI, 0.77–0.79), the pooled +LR was 3.32 (95% CI, 2.92–3.80), the pooled −LR was 0.27 (95% CI, 0.24–0.31), the pooled DOR was 14.56 (95% CI, 11.55–18.34), and pooled AUC was 0.86 (95% CI, 0.84–0.88). Discussion This meta-analysis demonstrated that miRNA makes a significant impact in the pancreatic cancer diagnosis with a high SEN and SPE, particularly using multiple miRNAs.
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31
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Li T, Cox CD, Ozer BH, Nguyen NT, Nguyen HN, Lai TJ, Li S, Liu F, Kornblum HI, Liau LM, Nghiemphu PL, Cloughesy TF, Lai A. D-2-Hydroxyglutarate Is Necessary and Sufficient for Isocitrate Dehydrogenase 1 Mutant-Induced MIR148A Promoter Methylation. Mol Cancer Res 2018; 16:947-960. [PMID: 29545476 DOI: 10.1158/1541-7786.mcr-17-0367] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 01/13/2018] [Accepted: 02/20/2018] [Indexed: 12/14/2022]
Abstract
Mutant isocitrate dehydrogenase (IDH) 1/2 converts α-ketoglutarate (α-KG) to D-2 hydroxyglutarate (D-2-HG), a putative oncometabolite that can inhibit α-KG-dependent enzymes, including ten-eleven translocation methylcytosine dioxygenase (TET) DNA demethylases. We recently established that miRNAs are components of the IDH1 mutant-associated glioma CpG island methylator phenotype (G-CIMP) and specifically identified MIR148A as a tumor-suppressive miRNA within G-CIMP. However, the precise mechanism by which mutant IDH induces hypermethylation of MIR148A and other G-CIMP promoters remains to be elucidated. In this study, we demonstrate that treatment with exogenous D-2-HG induces MIR148A promoter methylation and transcriptional silencing in human embryonic kidney 293T (293T) cells and primary normal human astrocytes. Conversely, we show that the development of MIR148A promoter methylation in mutant IDH1-overexpressing 293T cells is abrogated via treatment with C227, an inhibitor of mutant IDH1 generation of D-2-HG. Using dot blot assays for global assessment of 5-hydroxymethylcytosine (5-hmC), we show that D-2-HG treatment reduces 5-hmC levels, whereas C227 treatment increases 5-hmC levels, strongly suggesting TET inhibition by D-2-HG. Moreover, we show that withdrawal of D-2-HG treatment reverses methylation with an associated increase in MIR148A transcript levels and transient generation of 5-hmC. We also demonstrate that RNA polymerase II binds endogenously to the predicted promoter region of MIR148A, validating the hypothesis that its transcription is driven by an independent promoter.Implications: Establishment of D-2-HG as a necessary and sufficient intermediate by which mutant IDH1 induces CpG island methylation of MIR148A will help with understanding the efficacy of selective mutant IDH1 inhibitors in the clinic. Mol Cancer Res; 16(6); 947-60. ©2018 AACR.
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Affiliation(s)
- Tie Li
- Neuro-Oncology Program, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Christopher D Cox
- Neuro-Oncology Program, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Byram H Ozer
- Neuro-Oncology Program, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Nhung T Nguyen
- Neuro-Oncology Program, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - HuyTram N Nguyen
- Neuro-Oncology Program, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Thomas J Lai
- Neuro-Oncology Program, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Sichen Li
- Neuro-Oncology Program, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Fei Liu
- Neuro-Oncology Program, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Harley I Kornblum
- Department of Pediatrics, Psychiatry and Biobehavioral Sciences, Pediatric Neurology, Semel Institute for Neuroscience and Human Behavior, Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Linda M Liau
- Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Phioanh L Nghiemphu
- Neuro-Oncology Program, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Timothy F Cloughesy
- Neuro-Oncology Program, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Albert Lai
- Neuro-Oncology Program, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
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32
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Zhang X, Yin J, Zhang X. A Semi-Supervised Learning Algorithm for Predicting Four Types MiRNA-Disease Associations by Mutual Information in a Heterogeneous Network. Genes (Basel) 2018; 9:genes9030139. [PMID: 29498680 PMCID: PMC5867860 DOI: 10.3390/genes9030139] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2017] [Revised: 02/20/2018] [Accepted: 02/22/2018] [Indexed: 01/05/2023] Open
Abstract
Increasing evidence suggests that dysregulation of microRNAs (miRNAs) may lead to a variety of diseases. Therefore, identifying disease-related miRNAs is a crucial problem. Currently, many computational approaches have been proposed to predict binary miRNA-disease associations. In this study, in order to predict underlying miRNA-disease association types, a semi-supervised model called the network-based label propagation algorithm is proposed to infer multiple types of miRNA-disease associations (NLPMMDA) by mutual information derived from the heterogeneous network. The NLPMMDA method integrates disease semantic similarity, miRNA functional similarity, and Gaussian interaction profile kernel similarity information of miRNAs and diseases to construct a heterogeneous network. NLPMMDA is a semi-supervised model which does not require verified negative samples. Leave-one-out cross validation (LOOCV) was implemented for four known types of miRNA-disease associations and demonstrated the reliable performance of our method. Moreover, case studies of lung cancer and breast cancer confirmed effective performance of NLPMMDA to predict novel miRNA-disease associations and their association types.
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Affiliation(s)
- Xiaotian Zhang
- School of Mechanical, Electrical and Information Engineering, Shandong University, Weihai 264209, China.
| | - Jian Yin
- School of Mechanical, Electrical and Information Engineering, Shandong University, Weihai 264209, China.
| | - Xu Zhang
- School of Mechanical, Electrical and Information Engineering, Shandong University, Weihai 264209, China.
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33
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Lu CY, Chen SY, Peng HL, Kan PY, Chang WC, Yen CJ. Cell-free methylation markers with diagnostic and prognostic potential in hepatocellular carcinoma. Oncotarget 2018; 8:6406-6418. [PMID: 28031532 PMCID: PMC5351641 DOI: 10.18632/oncotarget.14115] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 12/16/2016] [Indexed: 12/30/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly malignant tumor with poor prognosis and high mortality. There is a dearth of effective early diagnostic tools, so liver resection surgery and liver transplantation are the only effective medical treatments. The most commonly used marker for HCC detection is serum alpha fetoprotein (AFP), which has low sensitivity and specificity. Because aberrant DNA methylation of genes and miRNAs occurs early in most cancers, we explored whether circulating methylation markers could be promising clinical tools for HCC diagnosis. Using a whole-genome approach, we identified many hyper-methylated miRNAs in HCC. Furthermore, three abnormally methylated genes and one miRNA were combined to establish a methylation predictive model and tested for its diagnostic and prognostic potential in HCC. Using plasma samples, the predictive model exhibited high sensitivity and specificity (> 80%) for HBV-related HCC. Most importantly, nearly 75% of patients who could not be diagnosed with AFP at 20 ng/mL were detected by this model. Further, the predictive model exhibited an exceedingly high ability to predict 5-year overall survival in HCC patients. These data demonstrate the high diagnostic and prognostic potential of methylation markers in the plasma of HCC patients.
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Affiliation(s)
- Chang-Yi Lu
- Biomedical Technology and Device Research Labs, Industrial Technology Research Institute, Hsinchu, Taiwan
| | - Shih-Ya Chen
- Biomedical Technology and Device Research Labs, Industrial Technology Research Institute, Hsinchu, Taiwan
| | - Hui-Ling Peng
- Biomedical Technology and Device Research Labs, Industrial Technology Research Institute, Hsinchu, Taiwan
| | - Pu-Yeh Kan
- Biomedical Technology and Device Research Labs, Industrial Technology Research Institute, Hsinchu, Taiwan
| | - Wan-Chi Chang
- Biomedical Technology and Device Research Labs, Industrial Technology Research Institute, Hsinchu, Taiwan
| | - Chia-Jui Yen
- Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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34
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Ku P, Wang C, Nie X, Ou R, Li K. Regulation of pregnane-X-receptor and microRNAs on detoxification-related genes expressions in Mugilogobius abei under the exposure to diclofenac. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2018; 233:395-406. [PMID: 29096313 DOI: 10.1016/j.envpol.2017.10.080] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 09/08/2017] [Accepted: 10/22/2017] [Indexed: 06/07/2023]
Abstract
Diclofenac (DCF) has been recognized as an emerging contaminant in aquatic environments. Though many studies have investigated the toxic effects of DCF in human and mammals, limited information is available for the responses of genes associated with detoxification metabolisms in non-target aquatic organisms such as fish. In the present study, a small benthic fish Mugilogobius abei, was chosen as the test organism and the effects of DCF on detoxification-related genes at transcriptional level in M. abei were investigated. Partial cDNAs of pregnane-X-receptor (pxr), cytochrome P450 3A (cyp 3a) and alpha-gst were cloned firstly. The responses of cyp 1a, cyp 3a, alpha-gst and p-gp genes and associated microRNAs expressions were measured under different concentrations of DCF exposure (0.5, 5, 50, 500 μg/L) for 24 h and 168 h. Induction of cyp 1a, cyp 3a, alpha-gst, p-gp and pxr mRNA expressions was observed under DCF exposure for different time. Positive concentration-response relationships between DCF concentrations and cyp 1a as well as alpha-gst mRNA expression were observed under DCF exposure for 24 h. The similar trend between pxr mRNA expression and cyp 3a gene expression suggested the role of pxr in regulation of its downstream detoxification genes involved in DCF detoxification in M. abei. The negative correlation between miR-27a and p-gp expression under DCF exposure for 24 h indicated the role of miRNA in post transcriptional regulation on detoxification-related genes mRNAs in M. abei exposed to DCF. Overall, DCF exposure, even at environmental levels, may interrupt the responses of the detoxification genes in M. abei, which may affect the response of the exposed organism to other pollutants. This work provides implications on the bio-monitoring and risk assessment of DCF in aquatic ecosystems by using of local native fish species.
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Affiliation(s)
- Peijia Ku
- Department of Ecology, Jinan University, Guangzhou 510632, China
| | - Chao Wang
- Department of Ecology, Jinan University, Guangzhou 510632, China
| | - Xiangping Nie
- Department of Ecology, Jinan University, Guangzhou 510632, China; Key Laboratory of Eutrophication and Red Tide Prevention of Guangdong Higher Education Institutes, Jinan University, Guangzhou 510632, China.
| | - Ruikang Ou
- Department of Ecology, Jinan University, Guangzhou 510632, China
| | - Kaibing Li
- Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China.
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Shi H, Chen X, Jiang H, Wang X, Yu H, Sun P, Sui X. miR-148a suppresses cell invasion and migration in gastric cancer by targeting DNA methyltransferase 1. Oncol Lett 2018. [PMID: 29541249 PMCID: PMC5835867 DOI: 10.3892/ol.2018.7907] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) is the fourth most common malignant tumor globally. The highest incidence of GC is found in Eastern Asia, particularly in China. It is therefore imperative to further elucidate the molecular pathogenesis of GC in order to identify new biomarkers and targets for effective therapy. In the present study, we determined whether miR-148a was aberrantly downregulated in gastric cancer tissues and significantly correlated with aggressive clinicopathological characteristics in the MGC-803, HGC-27 and GES-1 cell lines using reverse transcription-quantitative PCR and western blot analysis. The cell lines were obtained from 60 patients who presented at our hospital between September 2010 and July 2015. The results showed that, miR-148a was aberrantly downregulated in GC tissues and its expression was relatively lower in the MGC-803 and HGC-27 GC cell lines than in the normal gastric epithelial cell line, GES-1. The clinicopathological analysis revealed that a decrease of miR-148a was significantly correlated with lymph-node metastasis (P<0.01) and tumor node metastasis (TNM) stage (P<0.05). The transwell assay showed that the re-expression of miR-148a significantly reduced cell migratory and invasive abilities in vitro (P<0.01). The luciferase assay confirmed that, DNA methyltransferase 1 (DNMT1) was a direct and functional target of miR-148a. The miR-148a inhibitor increased the expression of DNMT1 in HGC-27 cells and the re-expression of miR-148a reduced the expression of DNMT1 in MGC-803 cells as confirmed by western blot analysis. Furthermore, we found that the re-expression of DNMT1 reversed the inhibition of cell migration and invasion induced by miR-148a. Taken together, we demonstrated that miR-148a suppresses cell invasion and migration in gastric cancer by regulating DNMT1 expression. The miR-148a/DNMT1 axis may therefore be a new potential target for GC therapy.
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Affiliation(s)
- Huaijie Shi
- Department of Gastrointestinal Surgery, Weihai Central Hospital, Weihai, Shandong 264400, P.R. China
| | - Xiaojing Chen
- First Department of Radiotherapy, Qingdao Center Hospital, Qingdao, Shandong 266000, P.R. China
| | - Hao Jiang
- Department of Gastrointestinal Surgery, Weihai Central Hospital, Weihai, Shandong 264400, P.R. China
| | - Xujie Wang
- Department of Gastrointestinal Surgery, Weihai Central Hospital, Weihai, Shandong 264400, P.R. China
| | - Hao Yu
- Department of Gastrointestinal Surgery, Weihai Central Hospital, Weihai, Shandong 264400, P.R. China
| | - Pijiang Sun
- Department of Gastrointestinal Surgery, Weihai Central Hospital, Weihai, Shandong 264400, P.R. China
| | - Xin Sui
- Department of Gastrointestinal Surgery, Weihai Central Hospital, Weihai, Shandong 264400, P.R. China
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Ren L, Yu Y. The role of miRNAs in the diagnosis, chemoresistance, and prognosis of pancreatic ductal adenocarcinoma. Ther Clin Risk Manag 2018; 14:179-187. [PMID: 29416345 PMCID: PMC5790163 DOI: 10.2147/tcrm.s154226] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a very challenging malignancy with late presentation, metastatic potential, chemoresistance, and poor prognosis. Therefore, there is an urgent need for novel diagnostic and prognostic biomarkers. miRNAs are small noncoding RNAs that regulate the expression of multitude number of genes. Aberrant expression of miRNAs has been linked to the development of various malignancies, including PDAC. A series of miRNAs have been defined as holding promise for early diagnostics, as indicators of therapy resistance, and even as markers for prognosis in PDAC patients. In this review, we summarize the current knowledge on the role of miRNAs in diagnosis, chemoresistance, and prognosis in PDAC patients.
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Affiliation(s)
- Le Ren
- Department of Gastroenterology, Affiliated Provincial Hospital, Anhui Medical University, Hefei, China
| | - Yue Yu
- Department of Gastroenterology, Affiliated Provincial Hospital, Anhui Medical University, Hefei, China
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Vila-Casadesús M, Vila-Navarro E, Raimondi G, Fillat C, Castells A, Lozano JJ, Gironella M. Deciphering microRNA targets in pancreatic cancer using miRComb R package. Oncotarget 2018; 9:6499-6517. [PMID: 29464088 PMCID: PMC5814228 DOI: 10.18632/oncotarget.24034] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Accepted: 01/02/2018] [Indexed: 12/23/2022] Open
Abstract
MiRNAs are small non-coding RNAs that post-transcriptionally regulate gene expression. They play important roles in cancer but little is known about the specific functions that each miRNA exerts in each type of cancer. More knowledge about their specific targets is needed to better understand the complexity of molecular networks taking part in cancer. In this study we report the miRNA-mRNA interactome occurring in pancreatic cancer by using a bioinformatic approach called miRComb, which combines tissue expression data with miRNA-target prediction databases (TargetScan, miRSVR and miRDB). MiRNome and transcriptome of 12 human pancreatic tissues (9 pancreatic ductal adenocarcinomas and 3 controls) were analyzed by next-generation sequencing and microarray, respectively. Analysis confirmed differential expression of both miRNAs and mRNAs in cancerous tissue versus control, and unveiled 17401 relevant miRNA-mRNA interactions likely to occur in pancreatic cancer. They were sorted according to the degree of negative correlation between miRNA and mRNA expression. Results highlighted the importance of miR-148a and miR-21 interactions among others. Two components of the Notch signaling pathway, ADAM17 and EP300, were confirmed as miR-148a targets in MiaPaca-2 pancreatic cancer cells overexpressing miR-148a. Moreover, a CRISPR-Cas9 cellular model was generated to knock-out the expression of miR-21 in PANC-1 cells. As expected, the expression of two miRComb miR-21 predicted targets, PDCD4 and BTG2, was significantly upregulated in these cells in comparison to control PANC-1.
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Affiliation(s)
- Maria Vila-Casadesús
- Gastrointestinal & Pancreatic Oncology Group, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain.,Bioinformatics Platform, CIBEREHD, Barcelona, Catalonia, Spain
| | - Elena Vila-Navarro
- Gastrointestinal & Pancreatic Oncology Group, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
| | - Giulia Raimondi
- Gene Therapy and Cancer, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Cristina Fillat
- Gene Therapy and Cancer, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Antoni Castells
- Gastrointestinal & Pancreatic Oncology Group, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
| | - Juan José Lozano
- Gastrointestinal & Pancreatic Oncology Group, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain.,Bioinformatics Platform, CIBEREHD, Barcelona, Catalonia, Spain
| | - Meritxell Gironella
- Gastrointestinal & Pancreatic Oncology Group, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
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Azizi M, Fard-Esfahani P, Mahmoodzadeh H, Fazeli MS, Azadmanesh K, Zeinali S, Teimoori-Toolabi L. MiR-377 reverses cancerous phenotypes of pancreatic cells via suppressing DNMT1 and demethylating tumor suppressor genes. Epigenomics 2017; 9:1059-1075. [PMID: 28758420 DOI: 10.2217/epi-2016-0175] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
AIM The aim was to investigate the effect of miR-377 on DNMT1 expression and cancer phenotype in pancreatic cancer cells. MATERIALS & METHODS Real-time PCR, luciferase assay, MTT and Annexin-PI staining were used. RESULTS Decreased miR-377 and increased DNMT1 (verified as a target for mir-377) levels in pancreatic cancer tissues and cell lines in comparison with normal tissues was confirmed to be influenced by promoter methylation. Also hypermethylation of BNIP3, SPARC, TFPI2 and PENK promoters was observed in tumor samples but not in normal tissues which negatively correlated with their expression. Restoration of miR-377 resulted in a reduction of the expression of DNMT1 and reactivation of BNIP3 and SPARC genes via promoter demethylation. Furthermore, enhanced expression of miR-377 could significantly inhibit cell proliferation and induce apoptosis. CONCLUSION Our findings showed that miR-377 through targeting DNMT1 could reduce DNA methylation of some tumor suppressor genes and restore their expression in pancreatic cancer cells.
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Affiliation(s)
- Masoumeh Azizi
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | | | - Habibollah Mahmoodzadeh
- Cancer Institute of Iran, Imam Khomeini Medical Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Sadegh Fazeli
- Department of Surgery, Division of Colo-Rectal Surgery, Imam Khomeini Medical Complex, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Sirous Zeinali
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Ladan Teimoori-Toolabi
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
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Peng L, Liu Z, Xiao J, Tu Y, Wan Z, Xiong H, Li Y, Xiao W. MicroRNA-148a suppresses epithelial-mesenchymal transition and invasion of pancreatic cancer cells by targeting Wnt10b and inhibiting the Wnt/β-catenin signaling pathway. Oncol Rep 2017; 38:301-308. [PMID: 28586066 DOI: 10.3892/or.2017.5705] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2016] [Accepted: 05/17/2017] [Indexed: 11/05/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) plays a critical role in the process of cancer invasion and metastasis. The Wnt/β-catenin signaling pathway is known as a stimulative factor, which may trigger EMT and metastasis of cancer cells. In addition, several microRNAs (miRNAs) have been proven to regulate the EMT process. Recent research revealed that miR‑148a is downregulated in pancreatic cancer. However, the definite role of miR-148a in EMT and invasion of pancreatic cancer is still unknown. The present study attempted to demonstrate the underlying mechanism of miR-148a in the regulation of EMT and invasion of pancreatic cancer cells. Our data revealed that the expression of miR-148a was markedly downregulated in human pancreatic ductal adenocarcinoma (PDAC) cell lines and tissues. In addition, the downregulation of miR-148a was associated with poor prognosis and EMT phenotype. Furthermore, restoration of miR-148a expression inhibited the EMT process, as well as the migration and invasion of BxPC-3 pancreatic cancer cells. Wnt10b, a promoting molecule of the Wnt/β-catenin signaling pathway, was demonstrated by dual‑luciferase reporter assay to be a direct target of miR‑148a. Subsequently, we found that miR‑148a negatively regulated the protein expression of β-catenin, cyclin D1 and MMP-9, which were important components of the Wnt/β-catenin signaling pathway. In conclusion, these findings revealed that miR-148a suppresses EMT and invasion of pancreatic cancer cells by targeting Wnt10b and inhibiting the Wnt/β-catenin signaling pathway, and thus, miR-148a may serve as a novel therapeutic target for pancreatic cancer.
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Affiliation(s)
- Long Peng
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Zhanying Liu
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Jian Xiao
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yi Tu
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Zhen Wan
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Haiwei Xiong
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yong Li
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Weidong Xiao
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Abreu FBD, Liu X, Tsongalis GJ. miRNA analysis in pancreatic cancer: the Dartmouth experience. Clin Chem Lab Med 2017; 55:755-762. [PMID: 28343174 DOI: 10.1515/cclm-2017-0046] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 02/28/2017] [Indexed: 12/17/2022]
Abstract
Pancreatic cancer is considered one of the most lethal cancers being the fourth leading cause of cancer deaths in adults in the United States because of the lack of early signs and symptoms and the lack of early detection. Pancreatic ductal adenocarcinoma (PDAC) is the most common histological type among pancreatic cancers, representing 80%-90% of all solid tumors of the pancreas. The majority of PDAC develops from three precursor lesions: pancreatic intraepithelial neoplasia, intraductual papillary mucinous neoplasm and mucinous cystic neoplasm. Although histologic tissue evaluation remains the gold standard for diagnosis, endoscopic ultrasound-guided fine needle aspiration has become the preferred modality for obtaining pathologic confirmation. At Dartmouth-Hitchcock Medical Center (DHMC),we have developed and validated a microRNA (miRNA) panel for patients with pancreatic diseases that can be used in association with the gold standard method for diagnosis. miRNAs have an important role in biological processes, such as apoptosis, metabolism, cell growth and differentiation. In cancer, miRNAs can be classified as either oncogenic or tumor suppressor according to their function in the carcinogenic process. In this study, we describe the expression of many miRNA in benign and malignant pancreatic tissues as well as their clinical significance. For this reason, miRNAs have been considered potential biomarkers of pancreatic diseases that could potentially contribute to an early diagnosis, predict disease progression, accurately monitor disease, contribute to better treatment strategies and reduce mortality by improving disease management.
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Affiliation(s)
- Francine B de Abreu
- Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center and Norris Cotton Cancer Center, Lebanon, NH
| | - Xiaoying Liu
- Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center and Norris Cotton Cancer Center, Lebanon, NH
| | - Gregory J Tsongalis
- Department of Pathology, Dartmouth Hitchcock Medical Center, Lebanon, NH 03756
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41
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Gao H, Wang H, Yang W. Identification of key genes and construction of microRNA–mRNA regulatory networks in multiple myeloma by integrated multiple GEO datasets using bioinformatics analysis. Int J Hematol 2017; 106:99-107. [DOI: 10.1007/s12185-017-2216-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Revised: 03/09/2017] [Accepted: 03/10/2017] [Indexed: 12/18/2022]
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Zhang Q, Chen S, Zeng L, Chen Y, Lian G, Qian C, Li J, Xie R, Huang KH. New developments in the early diagnosis of pancreatic cancer. Expert Rev Gastroenterol Hepatol 2017; 11:149-156. [PMID: 27937041 DOI: 10.1080/17474124.2017.1271323] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Pancreatic cancer is an aggressive carcinoma of the digestive system and radical resection, which is available to very few patients, is the only possibility for cure. Since therapeutic choices are limited at the advanced stage, screening and early diagnostic tools are indispensable for a better prognosis. Areas covered: This review illustrates serologic and imaging examinations, and carbohydrate antigens, microRNAs, methylation biomarkers, molecules in exosomes, ultrasound, computed tomography, magnetic resonance imaging, positron emission tomography and endoscopic retrograde cholangiopancreatography, among other topics. No matter which approach is used, the accuracy of early diagnosis is extremely low. Combining different methods greatly improves the accuracy of early diagnosis. This review was conducted utilizing PubMed with key search words pancreatic cancer, early diagnosis, biomarkers and imaging. Expert commentary: Appropriate combination of biomarkers and imaging technologies will become standard practice in the future. Because the incidence of and mortality from pancreatic cancer is rising, further study of new approaches for the early detection of pancreatic tumors is essential.
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Affiliation(s)
- QiuBo Zhang
- a Department of Gastroenterology , Lihuili Hospital of Ningbo Medical Center , Ningbo , China
| | - ShaoJie Chen
- b Department of Oncology , the Fifth Affiliated Hospital of Sun Yat-Sen University , Zhuhai , China
| | - LinJuan Zeng
- b Department of Oncology , the Fifth Affiliated Hospital of Sun Yat-Sen University , Zhuhai , China
| | - YinTing Chen
- c Department of Gastroenterology , Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University , Guangzhou , China
| | - GuoDa Lian
- c Department of Gastroenterology , Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University , Guangzhou , China
| | - ChenChen Qian
- c Department of Gastroenterology , Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University , Guangzhou , China
| | - JiaJia Li
- c Department of Gastroenterology , Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University , Guangzhou , China
| | - RuiJie Xie
- c Department of Gastroenterology , Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University , Guangzhou , China
| | - Kai-Hong Huang
- c Department of Gastroenterology , Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University , Guangzhou , China
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Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression mainly at the posttranscriptional level. Similar to protein-coding genes, their expression is also controlled by genetic and epigenetic mechanisms. Disruption of these control processes leads to abnormal expression of miRNAs in cancer. In this chapter, we discuss the supportive links between miRNAs and epigenetics in the context of carcinogenesis. miRNAs can be epigenetically regulated by DNA methylation and/or specific histone modifications. However, they can themselves (epi-miRNAs) repress key enzymes that drive epigenetic remodeling and also bind to complementary sequences in gene promoters, recruiting specific protein complexes that modulate chromatin structure and gene expression. All these issues affect the transcriptional landscape of cells. Most important, in the cancer clinical scenario, knowledge about miRNAs epigenetic dysregulation can not only be beneficial as a prognostic biomarker, but can also help in the design of new therapeutic approaches.
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Affiliation(s)
- Catia Moutinho
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain
| | - Manel Esteller
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain; School of Medicine and Health Sciences, University of Barcelona (UB), Catalonia, Spain.
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Chang X, Yu C, Li J, Yu S, Chen J. hsa-miR-96 and hsa-miR-217 Expression Down-Regulates with Increasing Dysplasia in Pancreatic Intraepithelial Neoplasias and Intraductal Papillary Mucinous Neoplasms. Int J Med Sci 2017; 14:412-418. [PMID: 28539816 PMCID: PMC5441032 DOI: 10.7150/ijms.18641] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 01/31/2017] [Indexed: 12/12/2022] Open
Abstract
AIM: To compare the clinicopathological features of pancreatic intraepithelial neoplasias (PanINs) and intraductal papillary mucinous neoplasms (IPMNs), and to investigate the role of hsa-miR-96 and hsa-miR-217 in these two lesions. Methods: Formalin-fixed paraffin-embedded pancreatic specimens were selected in this study, including 58 cases of pancreatic intraepithelial neoplasias (PanINs), 45 cases of pancreatic ductal adenocarcinomas (PDAs), and 57 cases of intraductal papillary mucinous neoplasms (IPMNs). MiRNAs hsa-miR-96 and hsa-miR-217 were detected using locked nucleic acid in situ hybridization (LNA-ISH) with the NBT/BCIP staining system. The differences in miRNA expression among sample sets were analyzed with the Chi-squared test. Results: PanIN-PDAs were inclined to present with higher rate of invasion (p=0.033), lymph node metastasis (p=0.0004) and poorer differentiation (p<0.001). Of the 45 PDAs, only 2 cases were within AJCC Ⅰstage, while there were 11 cases of IPMN associated carcinomas (p=0.0018). In PanIN-1, PanIN-2 and PanIN-3, the expression of hsa-miR-96 was 91.3% (22/23), 78.6%(12/17) and 22.2%(4/18) respectively, while the expression of hsa-miR-217 was 95.7%(22/23) , 70.6% (12/17) and 27.8% (5/18). In IPMN with low-grade, intermediate-grade, high-grade dysplasia, associated carcinoma, the expression of hsa-miR-96 was 67%(9/13), 64%(7/11), 43%(3/7) and 27%(7/26) respectively, while the expression of hsa-miR-217 was 77%(10/13), 64%(7/11), 29%(2/7) and 38%(10/26). The expression of hsa-miR-96 and hsa-miR-217 in PanIN-1 lesions was not significantly different from that in the normal pancreatic ductal epithelium. However, their expression in PanIN-2/3 lesions was significantly different from that in normal pancreatic ductal epithelium (P<0.01). No difference was observed between PanIN derived adenocarcinomas and IPMN-associated carcinomas. Conclusion: IPMN associated carcinomas were in a statistically earlier stage than PanIN- PDAs at the time of operation. Abnormal expression of hsa-miR-96 and of hsa-miR-217 was observed in premalignant lesions (PanINs and IPMNs) of pancreatic carcinoma and down-regulated with increasing grades of PanINs and IPMNs. These microRNAs may serve as potentially early biomarker and act as tumor suppressor genes.
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Affiliation(s)
- XiaoYan Chang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tsinghua University, Beijing 100730, China
| | - ChunKai Yu
- Department of Pathology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Ji Li
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tsinghua University, Beijing 100730, China
| | - Shuangni Yu
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tsinghua University, Beijing 100730, China
| | - Jie Chen
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tsinghua University, Beijing 100730, China
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Liu HT, Fang L, Cheng YX, Sun Q. LncRNA PVT1 regulates prostate cancer cell growth by inducing the methylation of miR-146a. Cancer Med 2016; 5:3512-3519. [PMID: 27794184 PMCID: PMC5224852 DOI: 10.1002/cam4.900] [Citation(s) in RCA: 125] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Revised: 07/21/2016] [Accepted: 08/17/2016] [Indexed: 01/19/2023] Open
Abstract
Prostate cancer is the third most common causes of death from cancer in men. Our previous study demonstrated that lncRNA PVT1 was overexpressed and played an oncogenic role in the progression of prostate cancer. However, the molecular mechanism of modulating the prostate cancer tumorigenesis was still unknown. In this study, we aim to investigate the interaction between PVT1 and miR-146a in prostate cancer and reveal the potential mechanism in prostate cancer carcinogenesis. The expression level of miR-146a was assessed by quantitative RT-PCR. The correlation analysis and methylation status analysis was made to confirm the interaction between PVT1 and miR-146a. Biological function analysis was performed through gain-of-function and loss-of-function strategies. Our results showed that miR-146a was downregulated and negatively correlated with PVT1 level in prostate cancer. PVT1 mediated miR-146a expression by inducing the methylation of CpG Island in its promoter. miR-146a overexpression eliminated the effects of PVT1 knockdown on prostate cancer cells. PVT1 regulated prostate cancer cell viability and apoptosis depending on miR-146a. Our study suggested a regulatory relationship between lncRNA PVT1 and miR-146a during the process of the prostate cancer tumorigenesis. PVT1 regulated prostate cancer cell viability and apoptosis depending on miR-146a. It would contribute to the diagnosis, treatment and prognosis of prostate cancer.
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Affiliation(s)
- Hong-Tao Liu
- Department of Pathology, Qian-fo-shan Hospital Affiliated to Shandong University, No. 16766 Jingshi Road, Jinan, Shandong, 250014, China
| | - Lei Fang
- Department of Pathology, Qian-fo-shan Hospital Affiliated to Shandong University, No. 16766 Jingshi Road, Jinan, Shandong, 250014, China
| | - Yu-Xia Cheng
- Department of Pathology, Qian-fo-shan Hospital Affiliated to Shandong University, No. 16766 Jingshi Road, Jinan, Shandong, 250014, China
| | - Qing Sun
- Department of Pathology, Qian-fo-shan Hospital Affiliated to Shandong University, No. 16766 Jingshi Road, Jinan, Shandong, 250014, China
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MicroRNA in pancreatic adenocarcinoma: predictive/prognostic biomarkers or therapeutic targets? Oncotarget 2016; 6:23323-41. [PMID: 26259238 PMCID: PMC4695121 DOI: 10.18632/oncotarget.4492] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Accepted: 07/03/2015] [Indexed: 12/19/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a tumor with a poor prognosis, short overall survival and few chemotherapeutic choices. MicroRNAs (miRNAs) are non-coding, single-stranded RNAs of around 22 nucleotides involved in the pathogenic mechanisms of carcinogenesis and metastasis. They have been studied in many tumors in order to identify potential diagnostic, prognostic or therapeutic targets. In the current literature, many studies have analyzed the role of miRNAs in PDAC. In fact, the absence of appropriate biomarkers, the difficultly of early detection of this tumor, and the lack of effective chemotherapy in patients with unresectable disease have focused attention on miRNAs as new, interesting advance in this malignancy. In this review we analyzed the role of miRNAs in PDAC in order to understand the mechanisms of action and the difference between the onco-miRNA and the tumor suppressor miRNA. We also reviewed all the data related to the use of these molecules as predictive as well as prognostic biomarkers in the course of the disease. Finally, the possible therapeutic use of miRNAs or anti-miRNAs in PDAC is also discussed. In conclusion, although there is still no clinical application for these molecules in PDAC, it is our opinion that the preclinical evidence of the role of specific miRNAs in carcinogenesis, the possibility of using miRNAs as diagnostic or prognostic biomarkers, and their potential therapeutic role, warrant future studies in PDAC.
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Yu B, Lv X, Su L, Li J, Yu Y, Gu Q, Yan M, Zhu Z, Liu B. MiR-148a Functions as a Tumor Suppressor by Targeting CCK-BR via Inactivating STAT3 and Akt in Human Gastric Cancer. PLoS One 2016; 11:e0158961. [PMID: 27518872 PMCID: PMC4982598 DOI: 10.1371/journal.pone.0158961] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 06/26/2016] [Indexed: 01/19/2023] Open
Abstract
MicroRNAs (miRNAs) have been widely accepted as a class of gene expression regulators which post-translationally regulate protein expression. These small noncoding RNAs have been proved closely involved in the modulation of various pathobiological processes in cancer. In this research, we demonstrated that miR-148a expression was significantly down-regulated in gastric cancer tissues in comparison with the matched normal mucosal tissues, and its expression was statistically associated with lymph node metastasis. Ectopic expression of miR-148a inhibited tumor cell proliferation and migration in vitro, and inhibited tumor formation in vivo. Subsequently, we identified cholecystokinin B receptor (CCK-BR) as a direct target of miR-148a using western blot and luciferase activity assay. More importantly, siRNA-induced knockdown of CCK-BR elicited similar anti-oncogenic effects (decreased proliferation and migration) as those induced by enforced miR-148a expression. We also found that miR-148a-mediated anti-cancer effects are dependent on the inhibition of STAT3 and Akt activation, which subsequently regulates the pathways involved in cell proliferation and migration. Taken together, our results suggest that miR-148a serves as a tumor suppressor in human gastric carcinogenesis by targeting CCK-BR via inactivating STAT3 and Akt.
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Affiliation(s)
- Beiqin Yu
- Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xin Lv
- Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Vascular Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liping Su
- Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jianfang Li
- Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yingyan Yu
- Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qinlong Gu
- Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Yan
- Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenggang Zhu
- Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bingya Liu
- Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- * E-mail:
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48
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Botla SK, Savant S, Jandaghi P, Bauer AS, Mücke O, Moskalev EA, Neoptolemos JP, Costello E, Greenhalf W, Scarpa A, Gaida MM, Büchler MW, Strobel O, Hackert T, Giese NA, Augustin HG, Hoheisel JD. Early Epigenetic Downregulation of microRNA-192 Expression Promotes Pancreatic Cancer Progression. Cancer Res 2016; 76:4149-59. [PMID: 27216198 DOI: 10.1158/0008-5472.can-15-0390] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2015] [Accepted: 04/22/2016] [Indexed: 12/27/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by very early metastasis, suggesting the hypothesis that metastasis-associated changes may occur prior to actual tumor formation. In this study, we identified miR-192 as an epigenetically regulated suppressor gene with predictive value in this disease. miR-192 was downregulated by promoter methylation in both PDAC and chronic pancreatitis, the latter of which is a major risk factor for the development of PDAC. Functional studies in vitro and in vivo in mouse models of PDAC showed that overexpression of miR-192 was sufficient to reduce cell proliferation and invasion. Mechanistic analyses correlated changes in miR-192 promoter methylation and expression with epithelial-mesenchymal transition. Cell proliferation and invasion were linked to altered expression of the miR-192 target gene SERPINE1 that is encoding the protein plasminogen activator inhibitor-1 (PAI-1), an established regulator of these properties in PDAC cells. Notably, our data suggested that invasive capacity was altered even before neoplastic transformation occurred, as triggered by miR-192 downregulation. Overall, our results highlighted a role for miR-192 in explaining the early metastatic behavior of PDAC and suggested its relevance as a target to develop for early diagnostics and therapy. Cancer Res; 76(14); 4149-59. ©2016 AACR.
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Affiliation(s)
- Sandeep K Botla
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Soniya Savant
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faulty Mannheim, Heidelberg University, Mannheim, Germany
| | - Pouria Jandaghi
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Andrea S Bauer
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Oliver Mücke
- Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Evgeny A Moskalev
- Diagnostic Molecular Pathology, Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - John P Neoptolemos
- National Institute for Health Research, Liverpool Pancreas Biomedical Research Unit, Liverpool, UK
| | - Eithne Costello
- National Institute for Health Research, Liverpool Pancreas Biomedical Research Unit, Liverpool, UK
| | - William Greenhalf
- National Institute for Health Research, Liverpool Pancreas Biomedical Research Unit, Liverpool, UK
| | - Aldo Scarpa
- Department of Pathology and Diagnostics, Università di Verona, Verona, Italy
| | - Matthias M Gaida
- Department of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Markus W Büchler
- Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Oliver Strobel
- Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Thilo Hackert
- Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Nathalia A Giese
- Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Hellmut G Augustin
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faulty Mannheim, Heidelberg University, Mannheim, Germany. German Cancer Consortium, Heidelberg, Germany
| | - Jörg D Hoheisel
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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49
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Hu XM, Yan XH, Hu YW, Huang JL, Cao SW, Ren TY, Tang YT, Lin L, Zheng L, Wang Q. miRNA-548p suppresses hepatitis B virus X protein associated hepatocellular carcinoma by downregulating oncoprotein hepatitis B x-interacting protein. Hepatol Res 2016; 46:804-15. [PMID: 26583881 DOI: 10.1111/hepr.12618] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Revised: 10/04/2015] [Accepted: 11/06/2015] [Indexed: 12/12/2022]
Abstract
AIM miR-548p is a recently identified and poorly characterized miRNA. However, its role of miR-548p in tumorigenesis and progression remains poorly understood. Here, we aimed to investigate the biofunction of miR-548p in hepatocellular carcinogenesis. METHODS The expression levels of miR-548p were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The role of miR-548p in hepatocellular carcinoma (HCC) was determined by colony formation, flow cytometry assay and nude mice xenograft experiments. miR-548p target genes were analyzed by miRNA target predication programs and verified by qRT-PCR, western blotting assay and dual-luciferase reporter assay. RESULTS miR-548p is repressed by hepatitis B virus X protein (HBx) in HCC tumor tissues and hepatoma cells, and inhibited cell growth by inhibiting cell proliferation and promoting cell apoptosis. miR-548p directly downregulated the expression of hepatitis B x-interacting protein (HBXIP) by binding to the 3'-untranslated region of HBXIP mRNA. Further study showed that hepatocyte nuclear factor-4a (HNF4A) promoted the expression of miR-548p and inhibited the transcription of HBXIP. HNF4A is a dominant transcriptional regulator of hepatocyte differentiation and hepatocellular carcinogenesis, and is shown to be repressed by HBx. CONCLUSION We proposed the model for HBx/HNF4A/miR-548p/HBXIP pathway that controls hepatoma cell growth and tumorigenesis of HCC. miR-548p was identified as a tumor-suppressor in HBx-associated hepatocellular carcinogenesis.
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Affiliation(s)
- Xiu-Mei Hu
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiao-Hui Yan
- Research Center of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yan-Wei Hu
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jin-Lan Huang
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shun-Wang Cao
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ting-Yu Ren
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yue-Ting Tang
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Li Lin
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lei Zheng
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qian Wang
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
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50
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Li Y, Deng X, Zeng X, Peng X. The Role of Mir-148a in Cancer. J Cancer 2016; 7:1233-41. [PMID: 27390598 PMCID: PMC4934031 DOI: 10.7150/jca.14616] [Citation(s) in RCA: 118] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Accepted: 05/07/2016] [Indexed: 12/16/2022] Open
Abstract
MicroRNAs (miRNAs) are highly conserved noncoding RNAs of about 19-25 nucleotides. Through specifically pairing with complementary sites in 3' untranslated regions (UTRs) of target mRNAs, they mediate post-transcriptional silencing. MicroRNAs have been implicated in many physiological processes including proliferation, differentiation, development, apoptosis, and metabolism. In recent years many studies have revealed that the aberrant expression of miRNA is closely related to oncogenesis and is now an intense field of study. Mir-148a is aberrantly expressed in various cancers and has been identified as an oncogenic or tumor suppressor with crucial roles in the molecular mechanisms of oncogenesis. In this review, we have summarized the role of mir-148a in the oncogenic pathways of gastric, liver, breast and urogenital cancers, and in neurogliocytoma oncogenesis. Studying the functional role of mir-148a is crucial in discovering novel tumor molecular markers and identifying potential therapeutic targets.
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Affiliation(s)
- Yue Li
- 1. Department of Pathology and Pathophysiology, Hunan Normal University Medical School, Changsha 410013, Hunan, China
| | - Xiyun Deng
- 1. Department of Pathology and Pathophysiology, Hunan Normal University Medical School, Changsha 410013, Hunan, China
| | - Xiaomin Zeng
- 2. Department of Statistics and Epidemiology, Public Health School, Central South University, Changsha 410078, Hunan, China
| | - Xiaoning Peng
- 1. Department of Pathology and Pathophysiology, Hunan Normal University Medical School, Changsha 410013, Hunan, China
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