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      miR-29a-5p Regulates the Proliferation, Invasion, and Migration of Gliomas by Targeting DHRS4

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          Abstract

          Gliomas are the most common malignant primary brain tumors in adults and exhibit a spectrum of aberrantly aggressive phenotypes. MicroRNAs (miRNAs) play a regulatory role in various cancers, including gliomas; however, their specific roles and mechanisms have not been fully investigated. Studies have indicated that miR-29a is a tumor-suppressive miRNA, but the data are limited. In this study, we investigated the role of miR-29a-5p in glioma and further explored its underlying mechanisms. On the basis of bioinformatics, dehydrogenase/reductase 4 (DHRS4) was considered a potential target of miR-29a-5p and was also found to be highly expressed in gliomas in our experiments. Moreover, with a luciferase reporter assay, DHRS4 was found to be a target gene of miR-29a-5p and to be correlated with glioma proliferation, invasion, and migration in our in vivo and in vitro experiments. Simultaneously, we observed that the knockdown of DHRS4 rescued the downregulation of glioma proliferation, invasion, and migration caused by treatment with a mir-29a-5p inhibitor. The present findings demonstrate that miR-29a-5p suppresses cell proliferation, invasion, and migration by targeting DHRS4, and DHRS4 may be a potential new oncogene and prognostic factor in gliomas.

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          Most cited references20

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          miR-137 forms a regulatory loop with nuclear receptor TLX and LSD1 in neural stem cells.

          miR-137 is a brain-enriched microRNA. Its role in neural development remains unknown. Here we show that miR-137 has an essential role in controlling embryonic neural stem cell fate determination. miR-137 negatively regulates cell proliferation and accelerates neural differentiation of embryonic neural stem cells. In addition, we show that the histone lysine-specific demethylase 1 (LSD1), a transcriptional co-repressor of nuclear receptor TLX, is a downstream target of miR-137. In utero electroporation of miR-137 in embryonic mouse brains led to premature differentiation and outward migration of the transfected cells. Introducing a LSD1 expression vector lacking the miR-137 recognition site rescued miR-137-induced precocious differentiation. Furthermore, we demonstrate that TLX, an essential regulator of neural stem cell self-renewal, represses the expression of miR-137 by recruiting LSD1 to the genomic regions of miR-137. Thus, miR-137 forms a feedback regulatory loop with TLX and LSD1 to control the dynamics between neural stem cell proliferation and differentiation during neural development.
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            Diverse roles of miR-29 in cancer (review).

            microRNAs (miRNAs) are non-coding RNAs which have the capacity to regulate gene expression at the post-transcriptional level, and have emerging as key factors involved in cancer at all stages ranging from initiation to metastasis. In the present review, we summmarize the diverse roles of the microRNA-29 (miR-29) family in cancer. First, we present a concise introduction to the miR-29 family and the expression profile of miR-29 in various cancer types. We next highlight the upstream regulatory pathway of miR-29 and describe the relationship between miR-29 and cancer in detail. As a tumor suppressor, miR-29 restrains cancer progression by promoting tumor cell apoptosis, by suppressing DNA methylation of tumor-suppressor genes, by reducing proliferation of tumors and by increasing chemosensitivity. However, as a tumor promoter, miR-29 mediates epithelial-mesenchymal transition (EMT) and promotes metastasis in breast cancer and colon cancer. Finally, we suggest that miR-29 represents a novel diagnostic and prognostic biomarker or a therapeutic target for cancer. Our review highlights the diverse relationship between miR-29 and cancer (particularly digestive system neoplasms). Further research of miR-29 in cancer is warranted.
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              miR-146b-5p inhibits glioma migration and invasion by targeting MMP16.

              miR-146b-5p is frequently down-regulated in solid tumours, including prostate cancer, pancreatic cancer, and glioblastoma. However, the tumour-suppressive effects of miR-146b-5p in malignant gliomas have not been investigated thoroughly. Here, we found that decreased miR-146b-5p expression was strongly correlated with chromosome 10q loss in gliomas, especially glioblastomas. The overexpression of miR-146b-5p in glioblastoma cell lines led to MMP16 mRNA silencing, MMP2 inactivation, and the inhibition of tumour cell migration and invasion. Our results suggest that the restoration of miR-146b-5p expression may be a feasible approach for inhibiting the migration and invasion of malignant gliomas. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                10 September 2020
                2020
                : 10
                : 1772
                Affiliations
                [1] 1Department of Neurosurgery, Second Affiliated Hospital of Nantong University , Nantong, China
                [2] 2Department of Neurosurgery, Changzheng Hospital, Second Military Medical University , Shanghai, China
                Author notes

                Edited by: Giorgio Seano, Institut Curie, France

                Reviewed by: Shanmugarajan Krishnan, Massachusetts General Hospital, United States; Anna Golebiewska, Luxembourg Institute of Health, Luxembourg

                *Correspondence: Yi Zhang, zhangyi9285@ 123456sina.com

                These authors share first authorship

                This article was submitted to Cancer Molecular Targets and Therapeutics, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2020.01772
                7511594
                33014873
                83010a90-8ae5-4729-a8a2-5c3297e4b863
                Copyright © 2020 Dai, Chen, Zhao, Cai, Wang, Wang, Hu and Zhang.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 19 March 2020
                : 07 August 2020
                Page count
                Figures: 6, Tables: 0, Equations: 1, References: 34, Pages: 12, Words: 0
                Categories
                Oncology
                Original Research

                Oncology & Radiotherapy
                gliomas,mir-29a-5p,dhrs4,proliferation,invasion,migration
                Oncology & Radiotherapy
                gliomas, mir-29a-5p, dhrs4, proliferation, invasion, migration

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