{"title":"Suppression of endometriosis by miRNA-34a via inhibition of matrix metalloproteinase-2: An alternative pathway to impede invasion","authors":"Yasmin Begum , Anuradha Pandit , Devendra Shukla , Rahul Gupta , Pramathes DasMahapatra , Amit Kumar Srivastava , Snehasikta Swarnakar","doi":"10.1016/j.ncrna.2025.02.001","DOIUrl":null,"url":null,"abstract":"<div><div>Matrix metalloproteinases (MMPs) cleave proteins of extracellular matrix thus facilitating cellular invasion and cancer progression. High MMP-2 activity is frequently reported in several diseases including endometriosis and cancer. Endometriosis, though benign causing pain and infertility, rarely culminate into ovarian cancer. New diagnostic markers are needed for early diagnosis and proper therapeutic avenues since the only diagnostic method is laparoscopy to date. Emerging evidence shows the importance of MMP activity and involvement of noncoding RNA, e.g. miRNA thereon. We investigated the role of miRNA-34a in MMP-2-mediated regulation of invasion and tumorigenesis in endometriosis. Database analysis showed a decreased miRNA-34a in different gynecological malignancies. qRT-PCR with human endometriotic and control tissues revealed a significant elevation in MMP-2 activity with downregulated miR-34a in diseased individuals proving an inverse correlation between miRNA-34a and MMP-2. Luciferase assay in SK-OV-3 cells demonstrated that miRNA-34a-5p directly binds the 3′UTR of the MMP-2 promoter to reduce its transcription followed by suppression of invasion. The zymographic assay also showed a reduced MMP-2 activity upon miR-34a treatment in End1/E6E7 and SK-OV-3 cells. We also found that miRNA-34a-5p inhibits invasion, migration, colony/spheroid formation, and stemness of the cells thereby reducing in vitro tumorigenesis. Subsequently, the immunoblotting results confirmed that MMP-2, and mesenchymal markers like n-cadherin, vimentin, and slug expression were downregulated, whereas the e-cadherin was upregulated in the cells treated with miRNA-34a mimic. Our study demonstrates the direct binding of miR-34a-5p with the MMP-2 gene's 3′UTR and thus repressed its transcription as well as suppressing endometriosis progression.</div></div>","PeriodicalId":37653,"journal":{"name":"Non-coding RNA Research","volume":"12 ","pages":"Pages 92-101"},"PeriodicalIF":5.9000,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Non-coding RNA Research","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S246805402500023X","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Matrix metalloproteinases (MMPs) cleave proteins of extracellular matrix thus facilitating cellular invasion and cancer progression. High MMP-2 activity is frequently reported in several diseases including endometriosis and cancer. Endometriosis, though benign causing pain and infertility, rarely culminate into ovarian cancer. New diagnostic markers are needed for early diagnosis and proper therapeutic avenues since the only diagnostic method is laparoscopy to date. Emerging evidence shows the importance of MMP activity and involvement of noncoding RNA, e.g. miRNA thereon. We investigated the role of miRNA-34a in MMP-2-mediated regulation of invasion and tumorigenesis in endometriosis. Database analysis showed a decreased miRNA-34a in different gynecological malignancies. qRT-PCR with human endometriotic and control tissues revealed a significant elevation in MMP-2 activity with downregulated miR-34a in diseased individuals proving an inverse correlation between miRNA-34a and MMP-2. Luciferase assay in SK-OV-3 cells demonstrated that miRNA-34a-5p directly binds the 3′UTR of the MMP-2 promoter to reduce its transcription followed by suppression of invasion. The zymographic assay also showed a reduced MMP-2 activity upon miR-34a treatment in End1/E6E7 and SK-OV-3 cells. We also found that miRNA-34a-5p inhibits invasion, migration, colony/spheroid formation, and stemness of the cells thereby reducing in vitro tumorigenesis. Subsequently, the immunoblotting results confirmed that MMP-2, and mesenchymal markers like n-cadherin, vimentin, and slug expression were downregulated, whereas the e-cadherin was upregulated in the cells treated with miRNA-34a mimic. Our study demonstrates the direct binding of miR-34a-5p with the MMP-2 gene's 3′UTR and thus repressed its transcription as well as suppressing endometriosis progression.
期刊介绍:
Non-coding RNA Research aims to publish high quality research and review articles on the mechanistic role of non-coding RNAs in all human diseases. This interdisciplinary journal will welcome research dealing with all aspects of non-coding RNAs-their biogenesis, regulation and role in disease progression. The focus of this journal will be to publish translational studies as well as well-designed basic studies with translational and clinical implications. The non-coding RNAs of particular interest will be microRNAs (miRNAs), small interfering RNAs (siRNAs), small nucleolar RNAs (snoRNAs), U-RNAs/small nuclear RNAs (snRNAs), exosomal/extracellular RNAs (exRNAs), Piwi-interacting RNAs (piRNAs) and long non-coding RNAs. Topics of interest will include, but not limited to: -Regulation of non-coding RNAs -Targets and regulatory functions of non-coding RNAs -Epigenetics and non-coding RNAs -Biological functions of non-coding RNAs -Non-coding RNAs as biomarkers -Non-coding RNA-based therapeutics -Prognostic value of non-coding RNAs -Pharmacological studies involving non-coding RNAs -Population based and epidemiological studies -Gene expression / proteomics / computational / pathway analysis-based studies on non-coding RNAs with functional validation -Novel strategies to manipulate non-coding RNAs expression and function -Clinical studies on evaluation of non-coding RNAs The journal will strive to disseminate cutting edge research, showcasing the ever-evolving importance of non-coding RNAs in modern day research and medicine.