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microRNA-216b enhances cisplatin-induced apoptosis in osteosarcoma MG63 and SaOS-2 cells by binding to JMJD2C and regulating the HIF1α/HES1 signaling axis

BACKGROUND: Although cisplatin-based chemotherapy represents the standard regimen for osteosarcoma (OS), OS patients often exhibit treatment failure and poor prognosis due to chemoresistance to cisplatin. Emerging research has highlighted the tumor suppressive properties of microRNAs (miRNAs or miRs...

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Autores principales: Yang, Dong, Xu, Tianyang, Fan, Lin, Liu, Kaiyuan, Li, Guodong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517798/
https://www.ncbi.nlm.nih.gov/pubmed/32972441
http://dx.doi.org/10.1186/s13046-020-01670-3
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author Yang, Dong
Xu, Tianyang
Fan, Lin
Liu, Kaiyuan
Li, Guodong
author_facet Yang, Dong
Xu, Tianyang
Fan, Lin
Liu, Kaiyuan
Li, Guodong
author_sort Yang, Dong
collection PubMed
description BACKGROUND: Although cisplatin-based chemotherapy represents the standard regimen for osteosarcoma (OS), OS patients often exhibit treatment failure and poor prognosis due to chemoresistance to cisplatin. Emerging research has highlighted the tumor suppressive properties of microRNAs (miRNAs or miRs) in various human cancers via the inhibition of the histone demethylase jumonji domain containing protein 2C (JMJD2C). As a coactivator for hypoxia-inducible factor 1α (HIF1α), JMJD2C targets hairy and enhancer of split-1 (HES1) gene. Hence, the current study aimed to elucidate the role of miR-216b in OS cell cisplatin resistance to identify the underlying mechanism of miR-216b regulating the JMJD2C//HIF1α/HES1 signaling. METHODS: Tumor and paracancerous tissues were collected from OS patients to determine the expression patterns of miR-216b and JMJD2C. After ectopic expression and knockdown experiments in the OS cells, CCK-8 assay and flow cytometry were employed to determine cell viability and apoptosis. The interaction of miR-216b, JMJD2C, HIF1α and HES1 was subsequently determined by dual luciferase reporter, co-immunoprecipitation (IP) and ChIP-qPCR assays. In vivo experiments were conducted to further verify the role of the miR-216b in the resistance of OS cells to cisplatin. RESULTS: miR-216b expression was reduced in the OS tissues, as well as the MG63 and SaOS-2 cells. Heightened miR-216b expression was found to be positively correlated with patient survival, and miR-216b further enhanced cisplatin-induced apoptosis of MG63 and SaOS-2 cells. Mechanistically, miR-216b inhibited JMJD2C expression by binding to its 3’UTR. Through interaction with HIF1α, JMJD2C removed the H3K9 methylation modification at the HES1 promoter region, leading to upregulation of HES1 in vitro. Furthermore, miR-216b was observed to increase the tumor growth in nude mice in the presence of cisplatin treatment. HES1 overexpression weakened the effects of miR-216b in MG63 and SaOS-2 cells and in nude mouse xenografts. CONCLUSION: Overall, miR-216b enhanced the sensitivity of OS cells to cisplatin via downregulation of the JMJD2C/HIF1α/HES1 signaling axis, highlighting the capacity of miR-216b as an adjunct to cisplatin chemotherapy in the treatment of OS.
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spelling pubmed-75177982020-09-29 microRNA-216b enhances cisplatin-induced apoptosis in osteosarcoma MG63 and SaOS-2 cells by binding to JMJD2C and regulating the HIF1α/HES1 signaling axis Yang, Dong Xu, Tianyang Fan, Lin Liu, Kaiyuan Li, Guodong J Exp Clin Cancer Res Research BACKGROUND: Although cisplatin-based chemotherapy represents the standard regimen for osteosarcoma (OS), OS patients often exhibit treatment failure and poor prognosis due to chemoresistance to cisplatin. Emerging research has highlighted the tumor suppressive properties of microRNAs (miRNAs or miRs) in various human cancers via the inhibition of the histone demethylase jumonji domain containing protein 2C (JMJD2C). As a coactivator for hypoxia-inducible factor 1α (HIF1α), JMJD2C targets hairy and enhancer of split-1 (HES1) gene. Hence, the current study aimed to elucidate the role of miR-216b in OS cell cisplatin resistance to identify the underlying mechanism of miR-216b regulating the JMJD2C//HIF1α/HES1 signaling. METHODS: Tumor and paracancerous tissues were collected from OS patients to determine the expression patterns of miR-216b and JMJD2C. After ectopic expression and knockdown experiments in the OS cells, CCK-8 assay and flow cytometry were employed to determine cell viability and apoptosis. The interaction of miR-216b, JMJD2C, HIF1α and HES1 was subsequently determined by dual luciferase reporter, co-immunoprecipitation (IP) and ChIP-qPCR assays. In vivo experiments were conducted to further verify the role of the miR-216b in the resistance of OS cells to cisplatin. RESULTS: miR-216b expression was reduced in the OS tissues, as well as the MG63 and SaOS-2 cells. Heightened miR-216b expression was found to be positively correlated with patient survival, and miR-216b further enhanced cisplatin-induced apoptosis of MG63 and SaOS-2 cells. Mechanistically, miR-216b inhibited JMJD2C expression by binding to its 3’UTR. Through interaction with HIF1α, JMJD2C removed the H3K9 methylation modification at the HES1 promoter region, leading to upregulation of HES1 in vitro. Furthermore, miR-216b was observed to increase the tumor growth in nude mice in the presence of cisplatin treatment. HES1 overexpression weakened the effects of miR-216b in MG63 and SaOS-2 cells and in nude mouse xenografts. CONCLUSION: Overall, miR-216b enhanced the sensitivity of OS cells to cisplatin via downregulation of the JMJD2C/HIF1α/HES1 signaling axis, highlighting the capacity of miR-216b as an adjunct to cisplatin chemotherapy in the treatment of OS. BioMed Central 2020-09-24 /pmc/articles/PMC7517798/ /pubmed/32972441 http://dx.doi.org/10.1186/s13046-020-01670-3 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Yang, Dong
Xu, Tianyang
Fan, Lin
Liu, Kaiyuan
Li, Guodong
microRNA-216b enhances cisplatin-induced apoptosis in osteosarcoma MG63 and SaOS-2 cells by binding to JMJD2C and regulating the HIF1α/HES1 signaling axis
title microRNA-216b enhances cisplatin-induced apoptosis in osteosarcoma MG63 and SaOS-2 cells by binding to JMJD2C and regulating the HIF1α/HES1 signaling axis
title_full microRNA-216b enhances cisplatin-induced apoptosis in osteosarcoma MG63 and SaOS-2 cells by binding to JMJD2C and regulating the HIF1α/HES1 signaling axis
title_fullStr microRNA-216b enhances cisplatin-induced apoptosis in osteosarcoma MG63 and SaOS-2 cells by binding to JMJD2C and regulating the HIF1α/HES1 signaling axis
title_full_unstemmed microRNA-216b enhances cisplatin-induced apoptosis in osteosarcoma MG63 and SaOS-2 cells by binding to JMJD2C and regulating the HIF1α/HES1 signaling axis
title_short microRNA-216b enhances cisplatin-induced apoptosis in osteosarcoma MG63 and SaOS-2 cells by binding to JMJD2C and regulating the HIF1α/HES1 signaling axis
title_sort microrna-216b enhances cisplatin-induced apoptosis in osteosarcoma mg63 and saos-2 cells by binding to jmjd2c and regulating the hif1α/hes1 signaling axis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517798/
https://www.ncbi.nlm.nih.gov/pubmed/32972441
http://dx.doi.org/10.1186/s13046-020-01670-3
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