Abstract
BackgroundAlthough 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.MethodsTumor 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.ResultsmiR-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.ConclusionOverall, 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.
Highlights
Cisplatin-based chemotherapy represents the standard regimen for osteosarcoma (OS), OS patients often exhibit treatment failure and poor prognosis due to chemoresistance to cisplatin
Results miR-216b is poorly-expressed in OS and its high expression is positively-correlated with patient survival Firstly, the expression of miR-216b was found to be markedly lower in OS tissues compared to that in paracancerous tissues (Fig. 1a)
Findings obtained in the current study indicated that miR-216b could augment the effect of the chemotherapeutic agent cisplatin on cell viability and apoptosis in OS cells, which might be attributed to its binding to the Jumonji C domaincontaining 2C (JMJD2C) gene and the subsequent inhibition of JMJD2C expression, leading to the regulation of the hypoxiainducible factor 1α (HIF1α)/hairy and enhancer of split-1 (HES1) signaling axis
Summary
Cisplatin-based chemotherapy represents the standard regimen for osteosarcoma (OS), OS patients often exhibit treatment failure and poor prognosis due to chemoresistance to cisplatin. The current study aimed to elucidate the role of miR-216b in OS cell cisplatin resistance to identify the underlying mechanism of miR216b regulating the JMJD2C//HIF1α/HES1 signaling. A combination of surgical intervention as well as chemotherapy is regarded as the first line treatment for OS. It is well-documented that the advent of chemotherapy resistance is a big obstacle in the treatment of OS [7,8,9,10], which may, at least partly, contribute to the unfavorable outcomes seen in OS patients. The current study set out to identify the potential mechanism by which chemotherapy drug resistance occurs during the course of OS treatment
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