Epigenetic silencing of miR-130b in ovarian cancer promotes the development of multidrug resistance by targeting colony-stimulating factor 1

Abstract Objective The purpose of this study was to investigate the role of miR-130b in the development of multidrug-resistant ovarian cancer. Methods The expression of miR-130b was assessed in ovarian tissues and cell lines by qRT-PCR. In vitro, miR-130b level was manipulated by transfection with m...

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Published in:Gynecologic oncology 2012-02, Vol.124 (2), p.325-334
Main Authors: Yang, Chun, Cai, Jing, Wang, Qiyue, Tang, Huijuan, Cao, Jin, Wu, Liying, Wang, Zehua
Format: Article
Language:English
Subjects:
Cell Line, Tumor
CpG Islands
CSF-1
Cytosine - metabolism
DNA Methylation
Down-Regulation
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Drug Screening Assays, Antitumor
Epigenomics
Female
Gene Silencing
Hematology, Oncology and Palliative Medicine
Humans
Macrophage Colony-Stimulating Factor - biosynthesis
Macrophage Colony-Stimulating Factor - genetics
Macrophage Colony-Stimulating Factor - metabolism
Methylation
MicroRNAs - administration & dosage
MicroRNAs - biosynthesis
MicroRNAs - genetics
miR-130b
Multidrug resistance
Obstetrics and Gynecology
Ovarian cancer
Ovarian Neoplasms - drug therapy
Ovarian Neoplasms - genetics
Ovarian Neoplasms - metabolism
RNA, Small Interfering - administration & dosage
RNA, Small Interfering - genetics
Transfection
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Summary:Abstract Objective The purpose of this study was to investigate the role of miR-130b in the development of multidrug-resistant ovarian cancer. Methods The expression of miR-130b was assessed in ovarian tissues and cell lines by qRT-PCR. In vitro, miR-130b level was manipulated by transfection with mimics or inhibitors. Methylation level of miR-130b was evaluated by quantitative methylation-specific PCR (qMSP). CSF-1 expression in ovarian tissues and cells was determined by qRT-PCR, immunohistochemistry and ELISA, respectively. CSF-1 regulated by miR-130b was detected using Dual Luciferase Reporter system. Results Down-regulation of miR-130b in ovarian cancer was associated with FIGO III–IV clinical stages and poorer histological differentiation. MiR-130b was downregulated in multidrug resistant ovarian cancer cells. Restoration of miR-130b expression could sensitize these cells to anticancer drugs. MiR-130b hypermethylation was found in ovarian cancer tissues as well as in drug resistant cell lines and the methylation level was negatively correlated with its expression. Demethylation with 5-aza-CdR led to reactivation of miR-130b expression in drug resistant ovarian cancer cell lines concomitant with increase of sensibility to cisplatin and taxol. CSF-1 expression was negatively associated with miR-130b level in ovarian tissues and cell lines. Luciferase assay validated CSF-1 is a direct target of miR-130b. Knock-down of CSF-1 sensitized ovarian cancer cells to anticancer drugs and could partially attenuate the resistance inducing effect of miR-130b inhibitors. Conclusions Downregulation of miR-130b promotes the development of multidrug resistant ovarian cancer partially by targeting the 3′-UTR of CSF-1, and the silencing of miR-130b may be mediated by DNA methylation.
ISSN:0090-8258
1095-6859
DOI:10.1016/j.ygyno.2011.10.013