title: MiR-152 and miR-185 co-contribute to ovarian cancer cells cisplatin sensitivity by targeting DNMT1 directly: a novel epigenetic therapy independent of decitabine.
abstract: Epithelial ovarian cancer (EOC) is a highly lethal gynaecological malignancy. Cisplatin is the basal chemotherapeutic agent used to treat EOC, but resistance to cisplatin leads to chemotherapy failure. MicroRNAs are a novel class of regulators that function by controlling gene expression at the post-transcriptional level. Several recent reports have identified some microRNAs that are related to chemotherapy sensitivity. In this study, we found two microRNAs miR-152 and miR-185 that were significantly downregulated in the cisplatin-resistant ovarian cell lines SKOV3/DDP and A2780/DDP, compared with their sensitive parent line SKOV3 and A2780, respectively. Subsequently, the roles of miR-152 and miR-185 were evaluated in vitro and in vivo. The overexpression of miR-152 or miR-185 increased cisplatin sensitivity of SKOV3/DDP and A2780/DDP cells by inhibiting proliferation and promoting apoptosis, then we further confirmed that these miRNAs functioned through suppressing DNA methyltransferase 1 (DNMT1) directly. Concordantly, CD-1/CD-1 nude mice that were injected intraperitoneally with SKOV3/DDP cells transfected with miR-152 mimics exhibited upregulated cisplatin sensitivity in vivo. Interestingly, we found that there were no significant changes in the expression of these two microRNAs after treatment with decitabine (DAC), a traditional epigenetic therapeutic agent, suggesting these miRNAs represented two new regulators independent of DAC. Finally, the survival assay in A549 and HepG2 cells revealed that the two microRNAs involved in cisplatin sensitivity were related to cell types. Our results indicated that miR-152 and miR-185 were involved in ovarian cancer cisplatin resistance in vitro and in vivo by targeting DNMT1 directly. These molecules may serve as potential epigenetic therapeutic targets in other cancers.
authors: Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.
authors: Y
authors: Y
authors: Xiang
authors: Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.
authors: N
authors: N
authors: Ma
authors: Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.
authors: D
authors: D
authors: Wang
authors: Department of Laboratory Diagnosis, First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors: Y
authors: Y
authors: Zhang
authors: Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.
authors: J
authors: J
authors: Zhou
authors: Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.
authors: G
authors: G
authors: Wu
authors: Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.
authors: R
authors: R
authors: Zhao
authors: Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.
authors: H
authors: H
authors: Huang
authors: Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.
authors: X
authors: X
authors: Wang
authors: Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.
authors: Y
authors: Y
authors: Qiao
authors: Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.
authors: F
authors: F
authors: Li
authors: Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.
authors: D
authors: D
authors: Han
authors: Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.
authors: L
authors: L
authors: Wang
authors: Department of Obstetrics and Gynecology, First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors: G
authors: G
authors: Zhang
authors: 1] Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China [2] Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, Harbin, China [3] State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Harbin Medical University, Harbin, China.
authors: X
authors: X
authors: Gao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D000077209:Decitabine; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; C550856:MIRN152 microRNA, human; C552431:MIRN185 microRNA, human; D035683:MicroRNAs; D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; D001374:Azacitidine; D002945:Cisplatin