title: miR-145 sensitizes ovarian cancer cells to paclitaxel by targeting Sp1 and Cdk6.
abstract: Multidrug resistance (MDR) remains a major obstacle to effective chemotherapy treatment in ovarian cancer. In our study, paclitaxel-resistant ovarian cancer patients and cell lines had decreased miR-145 levels and expressed high levels of Sp1 and Cdk6. Introducing miR-145 into SKOV3/PTX and A2780/PTX cells led to a reduction in Cdk6 and Sp1 along with downregulation of P-gp and pRb. These changes resulted in increased accumulation of antineoplastic drugs and G1 cell cycle arrest, which rendered the cells more sensitive to paclitaxel in vitro and in vivo. These effects could be reversed by reintroducing Sp1 or Cdk6 into cells expressing high levels of miR-145, resulting in restoration of P-gp and pRb levels. Furthermore, we confirmed that both Cdk6 and Sp1 are targets of miR-145. Intriguingly, demethylation with 5-aza-dC led to reactivation of miR-145 expression in drug-resistant ovarian cancer cell lines, which also resulted in increased sensitivity to paclitaxel. Collectively, these findings begin to elucidate the role of miR-145 as an important regulator of chemoresistance in ovarian cancer by controlling both Cdk6 and Sp1.
authors: The Fourth Affiliated Hospital of Jiangsu University, Department of gynecology, Zhenjiang, Jiangsu, China; Jiangsu University, school of medical science and laborratory medicine, Zhenjiang, Jiangsu, China.
authors: Xiaolan
authors: X
authors: Zhu
authors: Yuefeng
authors: Y
authors: Li
authors: Chanjuan
authors: C
authors: Xie
authors: Xinming
authors: X
authors: Yin
authors: Yueqin
authors: Y
authors: Liu
authors: Yuan
authors: Y
authors: Cao
authors: Yue
authors: Y
authors: Fang
authors: Xin
authors: X
authors: Lin
authors: Yao
authors: Y
authors: Xu
authors: Wenlin
authors: W
authors: Xu
authors: Huiling
authors: H
authors: Shen
authors: Jian
authors: J
authors: Wen
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D051361:Cyclin-Dependent Kinase 6 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D016160:Retinoblastoma Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D016329:Sp1 Transcription Factor; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6; D017239:Paclitaxel
keywords: Cdk6; P-gp; Sp1; miR-145; pRb