title: MicroRNA-136 inhibits cancer stem cell activity and enhances the anti-tumor effect of paclitaxel against chemoresistant ovarian cancer cells by targeting Notch3.
abstract: To identify microRNAs (miRNAs) regulating Notch3 expression in association with paclitaxel resistance, candidate miRNAs targeting Notch3 were predicted using TargetScan. We found that miR-136 directly targets Notch3, and miR-136 was significantly downregulated in OSC tissues relative to normal control tissues, and low expression of miR-136 correlated with poor overall in ovarian cancer patients. Artificial miR-136 overexpression significantly reduced cell viability, proliferation, Cancer stem cell (CSC) spheroid formation, and angiogenesis, and increased apoptosis in paclitaxel-resistant SKpac cells compared with the effects of paclitaxel alone. miR-136 overexpression downregulated cell survival- (survivin, DNA-PK, pS6, S6) and cell cycle- (Cyclin D1, NF-κB) related proteins, and anti-apoptotic proteins (BCL2, and BCL-XL), and upregulated pro-apoptotic proteins (Bim, Bid, and Bax). Taken together, miR-136 targets the Notch3 oncogene and functions as a tumor suppressor. miR-136 overexpression resensitized paclitaxel-resistant ovarian cancer cells and reduced CSC activities, suggesting a promising new target for the treatment of chemoresistant ovarian cancers.
authors.affiliation: Department of Pathology, CHA Bundang Medical Center, CHA University, 463-712, South Korea; Institute for Clinical Research, CHA Bundang Medical Center, CHA University, 463-712, South Korea.
authors.forename: Ju-Yeon
authors.initials: JY
authors.lastname: Jeong
authors.affiliation: Department of Pathology, CHA Bundang Medical Center, CHA University, 463-712, South Korea; Institute for Clinical Research, CHA Bundang Medical Center, CHA University, 463-712, South Korea.
authors.forename: Haeyoun
authors.initials: H
authors.lastname: Kang
authors.affiliation: Department of Pathology, CHA Bundang Medical Center, CHA University, 463-712, South Korea; Institute for Clinical Research, CHA Bundang Medical Center, CHA University, 463-712, South Korea.
authors.forename: Tae Hoen
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Department of Pathology, CHA Bundang Medical Center, CHA University, 463-712, South Korea; Institute for Clinical Research, CHA Bundang Medical Center, CHA University, 463-712, South Korea.
authors.forename: Gwangil
authors.initials: G
authors.lastname: Kim
authors.affiliation: Department of Pathology, CHA Bundang Medical Center, CHA University, 463-712, South Korea.
authors.forename: Jin-Hyung
authors.initials: JH
authors.lastname: Heo
authors.affiliation: Department of Pathology, CHA Bundang Medical Center, CHA University, 463-712, South Korea.
authors.forename: Ah-Young
authors.initials: AY
authors.lastname: Kwon
authors.affiliation: Department of Pathology, CHA Bundang Medical Center, CHA University, 463-712, South Korea; Institute for Clinical Research, CHA Bundang Medical Center, CHA University, 463-712, South Korea.
authors.forename: Sewha
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Gynecologic Oncology, CHA Bundang Medical Center, CHA University, 463-712, South Korea.
authors.forename: Sang-Geun
authors.initials: SG
authors.lastname: Jung
authors.affiliation: Department of Pathology, CHA Bundang Medical Center, CHA University, 463-712, South Korea; Institute for Clinical Research, CHA Bundang Medical Center, CHA University, 463-712, South Korea. Electronic address: hjahn@cha.ac.kr.
authors.forename: Hee-Jung
authors.initials: HJ
authors.lastname: An
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D000071656:Receptor, Notch3 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; C577037:MIRN136 microRNA, human; D035683:MicroRNAs; C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D017239:Paclitaxel
keywords: Cancer stem cells; Chemoresistance; Notch3 signaling; Ovarian cancer; miR-136