title: Enhanced expression of DNA polymerase eta contributes to cisplatin resistance of ovarian cancer stem cells.
abstract: Cancer stem cells (CSCs) with enhanced tumorigenicity and chemoresistance are believed to be responsible for treatment failure and tumor relapse in ovarian cancer patients. However, it is still unclear how CSCs survive DNA-damaging agent treatment. Here, we report an elevated expression of DNA polymerase η (Pol η) in ovarian CSCs isolated from both ovarian cancer cell lines and primary tumors, indicating that CSCs may have intrinsically enhanced translesion DNA synthesis (TLS). Down-regulation of Pol η blocked cisplatin-induced CSC enrichment both in vitro and in vivo through the enhancement of cisplatin-induced apoptosis in CSCs, indicating that Pol η-mediated TLS contributes to the survival of CSCs upon cisplatin treatment. Furthermore, our data demonstrated a depletion of miR-93 in ovarian CSCs. Enforced expression of miR-93 in ovarian CSCs reduced Pol η expression and increased their sensitivity to cisplatin. Taken together, our data suggest that ovarian CSCs have intrinsically enhanced Pol η-mediated TLS, allowing CSCs to survive cisplatin treatment, leading to tumor relapse. Targeting Pol η, probably through enhancement of miR-93 expression, might be exploited as a strategy to increase the efficacy of cisplatin treatment.
authors.affiliation: Department of Radiology.
authors.forename: Amit Kumar
authors.initials: AK
authors.lastname: Srivastava
authors.affiliation: Department of Radiology.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Han
authors.affiliation: Department of Radiology.
authors.forename: Ran
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Department of Radiology.
authors.forename: Tiantian
authors.initials: T
authors.lastname: Cui
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics.
authors.forename: Yuntao
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Comprehensive Cancer Center.
authors.forename: Charlene
authors.initials: C
authors.lastname: Mao
authors.affiliation: Department of Pathology.
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Center for Biostatistics, and.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Comprehensive Cancer Center, Division of Hematology/Oncology, The Ohio State University, Columbus, OH 43210.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Radiology, Comprehensive Cancer Center, qi-en.wang@osumc.edu.
authors.forename: Qi-En
authors.initials: QE
authors.lastname: Wang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D002945:Cisplatin / Q000737:chemistry*; D004247:DNA / Q000737:chemistry; D004249:DNA Damage; D004260:DNA Repair; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism; D012008:Recurrence; D000099270:Y-Family DNA Polymerases
chemical_list: D002945:Cisplatin; D004247:DNA; D004259:DNA-Directed DNA Polymerase; D035683:MicroRNAs; C543350:MIRN93 microRNA, human; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases
keywords: DNA polymerase eta; cancer stem cell; cisplatin; miR-93; translesion synthesis
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