title: Increasing sensitivity to DNA damage is a potential driver for human ovarian cancer.
abstract: Ovarian cancer is one of the most common cancers among women, accounting for more deaths than any other gynecological diseases. However, the survival rate for ovarian cancer has not essentially improved over the past thirty years. Thus, to understand the molecular mechanism of ovarian tumorigenesis is important for optimizing the early diagnosis and treating this disease. In this study, we observed obvious DNA lesions, especially DNA double strand breaks (DSBs) accompanying cell cycle checkpoint activation, in the human epithelial ovarian cancer samples, which could be due to the impaired DNA response machinery. Following this line, we found that these DNA damage response-deficient primary cancer cells were hypersensitive to DNA damage and lost their ability to repair the DNA breaks, leading to genomic instability. Of note, three key DNA damage response factors, RNF8, Ku70, and FEN1 exhibited dramatically decreased expression level, implying the dysfunctional DNA repair pathways. Re-expression of wild type RNF8, Ku70, or FEN1 in these cells restored the DNA lesions and also partially rescued the cells from death. Our current study therefore proposes that accumulated DNA lesions might be a potential driver of ovarian cancer and the impaired DNA damage responders could be the targets for clinical treatment.
authors.affiliation: Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, P.R. China.
authors.forename: Yimei
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, P.R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Molecular and Medical pharmacology, University of California, Los Angeles, 90095, USA.
authors.forename: Xuemeng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Medical School and University of Michigan, Ann Arbor, Michigan, 48109, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Kuang
authors.affiliation: School of Public Health, University of Michigan, Ann Arbor, Michigan, 48109, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Osterman
authors.affiliation: Education Department, Peking University Third Hospital, Beijing, 100191, P.R. China.
authors.forename: Shi
authors.initials: S
authors.lastname: Feng
authors.affiliation: Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100005, China.
authors.forename: Deqiang
authors.initials: D
authors.lastname: Han
authors.affiliation: Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, P.R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, P.R. China.
authors.forename: Mo
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, P.R. China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Guo
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000378:metabolism; D002453:Cell Cycle; D020552:Comet Assay; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D045585:Flap Endonucleases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000072200:Ku Autoantigen / Q000378:metabolism; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D044767:Ubiquitin-Protein Ligases
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C486521:RNF8 protein, human; D044767:Ubiquitin-Protein Ligases; D045585:Flap Endonucleases; C468317:FEN1 protein, human; D000072200:Ku Autoantigen
keywords: DNA damage; DNA repair; genomic instability; ovarian cancer