Increasing sensitivity to DNA damage is a potential driver for human ovarian cancer
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Yimei Jin1, Xin Xu1, Xuemeng Wang2, Henry Kuang3, Michael Osterman4, Shi Feng5, Deqiang Han6, Yu Wu1, Mo Li1, Hongyan Guo1
1Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, P.R. China
2Department of Molecular and Medical pharmacology, University of California, Los Angeles, 90095, USA
3Medical School and University of Michigan, Ann Arbor, Michigan, 48109, USA
4School of Public Health, University of Michigan, Ann Arbor, Michigan, 48109, USA
5Education Department, Peking University Third Hospital, Beijing, 100191, P.R. China
6Department 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
Mo Li, email: [email protected]
Hongyan Guo, email: [email protected]
Keywords: ovarian cancer, DNA damage, DNA repair, genomic instability
Received: January 12, 2016 Accepted: June 29, 2016 Published: July 06, 2016
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.
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