1128 INVASIVE BLADDER CANCER CELLS ARE DEFICIENT IN DNA REPAIR AND HAVE MUTATOR PHENOTYPES THAT ARE DUE TO SUPPRESSION OF P63 GENE EXPRESSION

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research (III)1 Apr 20131128 INVASIVE BLADDER CANCER CELLS ARE DEFICIENT IN DNA REPAIR AND HAVE MUTATOR PHENOTYPES THAT ARE DUE TO SUPPRESSION OF P63 GENE EXPRESSION Hyun-Wook Lee, Hsiang-Tsui Wang, Mao-wen Weng, Josephine Kuo, William C. Huang, Nicholas Donin, Herbert Lepor, Xue-Ru Wu, and Moon-shong Tang Hyun-Wook LeeHyun-Wook Lee New York, NY More articles by this author , Hsiang-Tsui WangHsiang-Tsui Wang New York, NY More articles by this author , Mao-wen WengMao-wen Weng New York, NY More articles by this author , Josephine KuoJosephine Kuo New York, NY More articles by this author , William C. HuangWilliam C. Huang New York, NY More articles by this author , Nicholas DoninNicholas Donin New York, NY More articles by this author , Herbert LeporHerbert Lepor New York, NY More articles by this author , Xue-Ru WuXue-Ru Wu New York, NY More articles by this author , and Moon-shong TangMoon-shong Tang New York, NY More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.743AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Although it is well established that the two distinct clinical phenotypes of human bladder cancer, e.g. the non–invasive low–grade papillary urothelial carcinoma (N–inv–UC) and the high–grade invasive UC (Inv–UC), develop through divergent pathways, the molecular mechanisms underlying the development of these phenotypes remain unclear. We hypothesize that Inv–UC cells have a mutator phenotype because of a low DNA repair capacity and that these tumor cells have a high probability of escaping the immune surveillance system. In contrast, N–inv–UC cells have efficient DNA repair capacity and do not have a mutator phenotype; therefore, these tumor cells have a low probability of accumulating mutations that lead to tumor invasion. METHODS Using host cell reactivation, in vitro DNA damage dependent repair synthesis, and a shuttle vector supF system, we determined 1) DNA repair capacity, 2) ability to carry out DNA damage–dependent mutagenesis, and 3) expression of nucleotide excision repair (NER) genes (XPC & XPA), base excision repair (BER) gene (hOGG1), mismatch repair genes (MLH1, MSH2 & PMS2), and p53 and p63 genes, in cultured human N–inv–UC and Inv–UC cells. RESULTS We found that: 1) N–inv–UC cells have a much higher DNA repair capacity than Inv–UC cells for both oxidative and UV light–induced DNA damage, 2) both oxidative and UV–induced DNA damage elicit significantly more mutations in Inv–UC cells than in N–inv–UC cells, 3) Inv–UC cells do not express nucleotide excision repair gene XPC; base excision repair gene hOGG1, or p63 gene, and 4) the deficiency of DNA repair and the expression of XPC gene in Inv–UC can be partially rescued by transient expression of the p63 gene. CONCLUSIONS Our results provide the first experimental evidence indicating that Inv–UC cells are deficient in both nucleotide excision repair and base excision repair; that these deficiencies cause these cells to have a mutator phenotype which underlies their invasive behavior; and that the deficiency in DNA repair in Inv–UC can be rescued by the restoration of p63 expression. These results provide insight into the molecular underpinnings behind the two major bladder cancer oncogenic pathways, and provide a foundation for further studies to better molecularly differentiate these two distinct phenotypes. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e461 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hyun-Wook Lee New York, NY More articles by this author Hsiang-Tsui Wang New York, NY More articles by this author Mao-wen Weng New York, NY More articles by this author Josephine Kuo New York, NY More articles by this author William C. Huang New York, NY More articles by this author Nicholas Donin New York, NY More articles by this author Herbert Lepor New York, NY More articles by this author Xue-Ru Wu New York, NY More articles by this author Moon-shong Tang New York, NY More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...