title: FAVL impairment of the Fanconi anemia pathway promotes the development of human bladder cancer.
abstract: Effectiveness of DNA cross-linking drugs in the treatment of bladder cancer suggests that bladder cancer cells may have harbored an insufficient cellular response to DNA cross-link damage, which will sensitize cells to DNA cross-linking agents. Cell sensitivity benefits from deficient DNA damage responses, which, on the other hand, can cause cancer. Many changed cellular signaling pathways are known to be involved in bladder tumorigenesis; however, DNA cross-link damage response pathway [Fanconi anemia (FA) pathway], whose alterations appear to be a plausible cause of the development of bladder cancer, remains an under-investigated area in bladder cancer research. In this study, we found FAVL (variant of FA protein L--FANCL) was elevated substantially in bladder cancer tissues examined. Ectopic expression of FAVL in bladder cancer cells as well as normal human cells confer an impaired FA pathway and hypersensitivity to Mitomycin C, similar to those found in FA cells, indicating that FAVL elevation may possess the same tumor promotion potential as an impaired FA pathway harbored in FA cells. Indeed, a higher level of FAVL expression can promote the growth of bladder cancer cells in vitro and in vivo, which, at least partly, results from FAVL perturbation of FANCL expression, an essential factor for the activation of the FA pathway. Moreover, a higher level of FAVL expression was found to be associated with chromosomal instability and the invasiveness of bladder cancer cells. Collectively, FAVL elevation can increase the tumorigenic potential of bladder cancer cells, including the invasive potential that confers the development of advanced bladder cancer. These results enhance our understanding the pathogenesis of human bladder cancer, holding a promise to develop additional effective tools to fight human bladder cancer.
authors: University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, USA.
authors: Jayabal
authors: J
authors: Panneerselvam
authors: Hwan Ki
authors: HK
authors: Park
authors: Jun
authors: J
authors: Zhang
authors: Fred Duafalia
authors: FD
authors: Dudimah
authors: Piyan
authors: P
authors: Zhang
authors: Hong
authors: H
authors: Wang
authors: Peiwen
authors: P
authors: Fei
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004249:DNA Damage; D004260:DNA Repair; D005199:Fanconi Anemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D052240:Fanconi Anemia Complementation Group L Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016685:Mitomycin / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000235:genetics; D014183:Transplantation, Heterologous; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D016685:Mitomycin; D052240:Fanconi Anemia Complementation Group L Protein