University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, USA.
Cell Cycle. 2012 Aug 1;11(15):2947-55. doi: 10.4161/cc.21400.
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.
DNA 交联药物在膀胱癌治疗中的有效性表明，膀胱癌细胞可能对 DNA 交联损伤的细胞反应不足，这将使细胞对 DNA 交联剂敏感。细胞敏感性受益于 DNA 损伤反应的缺陷，而另一方面，这种缺陷会导致癌症。许多改变的细胞信号通路被认为参与了膀胱癌的发生；然而，DNA 交联损伤反应途径（范可尼贫血[FA]途径），其改变似乎是膀胱癌发展的一个合理原因，在膀胱癌研究中仍然是一个研究不足的领域。在这项研究中，我们发现 FAVL（FA 蛋白 L 的变体--FANCL）在检查的膀胱癌组织中显著升高。FAVL 在膀胱癌细胞以及正常人类细胞中的异位表达赋予 FA 途径受损和对丝裂霉素 C 的敏感性增加，类似于在 FA 细胞中发现的，表明 FAVL 升高可能具有与 FA 细胞中存在的受损 FA 途径相同的肿瘤促进潜力。事实上，较高水平的 FAVL 表达可以促进膀胱癌细胞在体外和体内的生长，这至少部分归因于 FAVL 对 FANCL 表达的干扰，这是 FA 途径激活的一个重要因素。此外，较高水平的 FAVL 表达与膀胱癌细胞的染色体不稳定性和侵袭性有关。总之，FAVL 升高可增加膀胱癌细胞的致瘤潜能，包括赋予晚期膀胱癌发展的侵袭潜能。这些结果增强了我们对人类膀胱癌发病机制的理解，有望开发额外有效的工具来对抗人类膀胱癌。
