Schrock Morgan S, Karras Jenna R, Guggenbiller Matthew J, Druck Teresa, Batar Bahadir, Huebner Kay
Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
Adv Biol Regul. 2017 Jan;63:167-176. doi: 10.1016/j.jbior.2016.09.008. Epub 2016 Sep 26.
Expression of Fhit and Wwox protein is frequently lost or reduced in many human cancers. In this report, we provide data that further characterizes the molecular consequences of Fhit loss in the initiation of DNA double-strand breaks (DSBs), and of Wwox loss in altered repair of DSBs. We show that loss of Fhit initiates mild genome instability in early passage mouse kidney cells, confirming that DNA damage associated with Fhit-deficiency is not limited to cancer cells. We also demonstrate that the cause of Fhit-deficient DSBs: thymidine deficiency-induced replication stress, can be resolved with thymidine supplementation in early passage mouse kidney cells before extensive genome instability occurs. As for consequences of Wwox loss in cancer, we show in a small panel of breast cancer cells and mouse embryonic fibroblasts that Wwox expression predicts response to radiation and mitomycin C, all agents that cause DSBs. In addition, loss of Wwox significantly reduced progression free survival in a cohort of ovarian cancer patients treated with platin-based chemotherapies. Finally, stratification of a cohort of squamous lung cancers by Fhit expression reveals that Wwox expression is significantly reduced in the low Fhit-expressing group, suggesting that loss of Fhit is quickly succeeded by loss of Wwox. We propose that Fhit and Wwox loss work synergistically in cancer progression and that DNA damage caused by Fhit could be targeted early in cancer initiation for prevention, while DNA damage caused by Wwox loss could be targeted later in cancer progression, particularly in cancers that develop resistance to genotoxic therapies.
Fhit和Wwox蛋白的表达在许多人类癌症中经常缺失或减少。在本报告中，我们提供的数据进一步描述了Fhit缺失在DNA双链断裂（DSB）起始过程中的分子后果，以及Wwox缺失在DSB修复改变中的分子后果。我们表明，Fhit的缺失在早期传代的小鼠肾细胞中引发了轻度的基因组不稳定，证实了与Fhit缺陷相关的DNA损伤并不局限于癌细胞。我们还证明，Fhit缺陷型DSB的原因：胸苷缺乏诱导的复制应激，可以在早期传代的小鼠肾细胞中通过补充胸苷来解决，在广泛的基因组不稳定发生之前。至于Wwox缺失在癌症中的后果，我们在一小部分乳腺癌细胞和小鼠胚胎成纤维细胞中表明，Wwox表达预测对辐射和丝裂霉素C的反应，所有这些药物都会导致DSB。此外，Wwox的缺失显著降低了一组接受铂类化疗的卵巢癌患者的无进展生存期。最后，通过Fhit表达对一组肺鳞癌进行分层分析发现，在低Fhit表达组中Wwox表达显著降低，这表明Fhit的缺失很快会导致Wwox的缺失。我们提出，Fhit和Wwox的缺失在癌症进展中协同作用，并且由Fhit引起的DNA损伤可以在癌症起始早期作为预防靶点，而由Wwox缺失引起的DNA损伤可以在癌症进展后期作为靶点，特别是在对基因毒性疗法产生抗性的癌症中。
