Key Laboratory of Experimental Teratology, Ministry of Education, Department of Obstetrics and Gynecology, Qilu Hospital, Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Department of Obstetrics & Gynecology, Jinhua Hospital of Zhejiang University, Jinhua, China.
J Cell Mol Med. 2021 Dec;25(23):10961-10972. doi: 10.1111/jcmm.17017. Epub 2021 Nov 3.
Rad50 is a component of MRN (Mre11-Rad50-Nbs1), which participates in DNA double-strand break repair and DNA-damage checkpoint activation. Here, we sought to investigate the clinical and functional significance of Rad50 in high-grade serous ovarian cancer (HGSOC). We found that Rad50 was frequently upregulated in HGSOCs and enhanced Rad50 expression inversely correlated with patient survival. In addition, ectopic expression of Rad50 promoted proliferation/invasion and induced EMT of ovarian cancer cells, whereas knockdown of Rad50 led to decreased aggressive behaviors. Mechanistic investigations revealed that Rad50 induced aggressiveness in HGSOC via activation of NF-κB signaling pathway. Moreover, we identified CARD9 as an interacting protein of Rad50 in ovarian cancer cells and the activation of NF-κB pathway by Rad50 is CARD9 dependent. Our findings provide evidence that Rad50 exhibits oncogenic property via NF-κB activation in HGSOC.
Rad50 是 MRN（Mre11-Rad50-Nbs1）的一个组成部分，参与 DNA 双链断裂修复和 DNA 损伤检查点激活。在这里，我们试图研究 Rad50 在高级别浆液性卵巢癌（HGSOC）中的临床和功能意义。我们发现 Rad50 在 HGSOC 中经常上调，并且增强的 Rad50 表达与患者生存呈负相关。此外，Rad50 的异位表达促进了卵巢癌细胞的增殖/侵袭，并诱导了 EMT，而 Rad50 的敲低导致侵袭性行为减少。机制研究表明，Rad50 通过激活 NF-κB 信号通路诱导 HGSOC 的侵袭性。此外，我们在卵巢癌细胞中鉴定出 CARD9 是 Rad50 的相互作用蛋白，并且 Rad50 对 NF-κB 通路的激活依赖于 CARD9。我们的研究结果表明，Rad50 通过在 HGSOC 中激活 NF-κB 表现出致癌特性。
