Wei Wen-Su, Wang Ning, Deng Min-Hua, Dong Pei, Liu Jian-Ye, Xiang Zhen, Li Xiang-Dong, Li Zhi-Yong, Liu Zhen-Hua, Peng Yu-Lu, Li Zhen, Jiang Li-Juan, Yao Kai, Ye Yun-Lin, Lu Wen-Hua, Zhang Zhi-Ling, Zhou Fang-Jian, Liu Zhuo-Wei, Xie Dan, Yu Chun-Ping
State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, No. 651, Dongfeng Road East, Guangzhou, PR China; Department of Urology, Sun Yat-Sen University Cancer Center, No. 651, Dongfeng Road East, Guangzhou, PR China.
Department of Urology, Xiangya Third Hospital, No. 106, 2nd Zhongshan Road, Changsha, PR China.
Redox Biol. 2021 Nov 27;48:102201. doi: 10.1016/j.redox.2021.102201.
Reactive oxygen species (ROS) which are continuously generated mainly by mitochondria, have been proved to play an important role in the stress signaling of cancer cells. Moreover, pentatricopeptide repeat (PPR) proteins have been suggested to take part in mitochondrial metabolism. However, the mechanisms integrating the actions of these distinct networks in urothelial carcinoma of the bladder (UCB) pathogenesis are elusive. In this study, we found that leucine rich pentatricopeptide repeat containing (LRPPRC) was frequently upregulated in UCB and that it was an independent prognostic factor in UCB. We further revealed that LRPPRC promoted UCB tumorigenesis by regulating the intracellular ROS homeostasis. Mechanistically, LRPPRC modulates ROS balance and protects UCB cells from oxidative stress via mt-mRNA metabolism and the circANKHD1/FOXM1 axis. In addition, the SRA stem-loop interacting RNA binding protein (SLIRP) directly interacted with LRPPRC to protect it from ubiquitination and proteasomal degradation. Notably, we showed that LRPPRC modulated the tumorigenesis of UCB cells in a circANKHD1-FOXM1-dependent manner. In conclusion, LRPPRC exerts critical roles in regulating UCB redox homeostasis and tumorigenesis, and is a prognostic factor for UCB; suggesting that LRPPRC may serve as an exploitable therapeutic target in UCB.
活性氧（ROS）主要由线粒体持续产生，已被证明在癌细胞的应激信号传导中起重要作用。此外，已表明五肽重复序列（PPR）蛋白参与线粒体代谢。然而，在膀胱尿路上皮癌（UCB）发病机制中整合这些不同网络作用的机制尚不清楚。在本研究中，我们发现富含亮氨酸的五肽重复序列蛋白（LRPPRC）在UCB中经常上调，并且它是UCB的一个独立预后因素。我们进一步揭示，LRPPRC通过调节细胞内ROS稳态促进UCB肿瘤发生。机制上，LRPPRC通过线粒体mRNA代谢和circANKHD1/FOXM1轴调节ROS平衡并保护UCB细胞免受氧化应激。此外，SRA茎环相互作用RNA结合蛋白（SLIRP）直接与LRPPRC相互作用以保护其免受泛素化和蛋白酶体降解。值得注意的是，我们表明LRPPRC以circANKHD1-FOXM1依赖性方式调节UCB细胞的肿瘤发生。总之，LRPPRC在调节UCB氧化还原稳态和肿瘤发生中发挥关键作用，并且是UCB的预后因素；这表明LRPPRC可能作为UCB中一个可利用的治疗靶点。
