Fan Jiaxin, Zhao Yan, Yuan Hongling, Yang Jinxiao, Li Ting, He Zhenting, Wu Xiaohou, Luo Chunli
Key Laboratory of Diagnostics Medicine Designated by The Ministry of Education, Chongqing Medical University Chongqing, China.
Department Blood of Transfusion, Affiliated Hospital of Jining Medical University Shandong, China.
Am J Cancer Res. 2020 Aug 1;10(8):2319-2336. eCollection 2020.
Whole human genome microarray was performed to identify the potential molecular mechanisms associated with phospholipase C epsilon (PLCε). Gene Ontology, Kyoto Encyclopedia of Genes, and Genomes pathway analysis revealed that differentially expressed genes were significantly enriched in DNA repair-related pathways. Gene expression of PLCε, exonuclease 1 (EXO1), and ATM serine/threonine kinase (ATM) was significantly higher in 72 bladder cancer (BCa) tissue samples than in 24 samples of adjacent nonneoplastic tissue. The protein levels of PLCε and EXO1 showed appositive correlation in clinical bladder samples. Subsequent experiments showed that PLCε expression facilitated DNA repair in BCa by regulating ATM/EXO1 signaling. Additionally, we found that microRNA-145 is an antagonist of PLCε in T24 cells by directly targeting the 3'untranslated region of PLCε mRNA. Notably, microRNA-145 overexpression significantly increased the sensitivity to cisplatin, consistent with its PLCε silencing effect in BCa cells. Taken together, these findings reveal a novel physiological role for PLCε in DNA repair-related pathways with significant implications for the understanding of BCa biology.
进行全人类基因组微阵列分析以确定与磷脂酶Cε（PLCε）相关的潜在分子机制。基因本体论、京都基因与基因组百科全书通路分析表明，差异表达基因在DNA修复相关通路中显著富集。在72例膀胱癌（BCa）组织样本中，PLCε、核酸外切酶1（EXO1）和ATM丝氨酸/苏氨酸激酶（ATM）的基因表达显著高于24例相邻非肿瘤组织样本。在临床膀胱样本中，PLCε和EXO1的蛋白水平呈正相关。后续实验表明，PLCε表达通过调节ATM/EXO1信号促进BCa中的DNA修复。此外，我们发现微小RNA-145通过直接靶向PLCε mRNA的3'非翻译区，在T24细胞中是PLCε的拮抗剂。值得注意的是，微小RNA-145的过表达显著增加了对顺铂的敏感性，这与其在BCa细胞中的PLCε沉默效应一致。综上所述，这些发现揭示了PLCε在DNA修复相关通路中的新生理作用，对理解BCa生物学具有重要意义。
