Yu Liying, Luo Yan, Ding Xile, Tang Miaomiao, Gao Huan, Zhang Renfang, Chen Mingfu, Liu Yuchen, Chen Qiongxia, Ouyang Yanli, Wang Xiang, Zhen Hongyan
Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, China.
Cancer Institute, School of Medicine, Jianghan University, Wuhan, China.
Front Oncol. 2023 May 3;13:1146617. doi: 10.3389/fonc.2023.1146617. eCollection 2023.
WD Repeat Domain Phosphoinositide Interacting 2 (WIPI2) is a WD repeat protein that interacts with phosphatidylinositol and regulates multiprotein complexes by providing a b-propeller platform for synchronous and reversible protein-protein interactions assembled proteins. Ferroptosis is a novel iron-dependent form of cell death. It is usually accompanied with the accumulation of membrane lipid peroxides. Our study is to focus on investigating the effect of WIPI2 on the growth and ferroptosis of colorectal cancer (CRC) cells and its potential mechanism.
We analyzed the expression of WIPI2 in colorectal cancer versus normal tissues through The Cancer Genome Atlas (TCGA), and the relationship between clinical traits and WIPI2 expression and prognosis was assessed by univariate and multifactorial cox analysis. Next, we constructed the siRNAs targeting the WIPI2 sequence si-WIPI2 to further investigate the mechanism of WIPI2 in CRC cells through vitro experiments.
Public data from the TCGA platform showed that WIPI2 expression was significantly elevated in colorectal cancer tissues compared to paracancerous tissues, and high WIPI2 expressionpredicted poor prognosis for CRC patients. Moreover, we found that the knockdown of WIPI2 expression could inhibit the growth and proliferation of HCT116 and HT29 cells. Furthermore, we found that the expression level of ACSL4 decreased and that of GPX4 increased when WIPI2 was knocked down, suggesting that WIPI2 can potentially positively regulate CRC ferroptosis. Meanwhile, both NC and si groups were able to further inhibit cell growth activity, as well as increase WIPI2 and decrease GPX4 expression when treated with Erastin, but the rate of cell viability inhibition and the trend of protein changes were more significantly in the NC group than si groups, which indicated that Erastin induced CRC ferroptosis through the WIPI2/GPX4 pathway thereby enhancing the sensitivity of colorectal cancer cells to Erastin.
Our study suggested that WIPI2 had a promotional effect on the growth of colorectal cancer cells, and it also played an important role in the ferroptosis pathway.
WD重复结构域磷脂酰肌醇相互作用蛋白2（WIPI2）是一种WD重复蛋白，可与磷脂酰肌醇相互作用，并通过为组装蛋白的同步和可逆蛋白质-蛋白质相互作用提供β-螺旋桨平台来调节多蛋白复合物。铁死亡是一种新型的铁依赖性细胞死亡形式。它通常伴随着膜脂过氧化物的积累。我们的研究旨在聚焦于探究WIPI2对结直肠癌（CRC）细胞生长和铁死亡的影响及其潜在机制。
我们通过癌症基因组图谱（TCGA）分析了WIPI2在结直肠癌组织与正常组织中的表达情况，并通过单因素和多因素cox分析评估了临床特征与WIPI2表达及预后之间的关系。接下来，我们构建了靶向WIPI2序列的小干扰RNA（siRNA），即si-WIPI2，以通过体外实验进一步探究WIPI2在CRC细胞中的作用机制。
来自TCGA平台的公开数据显示，与癌旁组织相比，结直肠癌组织中WIPI2表达显著升高，且WIPI2高表达预示CRC患者预后不良。此外，我们发现敲低WIPI2表达可抑制HCT116和HT29细胞的生长和增殖。此外，我们发现敲低WIPI2时，ACSL4表达水平降低，GPX4表达水平升高，这表明WIPI2可能正向调节CRC铁死亡。同时，用Erastin处理时，NC组和si组均能进一步抑制细胞生长活性，以及增加WIPI2表达并降低GPX4表达，但NC组的细胞活力抑制率和蛋白质变化趋势比si组更显著，这表明Erastin通过WIPI2/GPX4途径诱导CRC铁死亡，从而增强结直肠癌细胞对Erastin的敏感性。
我们的研究表明，WIPI2对结直肠癌细胞的生长具有促进作用，并且在铁死亡途径中也发挥着重要作用。
