目的:本研究探讨了POU6F1和lncRNA-CASC2对胃癌细胞铁凋亡的影响及其机制。
方法:检测用erastin和RSL3处理的GC细胞的铁凋亡,活性氧(ROS)水平,和细胞活力。还测量了POU6F1、lncRNA-CASC2、SOCS2和铁凋亡相关分子(GPX4和SLC7A11)的表达水平。确定了POU6F1、lncRNA-CASC2、FMR1、SOCS2和SLC7A11之间的规则。建立皮下肿瘤模型,免疫组化法检测Ki-67、SOCS2和GPX4的表达。
结果:POU6F1和lncRNA-CASC2表达降低的GC患者生存率较低。过表达POU6F1或lncRNA-CASC2降低GC细胞增殖和GSH水平,除了增加总铁,Fe2+,MDA,和ROS水平。POU6F1直接与lncRNA-CASC2启动子结合以促进其转录。LncRNA-CASC2可以靶向FMR1并增加SOCS2mRNA的稳定性以促进SLC7A11泛素化降解并激活铁凋亡信号传导。SOCS2敲低抑制GC细胞的铁凋亡敏感性,逆转POU6F1和lncRNA-CASC2过表达对GC细胞铁凋亡的影响。
结论:转录因子POU6F1直接与lncRNA-CASC2启动子结合以促进其表达,而上调的lncRNA-CASC2通过靶向FMR1增加SOCS2的稳定性和表达,从而抑制SLC7A11信号传导以促进GC细胞的铁凋亡并抑制GC进展。
This study investigated the effect and mechanism of POU6F1 and lncRNA-CASC2 on ferroptosis of gastric cancer (GC) cells.
GC cells treated with erastin and RSL3 were detected for ferroptosis, reactive oxygen species (ROS) level, and cell viability. The expression levels of POU6F1, lncRNA-CASC2, SOCS2, and ferroptosis-related molecules (GPX4 and SLC7A11) were also measured. The regulations among POU6F1, lncRNA-CASC2, FMR1, SOCS2, and SLC7A11 were determined. Subcutaneous tumor models were established, in which the expressions of Ki-67, SOCS2, and GPX4 were detected by immunohistochemistry.
GC patients with decreased expressions of POU6F1 and lncRNA-CASC2 had lower survival rate. Overexpression of POU6F1 or lncRNA-CASC2 decreased cell proliferation and GSH levels in GC cells, in addition to increasing total iron, Fe2+, MDA, and ROS levels. POU6F1 directly binds to the lncRNA-CASC2 promoter to promote its transcription. LncRNA-CASC2 can target FMR1 and increase SOCS2 mRNA stability to promote SLC7A11 ubiquitination degradation and activate ferroptosis signaling. Knockdown of SOCS2 inhibited the ferroptosis sensitivity of GC cells and reversed the effects of POU6F1 and lncRNA-CASC2 overexpression on ferroptosis in GC cells.
Transcription factor POU6F1 binds directly to the lncRNA-CASC2 promoter to promote its expression, while upregulated lncRNA-CASC2 increases SOCS2 stability and expression by targeting FMR1, thereby inhibiting SLC7A11 signaling to promote ferroptosis in GC cells and inhibit GC progression.