Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University and the Key Clinical Laboratory of Henan Province, Zhengzhou, China.
Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China.
Exp Cell Res. 2024 Oct 1;442(2):114271. doi: 10.1016/j.yexcr.2024.114271. Epub 2024 Sep 30.
Metabolic reprogramming is a hallmark of cancer, and abnormal lipid metabolism is associated with drug resistance in bladder cancer cells. The long noncoding RNA (lncRNA) UCA1 is overexpressed in bladder cancer, but its functional contribution to lipid metabolism remains uncharacterized. In this study, we demonstrated that lncRNA UCA1 inhibits epirubicin-induced cell apoptosis by supporting abnormal lipid metabolism in bladder cancer cells. Mechanistically, lncRNA UCA1 promotes lipid accumulation in vitro and in vivo by upregulating PPARα mRNA and protein expression, which is mediated by miR-30a-3p. Knockdown of lncRNA UCA1 increased epirubicin-induced apoptosis via miR-30a-3p/PPARα and downstream p-AKT/p-GSK-3β/β-catenin signaling. Furthermore, mixed free fatty acids upregulated lncRNA UCA1 expression by promoting recruitment of the transcription factor RXRα to the lncRNA UCA1 promoter. These findings were verified in a mouse xenograft model and are consistent with the expression patterns in human bladder cancer patients. Overall, these findings establish the role of lncRNA UCA1 in lipid metabolism and bladder cancer cell resistance to epirubicin, suggesting that lncRNA UCA1 may serve as a candidate target for enhancing bladder cancer chemotherapy.
代谢重编程是癌症的一个标志，异常的脂质代谢与膀胱癌细胞的耐药性有关。长链非编码 RNA (lncRNA) UCA1 在膀胱癌中过表达，但它对脂质代谢的功能贡献仍未被阐明。在这项研究中，我们证明 lncRNA UCA1 通过支持膀胱癌细胞异常的脂质代谢来抑制表柔比星诱导的细胞凋亡。在机制上，lncRNA UCA1 通过上调 PPARα mRNA 和蛋白表达，在体外和体内促进脂质积累，这是由 miR-30a-3p 介导的。lncRNA UCA1 的敲低通过 miR-30a-3p/PPARα 和下游 p-AKT/p-GSK-3β/β-catenin 信号增加表柔比星诱导的细胞凋亡。此外，混合游离脂肪酸通过促进转录因子 RXRα 募集到 lncRNA UCA1 启动子来上调 lncRNA UCA1 的表达。这些发现在小鼠异种移植模型中得到了验证，与人类膀胱癌患者的表达模式一致。总的来说，这些发现确立了 lncRNA UCA1 在脂质代谢和膀胱癌细胞对表柔比星耐药性中的作用，表明 lncRNA UCA1 可能作为增强膀胱癌化疗的候选靶点。
