Long Noncoding RNA LINC02470 Sponges MicroRNA-143-3p and Enhances SMAD3-Mediated Epithelial-to-Mesenchymal Transition to Promote the Aggressive Properties of Bladder Cancer

Simple Summary Long noncoding RNAs (lncRNAs) were proposed as novel tumor prognostic markers, including for predicting bladder cancer progression, and the competing endogenous RNA (ceRNA) hypothesis conceived an accessible entry point to discover potential lncRNA candidates. This study indicated that LINC02470 promotes bladder cancer cell viability, migration, invasion, and in vivo tumorigenicity by sponging miR-143-3p and consequently rescuing SMAD3 translation to activate the TGF-beta-induced EMT process. These data demonstrate that the LINC02470-miR-143-3p-SMAD3 ceRNA axis directly regulates the major transcription factor of TGF-beta signaling, SMAD3, thereby inducing the EMT process in bladder cancer and enhancing the aggressiveness of bladder cancer cells. Bladder cancer progression and metastasis have become major threats in clinical practice, increasing mortality and therapeutic refractoriness; recently, epigenetic dysregulation of epithelial-to-mesenchymal transition (EMT)-related signaling pathways has been explored. However, research in the fields of long noncoding RNA (lncRNA) and competing endogenous RNA (ceRNA) regulation in bladder cancer progression is just beginning. This study was designed to determine potential EMT-related ceRNA regulation in bladder cancer progression and elucidate the underlying mechanisms that provoke aggressiveness. After screening the intersection of bioinformatic pipelines, LINC02470 was identified as the most upregulated lncRNA during bladder cancer initiation and progression. Both in vitro and in vivo biological effects indicated that LINC02470 promotes bladder cancer cell viability, migration, invasion, and tumorigenicity. On a molecular level, miR-143-3p directly targets and reduces both LINC02470 and SMAD3 RNA expression. Therefore, the LINC02470-miR-143-3p-SMAD3 ceRNA axis rescues SMAD3 translation upon LINC02470 sponging miR-143-3p, and SMAD3 consequently activates the TGF-beta-induced EMT process. In conclusion, this is the first study to demonstrate that LINC02470 plays a pivotally regulatory role in the promotion of TGF-beta-induced EMT through the miR-143-3p/SMAD3 axis, thereby aggravating bladder cancer progression. Our study warrants further investigation of LINC02470 as an indicatively prognostic marker of bladder cancer.

Automated summary

This study demonstrates that LINC02470 plays a crucial role in promoting TGF-beta-induced EMT through the miR-143-3p/SMAD3 axis, thus aggravating bladder cancer progression. The findings suggest that LINC02470 could be a potential prognostic marker for bladder cancer.