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

Abstract

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-β-induced EMT process. In conclusion, this is the first study to demonstrate that LINC02470 plays a pivotally regulatory role in the promotion of TGF-β-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.