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

Cheng-Shuo Huang,Ming-Fong Yee,Cheng-Ping Yu,Ying-Si Wu,Dah-Shyong Yu,Jar-Yi Ho,Chen-Hua Tsai

doi:10.3390/cancers14040968

Abstract

Simple SummaryLong 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-β-induced EMT process. These data demonstrate that the LINC02470–miR-143-3p–SMAD3 ceRNA axis directly regulates the major transcription factor of TGF-β 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-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.

Highlights

Bladder cancer is the seventh most common cancer worldwide and the second most common malignancy of urological organs
Our findings demonstrate that the LINC02470–miR-143-3p–SMAD3 competing endogenous RNA (ceRNA) axis directly regulates the major transcription factor of TGF-β signaling, SMAD3, thereby inducing the Epithelial-to-mesenchymal transition (EMT) process in bladder cancer and enhancing the aggressiveness of bladder cancer cells
To identify potential long noncoding RNA (lncRNA) involved in bladder cancer progression, lncRNA screening targets were extracted from the lnCAR database

Summary

Introduction

Bladder cancer is the seventh most common cancer worldwide and the second most common malignancy of urological organs. A high frequency of relapse and poor clinical outcomes of bladder cancer are associated with tumor progression to muscle invasion, distant metastasis, and therapeutic refractoriness [3–6]. It is necessary to elucidate the mechanisms that underlie bladder cancer progression. Epithelial-to-mesenchymal transition (EMT) is a multistep process in which epithelial cells lose their epithelial properties and gain mesenchymal properties, such as migration and invasion abilities [7]. Accumulated evidence indicates that EMT is associated with cancer cell invasion and metastasis in various malignancies [8,9]. The EMT process has been found to be comprehensively involved in the relapse, progression, metastasis, and therapeutic refractoriness of bladder cancer [10,11]; the detailed regulation of each EMT factor is far from understood. Epigenetic regulation of EMT-related signaling pathways has been addressed on bladder cancer, especially the interactions of noncoding RNAs [12]

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