MicroRNA-146b Overexpression Promotes Human Bladder Cancer Invasion via enhancing ETS2-mediated mmp2 mRNA Transcription

Abstract Although microRNAs have been validated to play prominent roles in the occurrence and development of human bladder cancer (BC), alterations and function of many miRNAs in BC invasion are not fully explored yet. MiR-146b was reported to be a tumor suppressor or oncomiRNA in various types of cancer. However, its accurate expression, function, and mechanism in BC remain unclear. Here, we discovered that miR-146b was frequently upregulated in BC tissues compared with adjacent non-cancerous tissues. Inhibition of miR-146b resulted in a significant inhibitory effect on the invasion of BC cells by reducing mmp2 mRNA transcription and protein expression. We further demonstrated that knockdown of miR-146b attenuated ETS2 expression, which was the transcription factor of MMP2. Moreover, mechanistic studies revealed that miR-146b inhibition stabilized auf1 mRNA by directly binding to its mRNA 3'-UTR, further reduced ets2 mRNA stability, finally inhibiting mmp2 transcription and attenuating BC invasion abilities. The identification of the miR-146b/AUF1/ETS2/MMP2 mechanism for promoting BC invasion provides significant insights into understanding the nature of BC metastasis. Targeting the pathway described here may be a novel approach for inhibiting invasion and metastasis of BC.