1385

CREB1

Emerging evidence has suggested that microRNAs (miRNAs) have an important role in tumor development and progression by regulating diverse cellular pathways. Here we describe the function and regulation network of miR-433 in bladder cancer (BCa). miR-433 is frequently downregulated in BCa tissues compared with adjacent non-cancerous tissues. Epigenetic mechanisms may be involved in the regulation of miR-433 expression. Enforced expression of miR-433 significantly inhibits proliferation, colony formation, migration, and invasion in BCa cells. In addition, miR-433 inhibits the epithelial-mesenchymal transition (EMT) in BCa cells by regulating c-Met/Akt/GSK-3beta/Snail signaling pathway. Both c-Met and CREB1 are downstream target genes of miR-433. CREB1 can also indirectly regulate c-Met/Akt/GSK-3beta/Snail signaling via MITF. Furthermore, CREB1 expression is an independent prognostic factor for overall survival in patients with BCa. Finally, there appears to exist a reciprocal regulation between c-Met and miR-433/miR-409-3p. Taken together, this study reveals that miR-433-c-MET/CREB1-Akt/GSK-3beta/Snail signaling is critical to EMT in BCa. Targeting the pathway described here may open up new prospects to restrict metastatic progression of BCa.

A hallmark of aberrant activation of the Wnt/beta-catenin signaling pathway has been observed in most colorectal cancers (CRC), but little is known about the role of non-coding RNAs regulated by this pathway. Here, we found that miR-150 was the most significantly upregulated microRNA responsive to elevated of Wnt/beta-catenin signaling activity in both HCT116 and HEK293T cells. Mechanistically, the beta-catenin/LEF1 complex binds to the conserved TCF/LEF1-binding element in the miR-150 promoter and thereby transactivates its expression. Enforced expression of miR-150 in HCT116 cell line transformed cells into a spindle shape with higher migration and invasion activity. miR-150 markedly suppressed the CREB signaling pathway by targeting its core transcription factors CREB1 and EP300. Knockdown of CREB1 or EP300 and knockout of CREB1 by CRISPR/Cas9 phenocopied the epithelial-mesenchymal transition (EMT) observed in HCT116 cells in response to miR-150 overexpression. In summary, our data indicate that miR-150 is a novel Wnt effector that may significantly enhance EMT of CRC cells by targeting the CREB signaling pathway.