MIR133A regulates cell proliferation, migration, and apoptosis by targeting SOX9 in human colorectal cancer cells.

The human microRNA 133A (MIR133A) was identified as a CRC-associated miRNA. It was down-regulated in human CRC tissues. We identified the putative MIR133A1 and A2 target genes by comparing the transcriptome analysis data of MIR133A1 and A2 knock-in cells with the candidate MIR133A target genes predicted by bioinformatics tools. We identified 29 and 33 putative MIR133A and A2 direct target genes, respectively. Among them, we focused on the master transcription regulator gene SRY-box transcription factor 9 (SOX9), which exhibits a pleiotropic role in cancer. We confirmed that SOX9 is a direct target gene of MIR133A by luciferase reporter assay, quantitative RT-PCR, and western blot analysis. Overexpression of MIR133A in CRC cell lines significantly decreased SOX9 and its downstream PIK3CA-AKT1-GSK3B-CTNNB1 and KRAS-BRAF-MAP2K1-MAPK1/3 pathways and increased apoptosis. Furthermore, functional studies reveal that cell proliferation, colony formation, and migration ability were significantly decreased by MIR133A-overexpressed CRC cell lines. Knockdown of SOX9 in CRC cell lines by SOX9 gene silencing showed similar results. We also used a xenograft model to show that MIR133A overexpression suppresses tumor growth and proliferation. Our results suggest that MIR133A regulates cell proliferation, migration, and apoptosis by targeting SOX9 in human colorectal cancer. AJCR