MiR-29c mediates epithelial-to-mesenchymal transition in human colorectal carcinoma metastasis via PTP4A and GNA13 regulation of β-catenin signaling

We provide novel evidence that miR-29c acted as a switch that regulate epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) in colorectal cancer (CRC) metastasis. Further investigation revealed that miR-29c exert its regulation of EMT-MET switch in CRC metastasis via ERK/GSK-3 beta/beta-catenin and AKT/GSK-3 beta/beta-catenin signaling pathway, respectively.Distant metastasis is the major cause of cancer-related death, and epithelial-to-mesenchymal transition (EMT) has a critical role in this process. Accumulating evidence indicates that EMT can be regulated by microRNAs (miRNAs). miR-29c has been implicated as a tumor suppressor in several human cancers. However, the role of miR-29c in the progression of colorectal cancer (CRC) metastasis remains largely unknown. The expression of miR-29c was examined by qRT-PCR in a cohort of primary CRC (PC) and distant liver metastasis (LM) tissues. A series of in vivo and in vitro assays were carried out in order to elucidate the functions of miR-29c and the molecular mechanisms underlying the pathogenesis of metastatic CRC. miR-29c was markedly downregulated in PCs with distant metastasis and determined to be an independent predictor of shortened patient survival. But LM tissues showed higher levels of miR-29c than that in PC tissues. In CRC cells, miR-29c dramatically suppressed cell migration and invasion abilities in vitro and cancer metastasis in vivo. In addition, miR-29c inhibited EMT and negatively regulated Wnt/beta-catenin signaling pathway. Guanine nucleotide binding protein alpha13 (GNA13) and protein tyrosine phosphatase type IVA (PTP4A) were identified as direct targets of miR-29c, which acted through ERK/GSK3 beta/beta-catenin and AKT/GSK3 beta/beta-catenin pathways, respectively, to regulate EMT. Furthermore, significant associations between miR-29c, its target genes (GNA13 and PTP4A) and EMT markers were validated in both PC and LM tissues. Our findings highlight the important role of miR-29c in regulating CRC EMT via GSK-3 beta/beta-catenin signaling by targeting GNA13 and PTP4A and provide new insights into the metastatic basis of CRC.