Proteinase-activated Receptor 2 Promotes Cancer Cell Migration through RNA Methylation-mediated Repression of miR-125b

Proteinase activated-receptor 2 (PAR(2)) participates in cancer metastasis promoted by serine proteinases. The current study aimed to test the molecular mechanism by which PAR(2) promotes cancer cell migration. In different cancer cells, activation of PAR(2) by activating peptide (PAR(2)-AP) dramatically increased cell migration, whereas knock down of PAR(2) inhibited cellular motility. The PAR(2) activation also repressed miR-125b expression while miR-125b mimic successfully blocked PAR(2)-induced cell migration. Moreover, Grb associated-binding protein 2 (Gab2) was identified as a novel target gene of miR-125b and it mediated PAR(2)-induced cell migration. The correlation of PAR(2) with miR-125b and Gab2 was further supported by the findings obtained from human colorectal carcinoma specimens. Remarkably, knock down of NOP2/Sun domain family, member 2 (NSun2), a RNA methyltransferase, blocked the reduction in miR-125b induced by PAR(2). Furthermore, PAR(2) activation increased the level of N-6-methyladenosine (m(6)A)-containing pre-miR-125b in NSun2-dependent manner. Taken together, our results demonstrated that miR-125b mediates PAR(2)-induced cancer cell migration by targeting Gab2 and that NSun2-dependent RNA methylation contributes to the down-regulation of miR-125b by PAR(2) signaling. These findings suggest a novel epigenetic mechanism by which microenvironment regulates cancer cell migration by altering miRNA expression.