MicroRNA-34a Mediates the Autocrine Signaling of PAR(2)-Activating Proteinase and Its Role in Colonic Cancer Cell Proliferation

The tumor microenvironment is replete with proteinases. As a sensor of proteinases, proteinase activated receptor 2 (PAR(2)) plays critical roles in tumorigenesis. We showed that PAR(2) and its activating proteinase were coexpressed in different colon cancer cell lines, including HT29. Inactivating proteinase or knockdown of PAR(2) significantly not only reduced cell proliferation in vitro but also inhibited tumorigenicity of HT29 in vivo. In addition, activation of PAR(2) promoted DNA synthesis and upregulated Cyclin D1 activity at both transcriptional and post-transcriptional levels. Further studies showed that miRNA-34a mediated PAR(2)-induced Cyclin D1 upregulation. Inhibition of miR-34a partially abolished the suppression of Cyclin D1 induced by PAR(2) deficiency. In addition, we showed that TGF-β contributed to the regulation of miR-34a by PAR(2). Finally, in colorectal carcinoma samples, upregulation of PAR(2) and downregulation of miR-34a were significantly correlated with grade and lymphomatic metastasis. Our findings provide the first evidence that miRNA mediates autocrine proteinase signaling-mediated cancer cell proliferation.