MicroRNA-34a Mediates the Autocrine Signaling of PAR2-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.