MicroRNA-34a mediates the autocrine signaling of PAR2-activating proteinase and its role in colonic cancer cell proliferation

• Published in: PloS one Vol. 8; no. 8; p. e72383
• Main Authors: Ma, Yiming, Bao-Han, Wuyun, Lv, Xue, Su, Yuntao, Zhao, Xinhua, Yin, Yongmei, Zhang, Xingmao, Zhou, Zhixiang, MacNaughton, Wallace K, Wang, Hongying
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26.08.2013; Public Library of Science (PLoS)
• Subjects: Autocrine signalling; Base Sequence; Biology; Cancer; Cancer surgery; Cell cycle; Cell growth; Cell Line, Tumor; Cell Proliferation; Colon; Colon cancer; Colonic Neoplasms - genetics; Colonic Neoplasms - pathology; Colorectal cancer; Colorectal carcinoma; Cyclin D1; Cyclin D1 - metabolism; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA Primers; Gene Knockdown Techniques; Genomes; Growth factors; Humans; Laboratories; Lung cancer; Medicine; Metastases; MicroRNAs; MicroRNAs - metabolism; MicroRNAs - physiology; miRNA; Oncology; Polymerase Chain Reaction; Post-transcription; Proteinase; Receptor, PAR-2 - genetics; Receptor, PAR-2 - metabolism; Receptor, PAR-2 - physiology; Ribonucleic acid; RNA; RNA Processing, Post-Transcriptional; Signal Transduction - physiology; Transcription, Genetic; Tumor cell lines; Tumorigenesis; Tumorigenicity; Up-Regulation; Beijing China; Canada; Calgary Alberta Canada; Alberta Canada; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0072383

The tumor microenvironment is replete with proteinases. As a sensor of proteinases, proteinase activated receptor 2 (PAR2) plays critical roles in tumorigenesis. We showed that PAR2 and its activating proteinase were coexpressed in different colon cancer cell lines, including HT29. Inactivating proteinase or knockdown of PAR2 significantly not only reduced cell proliferation in vitro but also inhibited tumorigenicity of HT29 in vivo. In addition, activation of PAR2 promoted DNA synthesis and upregulated Cyclin D1 activity at both transcriptional and post-transcriptional levels. Further studies showed that miRNA-34a mediated PAR2-induced Cyclin D1 upregulation. Inhibition of miR-34a partially abolished the suppression of Cyclin D1 induced by PAR2 deficiency. In addition, we showed that TGF-β contributed to the regulation of miR-34a by PAR2. Finally, in colorectal carcinoma samples, upregulation of PAR2 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.