title: MicroRNA-34a mediates the autocrine signaling of PAR2-activating proteinase and its role in colonic cancer cell proliferation.
abstract: 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.
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Ma
authors.forename: Wuyun
authors.initials: W
authors.lastname: Bao-Han
authors.forename: Xue
authors.initials: X
authors.lastname: Lv
authors.forename: Yuntao
authors.initials: Y
authors.lastname: Su
authors.forename: Xinhua
authors.initials: X
authors.lastname: Zhao
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Yin
authors.forename: Xingmao
authors.initials: X
authors.lastname: Zhang
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Zhou
authors.forename: Wallace K
authors.initials: WK
authors.lastname: MacNaughton
authors.forename: Hongying
authors.initials: H
authors.lastname: Wang
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology*; D019938:Cyclin D1 / Q000378:metabolism; D017931:DNA Primers; D055785:Gene Knockdown Techniques; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism / Q000502:physiology*; D016133:Polymerase Chain Reaction; D012323:RNA Processing, Post-Transcriptional; D044464:Receptor, PAR-2 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D017931:DNA Primers; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D044464:Receptor, PAR-2; D019938:Cyclin D1