State Key Laboratory of Molecular Oncology, Cancer Institute/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
PLoS One. 2013 Aug 26;8(8):e72383. doi: 10.1371/journal.pone.0072383. eCollection 2013.
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.
肿瘤微环境中充满了蛋白酶。蛋白酶激活受体 2 (PAR2) 作为蛋白酶的传感器，在肿瘤发生中发挥着关键作用。我们发现 PAR2 及其激活蛋白酶在不同的结肠癌细胞系（包括 HT29）中共同表达。蛋白酶失活或 PAR2 敲低不仅显著降低了体外细胞增殖，而且还抑制了 HT29 在体内的致瘤性。此外，PAR2 的激活促进了 DNA 合成，并在上转录和后转录水平上调了 Cyclin D1 的活性。进一步的研究表明，miRNA-34a 介导了 PAR2 诱导的 Cyclin D1 上调。PAR2 缺乏引起的 Cyclin D1 抑制作用被 miR-34a 的抑制部分消除。此外，我们表明 TGF-β 促进了 PAR2 对 miR-34a 的调节。最后，在结直肠癌样本中，PAR2 的上调和 miR-34a 的下调与分级和淋巴转移显著相关。我们的研究结果首次提供了证据表明，miRNA 介导了自分泌蛋白酶信号介导的癌细胞增殖。
