ERS微环境中DNA甲基化富集内质网分子伴侣GRP78影响胰腺癌侵袭转移的实验研究

申请人目前承担的青年项目研究发现: (1) 内质网应激（endoplasmic reticulum stress，ERS）微环境是导致胰腺癌发生侵袭转移的重要原因; (2) ERS通过上调DNA甲基化转移酶DNMT3a，使抑癌分子miRNA-34b沉默、促癌分子MBD1上调，二者共同促进胰腺癌侵袭转移; (3) ERS环境下miR-34b的沉默和MBD1的上调，除了直接影响胰腺癌侵袭转移以外，其本身也可对内质网分子伴侣GRP78起到双重富集作用，并形成反馈机制，正向调节ERS状态。本课题基于此，研究ERS微环境中，DNA甲基化双向调控miR-34b与MBD1，富集GRP78，正反馈ERS，导致胰腺癌细胞不断获得更高侵袭转移潜能的具体机制与过程，为胰腺癌易转移的生物学特性提供理论依据，并为临床干预建立有效的靶点。

Our works underway supported by NSFC 2010 demonstrate that (1) ER stress microenvironment contributes to pancreatic cancer invasion and metastasis; (2) DNA methylation attributed by ER stress promotes the invasion and metastasis of pancreatic cancer through both silence of tumor suppressing miRNA-34b and up-regulation of oncogenic MBD1; (3) Apart from the direct effects on the pancreatic cancer metastasis, silence of miRNA-34b and activation of MBD1 in ER stress microenvironment result in a “double enrichment” of ER chaperone GRP78, which leads to a positive feedback loop to strengthen ER stress response. Accordingly, this study aims to elaborate the process that DNA methylation triggered by ER stress microenvironment not only suppresses miR-34b but activates MBD1, which both enrich the expression of GRP78, then build a positive ER stress feedback loop, whereby pancreatic cancer cells keep on acquiring higher invasive and metastatic properties. This study will provide us a novel insight into pancreatic cancer malignant profiles as well as establish an effective clinical intervention target.