血管生成素上调HMGA2表达促非小细胞肺癌上皮-间质转化及转移的机制研究

上皮-间质转化（EMT）是上皮类肿瘤转移发生的早期事件。尽管有研究表明血管生成素（ANG）表达与多种肿瘤转移相关，但迄今为止对于ANG是否具有调控EMT的作用仍不明确。我们在前期研究中发现，高表达ANG能够促进非小细胞肺癌细胞EMT的发生且与非小细胞肺癌转移相关。联系到我们发现调控EMT的重要基因高迁移率族蛋白A2(HMGA2)的5'-非翻译区含有ANG蛋白识别位点，据此我们假设：ANG可通过上调HMGA2表达促进非小细胞肺癌EMT及转移。本项目拟通过ChIP、荧光素酶报告基因实验明确ANG对HMGA2转录的促进作用，并通过细胞功能实验明确ANG通过上调HMGA2表达促非小细胞肺癌EMT的作用；此外，我们还将通过动物模型及临床统计分析明确ANG和HMGA2对非小细胞肺癌转移的促进作用及表达的临床意义。如获成功，将对揭示ANG调控非小细胞肺癌转移的机制及相关的临床诊疗研究起到积极的推动作用。

Increasing evidence supports a role for epithelial-mesenchymal transitions (EMT) in the acquisition of migratory and invasive properties that promote the dissemination of tumor cells and metastasis. Recent reports further demonstrated that angiogenesis growth factors regulate EMT in several cancers. However, the role of angiogenin (ANG) in the regulation of EMT in non-small cell lung cancer (NSCLC) remains unknown..In a recent work we demonstrated that the expresssion of ANG in NSCLC tissuses was significantly higher than that in matched normal tissues,and the the expresssion of ANG was correlated with metastasis in NSCLC patients.In addition, we found that ANG significantly induced the expression of high mobility group AT-hook 2 (HMGA2), which reportedly induces EMT in variety types of tumors.Moreover, over-expression of ANG (or HMGA2) could induce EMT in NSCLC cells.Therefore, we hypothesized that ANG might promote NSCLC EMT and metastasis via angiogenin mediated up-regulation of HMGA2 expression..In this project, we propose to evaluate the role of ANG/HMGA2 in the EMT of ESCC by multiple approaches including bioinformatic analysis, luciferase reporter assay, ChIP, adenovirus- (on lentivirus-) mediated gene delivery, metastasis assay in NOD/SCID mice and clinical investigation. .Conceivably, elucidation of the molecular pathways involved in the EMT of NSCLC by ANG will provide important clues for the development and evaluation of novel anticancer therapies.