海洋微生物候选药物Wentilactone A抗非小细胞肺癌直接作用靶点的鉴定及其靶点后效应机制研究

非小细胞肺癌（NSCLC）是全球最常见的肿瘤之一，具有恶性程度高，易转移、易复发的特点，而目前临床上仍然缺乏安全、高效的抗NSCLC药物。课题组前期已完成了海洋微生物来源新化合物Wentilactone A（WA）的成药性评价，证实WA抗NSCLC疗效显著且毒副作用小。全基因组表达芯片结果显示WA显著下降AKR1C1基因与相应蛋白表达，过表达该基因能逆转WA的作用。本研究拟整合现代药物靶标发现、鉴定新技术，从分子—细胞—整体水平，明确WA抑制NSCLC作用的直接靶点以及靶点后效应（信号通路），构建影响AKR1C1基因表达的转录因子调控互作网络图，揭示关键的转录调控因子。通过本项目的研究，将深入阐明WA抗NSCLC的分子机制，并为研究与开发新的抗NSCLC药物提供新靶点。

Non-small cell lung cancer (NSCLC) is the most frequent malignant tumor in the world, with the characteristics of high metastasis as well as high recurrence. Currently it still lacks safe and effective anti-NSCLC chemotherapeutic drugs clinically. In the previous works, we have completed the drug evaluation of Wentilactone (WA), a new compound isolated from a marine microorganism. The results showed WA exhibited a significant anti-NSCLC effect both in vitro cell culture and in vivo tumor transplanted nude-mouse model. However, its mechanisms are still not clear and remain to be elucidated. Genome-wide expression chip analysis showed a significant reduction of AKR1C1 gene expression in WA-treated cells, and over-expression of the gene could reverse the effect of WA. Through integrating the modern technology in discovery of drug targets, this study aims to discover the direct targets and to identify the post-target signaling pathway elicited by WA. In the meanwhile, we will also construct the regulation network that influence AKR1C1 gene expression, try to explore the key transcription factors involved. The completion of the present work will further elucidate the mechanisms of anti-NSCLC effect of WA, and hope to provide the new targets for NSCLC chemotherapeutic drug rational design.