胰腺癌的预后极差，早期的研究发现了一些在胰腺癌发生发展中起了重要作用的关键基因如K-ras，p16，p53，DPC4/Smad4，Cyclin D1及p21等。然而，在过去的30年，胰腺癌的临床疗效却并没有实质性的提升。因此，寻找新的胰腺癌治疗靶点具有迫切的临床意义。申请人通过人全基因组RNAi筛选发现MLL4基因可能是一个新的胰腺癌治疗靶点。前期研究发现：MLL4在胰腺癌中具有显著的致癌活性；通过基因芯片，我们找到了MLL4在胰腺癌中直接调控的下游靶标; MLL4可能通过H3K4甲基化来调控下游基因表达。在本课题中，我们将深入研究MLL4在胰腺癌发生发展中的作用及其分子机制；并解析MLL4通路在胰腺癌中的临床意义。此外，我们也将研究RNAi筛选出来的其他相关基因如GRIN2D、SNRK、ADH5等在胰腺癌中的功能。本课题的实验结果将为发展新的抗胰腺癌疗法提供理论基础。

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant cancers worldwide. Its 5-year survival rate is less than 5%, because most patients have already developed to the advanced stage of local invasion or distant metastasis once diagnosed, and missed the chances of curable surgical resection. We aimed at identifying novel therapeutic targets in PDAC. We performed genome-wide RNAi screening in PDAC xenografted mice model. MLL4 was identified as a potential oncogene highly associated with PDAC. The oncogenic activity of MLL4 was validated by our subsequent in vitro cell model and in vivo mouse model. We also identified the downstream targets of MLL4 by gene expression microarray. We found that a series of cancer associated genes were regulated by MLL4 through H3K4 methylation. In this proposal, we will further characterize the oncogenic roles of MLL4 in PDAC and delineate the underlying mechanisms. We will also characterize the function of the other genes such as GRIN2D、SNRK and ADH5 that were identified by RNAi screening in PDAC. Knowledge gained from this project will pave the way for the development of novel therapeutics for PDAC.