Klf4/MSI2信号通路在胰腺癌神经浸润中的作用及机制研究

项目名称： Klf4/MSI2信号通路在胰腺癌神经浸润中的作用及机制研究

项目编号： No.81502083

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 郭坤

作者单位： 西安交通大学

项目金额： 18万元

中文摘要： 神经浸润（PNI）是胰腺癌术后复发、预后差的重要原因，但其机制尚未阐明。研究表明MSI2在肿瘤进展及神经发育中发挥作用，Klf4在胰腺癌中表达缺失，且其与神经轴突的再生相关。课题组前期研究发现MSI2在胰腺癌中高表达，且与PNI密切相关，胰腺癌中MSI2与Klf4表达呈负相关，MSI2基因启动子区域存在Klf4结合位点。我们推测Klf4与MSI2共同参与胰腺癌PNI，Klf4参与了MSI2基因的转录调控，Klf4/MSI2信号通路及下游基因对胰腺癌PNI发挥重要调控作用。为证实这一假说，我们将构建肿瘤细胞体内外PNI模型，采用分子生物学、流式细胞仪、激光共聚焦、qRT-PCR、Western blot等方法从组织学、细胞学、分子生物学等水平，通过双向调节MSI2蛋白，探究Klf4/MSI2信号通路在胰腺癌PNI中的作用。本课题将从新的视觉阐明胰腺癌PNI的发病机制，为胰腺癌防治提供新依据。

中文关键词： 胰腺外分泌肿瘤；神经浸润；信号通路；MSI2

英文摘要： Perineural invasion (PNI) usually causes cancer pain and recurrence of postoperative pancreatic cancer patients, but its pathogenesis is unclear. Previous study showed that MSI2 played a role in tumor progression and neural development, and low expression of Klf4 in pancreatic carcinoma, also absence of Klf4 expression was correlation with axonal regeneration. Our preliminary study demonstrated that MSI2 expression was elevated in pancreatic cancer cells and tissues. High MSI2 expression is closely related to the degree of PNI. Also, Klf4 binding sites exist in the promoter region of MSI2 gene. And MSI2 gene promoter activity was significantly decreased in pancreatic cancer cells after Klf4 gene transfection. Thus we hypothesized that: both Klf4 and MSI2 participated in the process of PNI in pancreatic cancer, Klf4 involved in the transcriptional regulation of MSI2 gene, Klf4/MSI2 signaling pathway plays an important regulatory role in PNI of pancreatic cancer. In this study, we try to explore the transcriptional regulation mechanism of Klf4 on MSI2, as well as the impact of Klf4/MSI2 signaling pathway on the development of PNI from the histological, cellular and molecular levels, by a variety of ways, including construction of PNI model in vitro and in vivo, flow cytometry, laser scanning confocal microscope, qRT-PCR, Western blot etc. This project will reveal the role of Klf4/MSI2 signaling pathway in PNI process, and will provide a new idea and target for treatment of pancreatic cancer.

英文关键词： pancreatic cancer;perineural invasion;signaling pathway;MSI2