胰腺星状细胞与胰腺癌上皮间质转换的正向反馈机制研究及其在胰腺癌化疗耐药中的作用

The present study found that pancreatic stellate cells (PSCs) play an important role in pancreatic cancer development and resistance to chemotherapy.However, the molecular mechanisms is still controversial. Our previous study demonstrated that there was closed relationship between PSCs and pancreatic cancer cells. The project is designed to culture and identify the PSCs, and to observe the interaction between PSCs and epithelioid pancreatic cancer cell (EC) or mesenchymal pancreatic cancer cell (MC), and to explore the mechanism that PSCs induce the epithelial mesenchymal transition (EMT) of pancreatic cancer cells. Collect the EC and MC supernatant to culture PSCs, and observe effect of pancreatic cancer cells which undergo EMT on activation, proliferation and secretion of PSCs. Construct the specific siRNAs for CXCR-4 or CXCR-7 to investigate the role of SDF-1/CXCR-4 (CXCR-7) signaling axis in mediating interatioin between pancreatic stellate cell and pancreatic cancer cells. In order to explore the mechanism that PSCs mediate pancreatic cancer epithelial mesenchymal transition and resistance to chemotherapy, expression of SDF-1/CXCR-4 (CXCR-7) signaling axis is regulated and gemcitabine is added to PSCs supernatant for culturing pancreatic cancer cells. Implementation of the project will clarify the role of PSCs in occurrence and development of pancreatic cancer and chemotherapy resistance, and provide a new therapeutic strategy for the treatment of pancreatic cancer.

目前研究发现胰腺星状细胞（PSCs）是胰腺癌发生发展及化疗耐药中的关键因素，但其机制不明。本课题组前期研究提示PSCs与胰腺癌细胞两者存在密切的相关作用关系。本课题拟培养并鉴定胰腺星状细胞（PSCs），观察PSCs与上皮样胰腺癌细胞（EC）和间质样胰腺癌细胞（MC）相互作用关系，探讨PSCs诱导胰腺癌发生上皮间质转换的相关机制。收集EC和MC上清液培养PSCs，观察上皮间质转换的胰腺癌对PSCs活化、增殖及分泌功能影响。构建针对CXCR-4或CXCR-7的特异性siRNAs，探讨SDF-1/CXCR-4（CXCR-7）信号轴在介导胰腺星状细胞-胰腺癌上皮间质转换中的作用。调控SDF-1/CXCR-4（CXCR-7）信号轴表达水平，同时探讨PSCs在介导胰腺癌上皮间质转换及化疗耐药中的具体分子机制。本项目的实施可明确PSCs在胰腺癌中的作用及分子机制，为胰腺治疗提供新的治疗策略。

研究发现胰腺星状细胞（PSCs）是胰腺癌侵袭转移及化疗耐药过程中的关键因素，但其机制目前尚不明确。本课题组前期研究提示PSCs与胰腺癌细胞两者存在密切的相关作用关系。团队利用细胞及动物多层次实验，系统性探究了PSCs对胰腺癌细胞的作用及相关机制。通过该项目研究，团队成功培养并鉴定了PSCs，证实PSCs可以显著促进胰腺癌细胞的增殖、迁移、侵袭，诱导胰腺癌细胞EMT过程，并可诱导胰腺癌化疗耐药。进一步探究其作用机制，发现PSCs可分泌HGF，作为HGF在胰腺癌细胞中的受体分子，c-Met是PSCs诱导的胰腺癌细胞迁移侵袭过程中的关键分子，该分子促进胰腺癌细胞迁移侵袭的作用受P53/P21的负性调控，而survivin是HGF/c-Met通路的关键下游作用分子；此外，PI3K/Akt通路在HGF/c-Met诱导的胰腺癌细胞EMT及化疗耐药过程中发挥关键作用。该项目明确了PSCs对胰腺癌细胞增殖、迁移、侵袭等恶行生物学行为的作用，阐明了其诱导EMT及促进化疗耐药的具体机制，为从肿瘤微环境角度出发治疗胰腺癌提供了理论基础。