胰腺星形细胞诱导的AREG/EGFR信号通路对胰腺癌细胞生物学行为的影响与机制研究

In recent years, a new experimental model that explores the interactions between pancreatic stellate cell(PSC) and pancreatic cancer cells has been used to develop therapeutics for pancreatic cancer.However,the mechanism remains little known. In our previous study,we analyzed the differential gene expression patterns by cDNA microarray analysis and mRNA-Seq between activated and quiescent PSC.We found that SDF-1,AREG and ADAM were significantly upregulated in activated PSC compared those in quiescent PSC.And then the effects of paracrine SDF-1/CXCR4 signaling from PSC on Gem chemoresistance in pancreatic cancer cells were further discussed in our previous works.In this study, we choose AREG/EGFR axis as the potential mediator between PSC and pancreatic cancer cells.Our study aims to explore the effects of PSC-induced ARGE/EGFR axis on pancreatic cancer cell biology.We will further investigate the upstream regulation of ectodomain shedding of AREG and the downstream intracellular signaling activated by PSC-induced AREG/EGFR axis in pancreatic cancer cells. In this study, we will explore the pantogenesis of pancreatic cancer from a new perspective of PSC.Our study will provide new insights into pancreatic cancer research. Finally,we expect to find potential biomarkers and therapeutic targets for pancreatic cancer.

胰腺星形细胞（PSC）与胰腺癌细胞之间相互作用的研究是胰腺癌研究的新模式和突破点，但两种细胞间相互作用的具体分子机制目前仍知之甚少。我们在前期研究中通过基因芯片及RNA测序对比了活化与静止状态PSC中mRNA表达谱的差异，发现活化状态的PSC中SDF-1、AREG/EGFR通路上游调节因子ADAM均明显高表达，并深入探讨了PSC通过旁分泌SDF-1/CXCR4信号通路对胰腺癌细胞化疗耐药的影响机制。本课题重点研究AREG/EGFR通路，建立PSC与胰腺癌细胞的共培养体系，探讨PSC诱导的AREG/EGFR信号通路对胰腺癌细胞生物学行为的影响，并探索PSC中ADAM及SDF-1、CXCR4 等上游信号对AREG胞外区脱落的调节作用，继而探讨AREG/EGFR信号通路激活的胰腺癌细胞内下游信号机制。本研究将从PSC这个新的视角揭示胰腺癌的发病与耐药机制，为胰腺癌治疗提供新的研究思路和治疗靶点。

胰腺癌是目前恶性程度极高的消化系统恶性肿瘤，近年来胰腺癌患者死亡率不降反升，手术及放化疗并不能改善患者的预后，因此新的生物学治疗靶点是目前众多学者关注和研究的重中之重。肿瘤微环境是近年来的热点，而胰腺癌肿瘤实质中70%为间质成分，最主要的成分为胰腺星形细胞（pancreatic stellate cells，PSCs），目前多项研究证实PSCs并不仅仅只是形成肿瘤微环境。本项目另辟蹊径，从胰腺癌间质中最重要的细胞—PSCs入手，证明PSC分泌的一种细胞因子—AREG可以与胰腺癌细胞（Pancreatic cancer cells， PCCs）上的EGFR结合，进一步激活EGFR\ERK\NF-κB信号通路，诱导PCCs发生EMT，进而影响胰腺癌患者的预后。该研究通过临床病理分析证实AREG是胰腺癌预后的独立预测因素，分子生物学实验证实AREG可以与EGFR结合从而发挥下游的功能。该项研究证实了PSC可以分泌细胞因子AREG调控PCCs的临床生物学行为，进而推断PSCs可以分泌多种细胞因子调控PCCs生物学功能，说明胰腺癌间质在胰腺癌发生发展中具有重要的作用，为胰腺癌肿瘤微环境提供了新的证据。本项研究着重探讨了细胞外因子AREG对PCCs的作用及具体的分子生物学机制，并且证实AREG是胰腺癌的独立预后因素，为胰腺癌诊疗提供了新的潜在靶点。