胰腺星形细胞旁分泌的Asporin对胰腺癌细胞上皮-间质转化及侵袭迁移能力的影响与机制探索

Asporin is a recently identified extracellular matrix (ECM) protein. It is predominantly expressed in cancer-associated fibroblasts (CAFs), and exerts its paracrine effects on pancreatic cancer cells. Although upregulation of Asporin expression has been observed in CAFs of some types of cancers, the functions and mechanisms of Asporin in cancer progression have not yet been clarified. Our preliminary results revealed that Asporin are significantly upregulated in activated pancreatic stellate cell (PSC), and might promote epithelial-mesenchymal transition, invasion and migration of pancreatic cancer cells. Therefore, we hypothesized that Asporin mediates the interaction between PSC and pancreatic cancer cells. In this study, we aim to (1) conduct screening and verification of membrane receptor proteins, which interact with Asporin; (2) explore Asporin expression and its clinicopathological and prognostic significance in pancreatic cancer tissues; (3) explore the paracrine effecs and molecular mechanisms of PSC-induced Asporin on pancreatic cancer cells. This study will further clarify the interaction between PSC and pancreatic cancer cell and contribute to develop new strategies for pancreatic cancer treatment.

近年的研究显示，Asporin在肿瘤相关性纤维母细胞中高表达，通过旁分泌途径影响肿瘤细胞的生物学行为。然而，其作用机制及膜蛋白受体仍知之甚少。我们已证实Asporin在活化的人胰腺星形细胞（PSC）及胰腺癌间质中显著高表达，进一步功能预实验提示PSC旁分泌的Asporin促进胰腺癌细胞的EMT及侵袭迁移能力。因而，我们推测，PSC旁分泌的Asporin与胰腺癌细胞膜上的特异性受体结合，活化胰腺癌细胞内信号通路，影响其EMT及侵袭迁移能力。本项目拟（1）筛选并验证与Asporin相互作用的膜受体蛋白；(2）探讨Asporin及其膜受体蛋白在胰腺癌组织中的表达与定位情况及其临床病理意义；(3）探讨PSC旁分泌的Asporin对胰腺癌细胞EMT及侵袭迁移的影响及其分子机制。我们的研究有助于进一步阐明PSC与胰腺癌细胞间的相互作用机制，从PSC及肿瘤微环境的角度为胰腺癌的诊疗提供新的思路与策略。

Asporin是近年发现的细胞外基质蛋白。尽管已有研究显示，Asporin在一些实体肿瘤的肿瘤相关性纤维母细胞中高表达，然而，其在胰腺星形细胞（PSC）中的表达情况以及在PSC-胰腺癌细胞(PCC)相互作用中扮演的角色仍知之甚少。我们的研究首次证实了，活化PSCs高表达Asporin，且通过旁分泌Asporin促进胰腺癌细胞的侵袭迁移能力。外源性Asporin与PCC上的跨膜受体CD44结合，激活下游AKT和ERK信号通路，进而活化NF-kB/p65，促进上皮间质转化。PCC自分泌的Asporin也可以发挥类似的作用。我们的结果还显示，在人胰腺癌组织的间质（紧邻胰腺癌细胞的间质）中的Asporin表达与不良预后有关。我们的结果首次阐明了PSC旁分泌以及胰腺癌细胞自分泌的Asporin促进胰腺癌细胞侵袭及迁移能力的机制。我们的研究有助于进一步阐明PSC与胰腺癌细胞间的相互作用机制，从PSC及肿瘤微环境的角度为胰腺癌的诊疗提供新的思路与策略。.YAP1在PSC活化中扮演的角色尚不明确。本研究明确了YAP1在胰腺癌相关的活化PSC核内高表达，敲除YAP1可导致PSC失活。YAP可促进PSC的SPARC表达与分泌，RNUX1 能够抑制YAP的促SPARC表达与分泌效应。PSCs通过YAP介导SPARC的旁分泌，抑制胰腺癌细胞的增殖。我们的结果还证实，YAP1表达与胰腺癌组织中的SPARC表达及纤维化程度呈正相关关系。我们的研究为针对YAP1及胰腺癌肿瘤微环境的靶向治疗策略提供了理论依据。