Wang Lili, Wu Huanwen, Wang Li, Zhang Hui, Lu Junliang, Liang Zhiyong, Liu Tonghua
Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
Cancer Lett. 2017 Jul 10;398:24-36. doi: 10.1016/j.canlet.2017.04.001. Epub 2017 Apr 9.
Pancreatic cancer is histopathologically characterized by excessive desmoplasia induced by pancreatic stellate cells (PSCs). Asporin, an extracellular matrix (ECM) protein, is highly expressed in cancer-associated fibroblasts (CAFs). Asporin expression in PSCs and its roles in PSC-pancreatic cancer cell (PCC) interaction remain unclear. The present study firstly showed that Asporin is highly expressed in activated PSCs and is involved in PSC-mediated invasion and migration of PCCs. Exogenous Asporin interacted with the transmembrane receptor CD44 on PCCs to activate NF-κB/p65 and promoted the epithelial-mesenchymal transition (EMT) in PCCs. Furthermore, AKT and ERK pathways participated in Asporin/CD44-induced NF-κB/p65 activation in pancreatic cancer. Asporin had similar effects on PCCs via an autocrine mechanism. Consistent with our in vitro experiments, we showed that Asporin in peritumoral stroma of pancreatic cancer tissues was associated with poor clinical outcome. In conclusion, this is the first study to show that Asporin promotes EMT, invasion, and migration of PCCs by activating CD44-AKT/ERK-NF-κB pathway in paracrine and autocrine manners. Moreover, our results indicate that Asporin may be a prognostic marker and suggest that targeting the tumor microenvironment represents a promising therapeutic strategy in pancreatic cancer.
胰腺癌在组织病理学上的特征是胰腺星状细胞（PSC）诱导的过度纤维增生。骨桥蛋白是一种细胞外基质（ECM）蛋白，在癌症相关成纤维细胞（CAF）中高度表达。PSC中骨桥蛋白的表达及其在PSC与胰腺癌细胞（PCC）相互作用中的作用尚不清楚。本研究首次表明，骨桥蛋白在活化的PSC中高度表达，并参与PSC介导的PCC侵袭和迁移。外源性骨桥蛋白与PCC上的跨膜受体CD44相互作用，激活NF-κB/p65，并促进PCC中的上皮-间质转化（EMT）。此外，AKT和ERK信号通路参与了骨桥蛋白/CD44诱导的胰腺癌NF-κB/p65激活。骨桥蛋白通过自分泌机制对PCC有类似作用。与我们的体外实验一致，我们发现胰腺癌组织瘤周基质中的骨桥蛋白与不良临床预后相关。总之，这是第一项表明骨桥蛋白通过旁分泌和自分泌方式激活CD44-AKT/ERK-NF-κB信号通路促进PCC的EMT、侵袭和迁移的研究。此外，我们的结果表明骨桥蛋白可能是一种预后标志物，并提示靶向肿瘤微环境是胰腺癌一种有前景的治疗策略。
