细胞外基质蛋白SPON1激活WNT/β-catenin信号通路促进胰腺癌侵袭转移和免疫逃逸的机制研究

Pancreatic cancer is one of the most aggressive cancer characterized with strong invasiveness, high rate of tumor metastasis and poor prognosis. It is of great significance to study the interaction between pancreatic cancer cells and their microenvironment as a whole to reveal the mechanism of the occurrence and development of the disease and to find new therapeutic targets. Extracellular matrix protein SPON1 is associated with a variety of solid tumors, but little has been reported about its role in pancreatic cancer. The preliminary study revealed that the expression of SPON1 was up-regulated in pancreatic ductal adenocarcinoma, and the expression level was closely correlated with the survival time of the patients. SPON1 could not only promote the proliferation and migration of pancreatic cancer cells, but also increase the proportion of Treg cells in peripheral blood lymphocytes. These two effects were both related to the WNT/β-catenin signaling pathway. In terms of our preliminary datum, we will reveal the mechanism of SPON1 in pancreatic cancer and in its immune microenvironment by activating the WNT/β-catenin signaling pathway, so as to provide new insights for the diagnosis and treatment of pancreatic cancer.

胰腺癌是一种侵袭性强、转移率高的恶性肿瘤，总体预后差。将胰腺癌与其微环境作为相互作用的整体进行研究对揭示疾病进展的机理、寻找治疗的靶点具有极为重要的意义。细胞外基质蛋白SPON1与多种实体肿瘤有关，但其在胰腺癌中尚无研究报道。初步研究发现，SPON1在胰腺导管腺癌组织中表达上调，且表达水平与患者生存期密切相关。我们又发现，SPON1既促进胰腺癌细胞增殖和迁移，又升高外周血淋巴细胞中Treg细胞比例，且这两方面作用均与WNT/β-catenin信号通路有关。基于以上结果，我们提出科学假设：细胞外基质蛋白SPON1通过激活WNT/β-catenin信号通路促进胰腺癌细胞增殖迁移和微环境中Treg细胞的浸润。课题组拟进一步通过临床标本、细胞与分子生物学实验和动物实验，研究阐述SPON1-WNT/β-catenin轴在胰腺癌及其免疫微环境中的作用机制，进而为胰腺癌的诊治提供新的思路。

胰腺导管腺癌(Pancreatic ductal adenocarcinoma, PDAC)是恶性程度最高的肿瘤之一，其起病隐匿、侵袭性强、预后极差，被称为“癌中之王”。 胰腺癌至今缺乏有效治疗手段，因此筛选新的胰腺癌的诊疗靶点具有很强的研究和应用价值。本课题通过筛选发现细胞外基质蛋白SPON1蛋白在胰腺癌组织中的表达显著升高，并通过生存分析发现其表达水平与患者的预后密切相关。体外功能实验结果发现SPON1可以促进肿瘤的增殖以及侵袭转移能力。随后的机制研究分析发现SPON1能够促进IL6-STAT3信号通路，进一步研究发现SPON1能够与IL6R结合，维持其在细胞膜上的定位，持续激活IL6-STAT3信号通路。体内实验结果显示敲减SPON1的表达同样能够起到抑制肿瘤增殖的作用，并且原位模型显示敲减SPON1与吉西他滨呈现出协同效应。综上所述，本课题首次揭示了SPON1在胰腺癌发生发展中的作用及其具体机制，为胰腺癌的治疗提供了新的潜在靶点。