新型基质蛋白Frem2对IL-1/IL-1RI介导的食管癌侵袭转移的调控作用研究

近年来，炎症诱导的肿瘤（包括食管癌）侵袭转移备受关注，IL-1及其受体IL-1RI被报道在食管癌组织中高表达，并可介导食管癌侵袭转移。我们前期对术后转移复发及术后预后良好的食管癌组织分别进行转录组测序，结果发现，在转移组除IL-1受体信号上调外，细胞粘附相关的胞外基质蛋白Frem2显著高表达；免疫共沉淀结合质谱分析发现Frem2可与IL-1RI形成复合物；干扰Frem2可下调IL-1介导的食管癌细胞体外迁移。本项目拟进一步：1)在组织及细胞水平明确Frem2在食管癌中的表达及其与转移的相关性；2）免疫共沉淀结合免疫荧光等研究Frem2与IL-1RI的复合关系；3）应用基因转染及干扰，调节Frem2表达，体内外明确Frem2对IL-1/IL-1RI介导的食管癌侵袭转移的调控作用及其机制。以上内容的阐明将从胞外基质调控炎症应答的新视角阐释炎症诱导食管癌侵袭转移的机制。

Inflammatory microenvironment is decisive in tumor invasion and metastasis. IL-1 and its receptor, IL-1RI, were previously reported overexpressed in esophageal cancer, and thereby promoted its metastasis. Our previous screening by RNA-sequencing showed that, in spite of the activated IL-1RI related signaling, Frem2 (Fras1-related extracellular matrix protein 2) was dramatically upregulated in metastatic esophageal cancer tissues compared with non-metastatic esophageal cancer tissues. Furthermore, we performed co-immunoprecipitation combined with mass spectrometry analysis confirmed that Frem2 coupled IL-1RI, and blockage of Frem2 suppressed IL-1/IL-1RI induced cancer cell migration. In this project, to further investigate the role of Frem2 in IL-1/IL-1RI induced esophageal cancer metastasis, we plan to 1) analyze the expression of Frem2 in esophageal cancer tissues and cell lines, and confirm its correlation with esophageal cancer metastasis; 2) explore the relationship between Frem2 and IL-1RI using co-immunopreciptation; 3) investigate the regulatory role and mechanism of Frem2 in IL-1/IL-1RI mediated esophageal cancer metastasis after upregulation or downregulation of Frem2. As a result, this study will provide the new mechanism of inflammation induced esophageal cancer metastasis based on the regulation of extracellular matrix protein.