牙本质涎磷蛋白靶向整合素αvβ3调控肿瘤血管正常化介导结直肠癌化疗耐药的机制研究

化疗是晚期结直肠癌的重要治疗手段，但是肿瘤对化疗耐药严重影响患者预后，目前结直肠癌发生耐药的机制尚未完全阐明。课题组前期研究成功筛选结直肠癌进展候选基因牙本质涎磷蛋白（DSPP），初步证实肿瘤微环境炎症因子能调控其在肿瘤细胞中表达上调，并以外分泌的形式影响肿瘤生长及血管生成。结合预实验结果及相关报道，我们提出假设：结直肠癌微环境中Th-17细胞分泌的IL-17刺激肿瘤细胞DSPP蛋白的表达，后者通过自分泌和旁分泌与细胞表面整合素αvβ3结合，一方面介导肿瘤细胞中MAPK信号通路激活促进肿瘤生长，另一方面，通过激活MMPs降解肿瘤血管基膜，破坏肿瘤屏障功能，影响肿瘤血管新生及肿瘤血管正常化，从而诱导化疗耐药。本项目从肿瘤微环境的角度，全方位阐明DSPP调控肿瘤血管正常化促进结直肠癌化疗耐药的分子机制，为确立DSPP-αvβ3轴作为结直肠癌患者临床治疗靶点提供充分的科学依据。

Chemotherapy is an important treatment for colorectal cancer(CRC)，but tumor drug resistance seriously affects the prognosis of patients. Currently the mechanism of CRC drug resistance has not been fully elucidated. In our previous study, we successfully screened the candidate gene for colorectal cancer metastasis, dentin salivary phosphoprotein (DSPP), which preliminarily proved that tumor microenvironmental inflammatory factors could regulate the up-regulation of DSPP protein expression in tumor cells, and DSPP could affect tumor growth and angiogenesis in the form of paracrine.According to the preliminary experimental results and related reports, we hypothesized that the Th17 cells secreted IL-17, which stimulats the up-regulation of DSPP protein expression.DSPP combines with αvβ3 by autocrine and paracrine, on the one hand, it mediates the activation of MAPK signaling pathway in tumor cells to promote tumor growth, on the other hand, it degenerates tumor vascular basement membrane by activating MMPs, destroys tumor barrier function, affects tumor angiogenesis and tumor vascular normalization to induces durg resistance. From the tumor microenvironment perspective，the aim of the project is to systematically illustrate the molecular mechanism of DSPP regulating tumor vascular normalization and promoting chemotherapy resistance in colorectal cancer，and established DSPP-αvβ3 axis as a novel target for clinical therapy of patients with advanced CRC.