核心蛋白聚糖（decorin）缺失的肿瘤微环境与结直肠癌发生和转移机制研究

项目名称： 核心蛋白聚糖（decorin）缺失的肿瘤微环境与结直肠癌发生和转移机制研究

项目编号： No.81472821

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 毕秀丽

作者单位： 辽宁大学

项目金额： 72万元

中文摘要： 肿瘤微环境在恶性肿瘤的发展和转移中起着至关重要的作用。肿瘤的进展和转移是癌细胞与周围环境之间的相互作用的结果。肿瘤微环境由肿瘤相关的成纤维细胞、细胞外基质等成分组成。核心蛋白聚糖是细胞外基质的主要成分之一。 在前期的研究中E-cadherin蛋白下调和β-catenin蛋白的上调在核心蛋白聚糖缺陷小鼠被发现。β-catenin和E-cadherin这两种蛋白是上皮-间质转化（EMT ）的标志性分子。提示，核心蛋白聚糖与EMT之间有着密切的关系，本研究应用现代分子生物学，细胞生物学手段，结合偶氮甲烷AOM诱导的DCN野生型及基因缺失型的结直肠癌小鼠模型，研究DCN与上皮间质转换之间的相互作用在结直肠肿瘤发生、发展和转移过程中的作用，及核心蛋白聚糖对结直肠癌小鼠的治疗作用，研究成果为阐明结直肠癌的发病机制，也为将核心蛋白聚糖进一步开发为针对肿瘤微环境的新型防治结直肠癌生物制剂提供理论依据。

中文关键词： C08_结；直肠肿瘤；核心蛋白聚糖；微环境；上皮间质转化；胞外基质

英文摘要： Tumor microenvironment plays crucial roles in the development and metastasis of malignant tumors. Cancer progression and metastasis are the result of reciprocal interactions between cancer cells and their surrounding microenvironmental constituentsts. The tumor microenvironment encompasses cancer associated fibroblasts, inflammatory cells, angiogenesis and remodeling of extracellular matrix. Decorin is one of the main components of the extracellular matrix. We previously reported that in decorin-null mice there is a concurrent downregulation of E-cadherin and upregulation of β-catenin signaling. Both β-catenin and E-cadherin are hallmarks of epithelial-mesenchymal transition (EMT). E-cadherin loss promotes metastasis by disaggregating cancer cells from another, activates specific downstream signal transduction pathways and causes EMT, which facilitates metastasis. The focus of this proposal is the study of the role of decorin-deficient tumour microenvironment in colorectal cancer progression and metastasis. Specifically, we will investigate the cross-talk between decorin and EMT in colorectal cancer formation, invasion and metastasis. The result from this study would shed light on the colorectal cancer treatment using decorin targeting on the tumor microenvironment. We plan to: Aim 1: Investigate the effects of a decorin-deficient microenvironment on colorectal cancer formation and invasion in mice induced by azoxymethane (AOM). Aim 2: Study the anti-oncogenic properties of recombinant decorin protein core with or without the addition of decitabine in AOM induced decroin knockout colorectal cancer mice model. Aim 3: Investigate how a decorin-null microenvironment in host mice would affect colorectal cancer progression, metastasis, and how exogenous decorin would influence the tumor outcome. Aim 4: Utilize an in vitro co-culture syste of tumor fibroblasts and epithelial cells to discern the mechanism of cross-talk between decorin and EMT.

英文关键词： Colorectal cancer;Decorin;Microenvironment;Epithelial-mesenchymal transition;Extracellular matrix