MUCIN GLYCOPROTEINS IN COLON CANCER METASTASIS

结肠癌转移中的粘蛋白糖蛋白

• 批准号: 6686311
• 负责人: ROBERT S BRESALIER
• 金额: $ 35万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2005-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6686311
• 关键词: binding proteins; colon neoplasms; gene expression; gene induction /repression; glycoprotein structure; glycoproteins; human tissue; laboratory mouse; metastasis; mucins; neoplastic growth; protein localization; protein structure function

Colorectal cancer is the second most common epithelial cancer in North America with an estimated annual mortality of 55,000 in the United States. The majority of colon cancer-related deaths are due to metastasis, a complex multi-step process by which tumor cells escape the primary tumor and establish secondary foci at distant sites. Mucins, the major secreted glycoproteins of the colon and galectin-3 an endogenous mucin binding protein play an important role in colon cancer metastasis. Direct evidence in support of a particular function(s) for mucin and galectin-3 are now emerging through identification of interacting ligands and structural motifs. Mucins are encoded by at least 9 genes and while a role for the MUC2 gene in mucinous carcinomas has been established, it remains to be determined which structural domains of MUC2 and other mucins are necessary to promote metastasis of colon cancer cells. Galectin-3 also consists of distinct structural domains. The protein may be localized in the nucleus, cytoplasm, on the cell surface or be secreted by colon cancer cells, and may therefore act in several ways to promote metastasis. The long-term objective of this proposal is to determine how the cell surface and secreted glycoproteins of colon cancer cells influence their metastatic capacity. Based on progress during the current funding period efforts will continue which are designed to elucidate the structure-function relationships between colon cancer mucins, mucin-binding proteins and metastasis. We hypothesize that specific structural domains of mucin apoproteins and glaectin-3 are necessary for their metastasis-enhancing effects, and that these molecules interact to promote tumor spread during defined stages of colon cancer metastasis. To accomplish these goals the following specific aims are proposed 1) Determine which structural domains of mucins are necessary for promoting the metastasis of colon cancer cells 2) Determine whether MUC2 and galectin-3 interact to affect the metastatic potential of colon cancer cells 3) Determine at which stages of liver colonization MUC2 and galectin-3 act to augment the metastatic potential of mucinous colon cancer cells. Further understanding of the roles of mucins and galectin-3 in colon cancer metastasis may make it possible to design specific diagnostic and therapeutic strategies to alter the course of metastatic disease.

大肠癌是北美第二大最常见的上皮癌，估计在美国，年死亡率为55,000。 大多数与结肠癌相关的死亡是由于转移而引起的，这是一个复杂的多步骤过程，肿瘤细胞逃脱了原发性肿瘤并在远处的部位建立了二次灶。 粘蛋白是结肠和半乳糖素3的主要分泌糖蛋白，内源性粘蛋白结合蛋白在结肠癌转移中起重要作用。 现在，通过鉴定相互作用的配体和结构基序来支持粘蛋白和乳糖素3特定功能的直接证据。 粘蛋白至少由9个基因编码，虽然已经建立了MUC2基因在粘液性癌中的作用，但仍有待确定哪些MUC2的结构结构域以及其他粘蛋白对于促进结肠癌细胞转移是必要的。 Galectin-3还由不同的结构域组成。 该蛋白质可以定位于细胞核，细胞质，细胞表面或由结肠癌细胞分泌，因此可以以多种方式作用以促进转移。 该提案的长期目标是确定结肠癌细胞的细胞表面和分泌的糖蛋白如何影响其转移能力。 基于当前资金期间的进展，将继续进行，旨在阐明结肠癌粘蛋白，粘蛋白结合蛋白和转移之间的结构功能关系。 我们假设粘蛋白丙蛋白和青光蛋白3的特定结构结构域对于它们的转移增强作用是必需的，并且这些分子相互作用以促进结肠癌转移的定义阶段促进肿瘤扩散。 为了实现这些目标，提出了以下特定目标1）确定粘液的结构结构域对于促进结肠癌细胞的转移是必要的2）确定MUC2和Galectin-3是否相互作用以影响结肠癌细胞的转移潜力3）确定在该阶段的肝脏定植MUC2和Galectin-3作用以增强粘液结肠癌细胞的转移潜力。 进一步了解粘蛋白和Galectin-3在结肠癌转移中的作用可能使设计特定的诊断和治疗策略可以改变转移性疾病的进程。