Regulation of Claudin-1 mediated Colon Tumor Progression and Metastasis

Claudin-1 介导的结肠肿瘤进展和转移的调节

• 批准号: 8138300
• 负责人: PUNITA DHAWAN
• 金额: $ 4.43万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-05 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8138300
• 关键词: Adenomatous Polyposis Coli; Anoikis; Applications Grants; Cancer cell line; Carcinoma; Cell Line; Cell Nucleus; Cells; Cessation of life; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Cytoplasm; Data; Diagnostic Neoplasm Staging; E-Cadherin; Family; Frequencies; Future; Genetic; Genus Cola; Growth; Integrins; Intercellular Junctions; Investigation; Malignant Neoplasms; Mediating; Molecular; Mutation; Neoplasm Metastasis; Nuclear; Nuclear Export; Pathway interactions; Play; Proteins; Reagent; Regulation; Reporting; Resistance; Role; Sampling; Signal Transduction; Structure; Study models; Testing; Tight Junctions; Tissue Sample; Tissues; Transcriptional Regulation; Tumor Promoters; Tumor Suppressor Proteins; Tumor stage; Work; adherent junction; apical membrane; base; cancer cell; claudin-1 protein; clinically relevant; colon carcinogenesis; human tissue; in vivo Model; inhibitor/antagonist; insight; metastatic colorectal; mouse model; novel; protein protein interaction; small molecule; therapeutic development; tumor; tumor growth; tumor progression; tumorigenesis; Adenomatous Polyposis Coli; Anoikis; Applications Grants; Cancer cell line; Carcinoma; Cell Line; Cell Nucleus; Cells; Cessation of life; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Cytoplasm; Data; Diagnostic Neoplasm Staging; E-Cadherin; Family; Frequencies; Future; Genetic; Genus Cola; Growth; Integrins; Intercellular Junctions; Investigation; Malignant Neoplasms; Mediating; Molecular; Mutation; Neoplasm Metastasis; Nuclear; Nuclear Export; Pathway interactions; Play; Proteins; Reagent; Regulation; Reporting; Resistance; Role; Sampling; Signal Transduction; Structure; Study models; Testing; Tight Junctions; Tissue Sample; Tissues; Transcriptional Regulation; Tumor Promoters; Tumor Suppressor Proteins; Tumor stage; Work; adherent junction; apical membrane; base; cancer cell; claudin-1 protein; clinically relevant; colon carcinogenesis; human tissue; in vivo Model; inhibitor/antagonist; insight; metastatic colorectal; mouse model; novel; protein protein interaction; small molecule; therapeutic development; tumor; tumor growth; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Changes in the expression and/or cellular localization of cell-cell junction proteins is a hallmark of tumorigenesis, especially metastasis and invasion. The role of adherent junction proteins has been studied extensively in cancer; however, the role of tight junction proteins is less well understood. Claudins are a family of recently identified proteins that are integral to the structure and function of tight junctions (TJs). Recent studies have shown differential and tissue specific changes in expression/cellular localization for claudins during tumorigenesis; however, a cause and effect relationship has yet to be established. We have recently reported that in colon cancer, claudin-1 expression is increased in a tumor stage specific manner (normal>carcinoma>metastasis), and is predominantly localized to cell nucleus and cytoplasm. Most importantly, using over-expression or genetic inhibition of claudin-1 in non-metastatic & highly metastatic colon cancer cells, we demonstrated a role of claudin-1 in the regulation of tumor progression and metastasis. In this grant proposal, we have extended our previous studies to the determination of mechanism underlying the role of claudin-1 as a tumor promoter and metastasis. Since, metastasis is the principal cause of tumor related deaths, we have elected to first define the signaling and molecular mechanisms using anoikis as the model of study, which could potentially be applicable to in vivo model of metastasis and invasion. In addition, we have proposed to examine the mechanisms underlying the novel nuclear localization of claudin-1 in colon metastasis samples and cell lines and its correlation with metastasis. Also, we have proposed to determine the regulation of colon cancer specific expression/cellular localization of claudin-1 through the regulation of APC. It is noteworthy that APC mutation is a hallmark of colorectal cancer. The work described in this proposal is intended to provide insight for the mechanism of claudin-1 mediated regulation as well as its regulation and would help in future studies for development of therapeutic reagents or small molecule inhibitors to test their clinical relevance.

描述（由申请人提供）：细胞 - 细胞连接蛋白的表达和/或细胞定位的变化是肿瘤发生的标志，尤其是转移和侵袭。 在癌症中已经广泛研究了粘附连接蛋白的作用。但是，紧密连接蛋白的作用知之甚少。 Claudins是一个最近确定的蛋白质家族，它们是紧密连接（TJ）的结构和功能不可或缺的蛋白质。 最近的研究表明，在肿瘤发生过程中，claudins表达/细胞定位的差异和组织特异性变化。但是，因果关系尚未建立。 我们最近报道说，在结肠癌中，Claudin-1表达以肿瘤阶段的特异性方式（正常>癌>转移）增加，并且主要定位于细胞核和细胞质。 最重要的是，使用过度表达或遗传抑制Claudin-1在非转移性和高度转移性结肠癌细胞中，我们证明了Claudin-1在调节肿瘤进展和转移中的作用。 在这项赠款提案中，我们将以前的研究扩展到确定克劳丁1作为肿瘤启动子和转移的作用的机制。 由于转移是肿瘤相关死亡的主要原因，因此我们选择使用Anoikis作为研究模型来首先定义信号传导和分子机制，这可能适用于转移和入侵的体内模型。 此外，我们提出了研究Claudin-1在结肠转移样品和细胞系中新型核定位的基础机制及其与转移的相关性。 另外，我们提出的是通过调节APC来确定Claudin-1的结肠癌特异性表达/细胞定位的调节。 值得注意的是，APC突变是大肠癌的标志。 本提案中描述的工作旨在为Claudin-1介导的调节机制及其调节提供见解，并将有助于未来的治疗试剂或小分子抑制剂的开发研究，以测试其临床相关性。