Regulation of Claudin-1 mediated Colon Tumor Progression and Metastasis

细胞-细胞连接蛋白的表达和/或细胞定位的变化是免疫缺陷的标志。 肿瘤发生，特别是转移和侵袭。已经研究了粘附连接蛋白的作用 然而，紧密连接蛋白在癌症中的广泛作用还不太清楚。Claudin是一种 最近发现的紧密连接（TJ）结构和功能所必需的蛋白质家族。 最近的研究表明，在表达/细胞定位的差异和组织特异性变化， claudins在肿瘤发生过程中;然而，因果关系尚未建立。我们有 最近报道，在结肠癌中，claudin-1表达以肿瘤阶段特异性方式增加， （正常>癌>转移），并且主要定位于细胞核和细胞质。最 重要的是，在非转移性和高转移性肿瘤中使用claudin-1的过表达或遗传抑制， 在结肠癌细胞中，我们证明了claudin-1在调节肿瘤进展中的作用， 转移在这项拨款建议中，我们将以前的研究扩展到确定 claudin-1作为肿瘤促进剂和转移的潜在作用机制。因为转移是 肿瘤相关死亡的主要原因，我们选择首先定义信号传导和分子 使用失巢凋亡作为研究模型的机制，这可能适用于体内模型， 转移和侵袭。此外，我们还建议研究小说背后的机制 claudin-1在结肠转移样品和细胞系中的核定位及其与结肠癌的相关性 转移此外，我们已经提出确定结肠癌特异性表达/细胞的调节， 通过APC的调节定位claudin-1。值得注意的是，APC突变是 结肠直肠癌本提案中所述的工作旨在深入了解 claudin-1介导的调节以及其调节，并将有助于在未来的研究发展， 治疗试剂或小分子抑制剂，以测试它们的临床相关性。

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.