Regulation of Claudin-1 mediated Colon Tumor Progression and Metastasis

细胞-细胞连接蛋白表达和/或细胞定位的变化是 肿瘤的发生，尤其是转移和侵袭。粘附性连接蛋白的作用已被研究。 然而，在癌症中广泛存在的紧密连接蛋白的作用还不是很清楚。克劳丁斯是一个 最近发现的蛋白质家族，对紧密连接(TJ)的结构和功能是不可或缺的。 最近的研究表明，在表达/细胞定位方面的差异和组织特异性的变化 Claudins在肿瘤发生中的作用；然而，因果关系尚未建立。我们有 最近报道，在结肠癌中，claudin-1的表达以肿瘤分期特异性的方式增加。 (正常、癌、转移)，主要定位于胞核和胞浆。多数 重要的是，在非转移性和高转移性中使用claudin-1的过度表达或基因抑制 ，我们证明了claudin-1在肿瘤进展和调控中的作用。 转移。在这项拨款建议中，我们将先前的研究扩展至决定 Claudin-1作为肿瘤促进剂和转移的潜在机制。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和分子 以失巢细胞为研究模型的机制，可能适用于在体模型 转移和侵袭。此外，我们还建议研究这部小说背后的机制 Claudin-1在结肠转移癌标本和细胞系中的核定位及其与肿瘤转移的关系 转移。此外，我们还建议确定结肠癌特异性表达/细胞的调节。 Claudin-1通过APC的调节而定位。值得注意的是，APC突变是 结直肠癌。本提案中描述的工作旨在为以下机制提供见解 Claudin-1介导的调控及其调控，将有助于进一步研究 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.