Regulation of Claudin-1 mediated Colon Tumor Progression and Metastasis

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。 粘附连接蛋白在癌症中的作用已被广泛研究;然而，紧密连接蛋白的作用还不太清楚。 紧密连接蛋白（Claudin）是一个最近发现的蛋白质家族，与紧密连接（TJ）的结构和功能密切相关。 最近的研究表明，在肿瘤发生过程中，claudins的表达/细胞定位存在差异和组织特异性变化;然而，因果关系尚未建立。 我们最近报道，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结肠癌细胞中使用claudin-1的过表达或遗传抑制，我们证明了claudin-1在调节肿瘤进展和转移中的作用。 在这项资助提案中，我们将我们以前的研究扩展到确定claudin-1作为肿瘤促进剂和转移的机制。 由于转移是肿瘤相关死亡的主要原因，我们选择首先使用失巢凋亡作为研究模型来定义信号和分子机制，这可能适用于转移和侵袭的体内模型。 此外，我们已经提出了研究机制的新的核定位的claudin-1在结肠转移的样品和细胞系及其与转移的相关性。 此外，我们还提出通过调节APC来确定对结肠癌特异性表达/细胞定位的调节。 值得注意的是，APC突变是结直肠癌的标志。 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，并将有助于未来研究开发治疗试剂或小分子抑制剂以测试其临床相关性。

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.