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.
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