Role of Claudin-2 in Colon Tumorigenesis

Project: Research projectNon-HHS Research Projects

Description

? DESCRIPTION (provided by applicant): Despite the recent advances in the clinical management, colorectal cancer (CRC) remains 2nd leading cause of the cancer-related deaths in Veteran armed forces personnel. Each year Veterans affairs manage and treat ~175,000 CRC-patients and cancer progression remains the principal cause of CRC-associated death. Thus, need for therapies that can prevent CRC progression remains urgent. This proposal exploits a key clinical observation by us and other groups that expression of claudin-2, a tight junction (TJ) protein, is highly upregulated in CRC, promotes colon tumorigenesis in vivo and protects from cell death induced by chemotherapeutic drugs. However, despite the proven ability of claudin-2 to promote CRC, underlying mechanisms as well as therapeutic potential of claudin-2 remain unexplored. Importantly, among claudins expressed in colon, claudin-2 is uniquely expressed only among the undifferentiated colonocytes at crypt bottom, the proliferative zone, and promotes colonic epithelial cell (CEC) proliferation, in vitro and in vivo. Notably, claudin-2 is a transcriptional target of Wnt-signaling. Further, tissue microenvironment regulates colonic claudin-2 expression in EGFR-dependent manner. The EGFR- and Wnt-signaling regulate colonic stem cell niche and accordingly we have found upregulated expression of Lgr-5, Olf4 and CD-133, stem cell markers in cells or mice overexpressing claudin-2 versus respective controls. In CRC, a proliferative phenotype associates with dedifferentiation. In accordance, claudin-2 expression decreases with the differentiation in CRC-cells and resists differentiation when overexpressed. In addition, our preliminary studies suggest that claudin-2 may help protect CECs from stress-induced death by regulating autophagy. Our additional data using Villin-claudin-2 transgenic mice suggest that constitutive claudin-2 expression renders immune-suppression. Notably, immune suppressive conditions help promote tumor progression. Taken together, we hypothesize that claudin-2 expression promotes colon tumorigenesis by facilitating stem cell expansion and plasticity, resistance to cell death and modulation of the host-tumor immune interaction. To test our hypothesis, we propose following specific aims: Aim-1) to determine how claudin-2 regulates colon tumor growth and tumor cell plasticity. Here, we will determine: A) the role of claudin-2 in the regulation of colonocyte differentiation, stem cell niche and tumor cell plasticity; B) whether claudin-2 promotes autophagy to promote tumor cell survival and chemoresistance; and C) whether claudin-2 expression modulates host-tumor immune interaction to promote tumor progression; and Aim-2) to determine the role of EGFR- and Wnt-signaling in the regulation of colonic claudin-2 expression and therapeutic potential. Here, we will determine: A) the role of EGFR-dependent signaling, transcriptional mechanism/s and potential cross-talk with Wnt/?-catenin signaling in the regulation of claudin-2 expression; and B role of claudin-2 as a CRC-biomarker in conjunction with EGFR and Wnt-signaling. Our short term goal is to better understand how dysregulation of claudin-2 expression modulates the ability of colon cancer cells to form tumor and further progression. Our long term goal is to develop strategies to inhibit claudin-2 expression applicable specifically to the colon cancer cell and thus to create an anti-CRC drug that can prevent disease progression. We believe such therapeutic interventions can significantly increase survival and quality of life US Veterans who are suffering from colorectal cancer.
StatusActive
Effective start/end date4/1/163/31/20

Funding

  • National Institutes of Health

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Claudin-2
Colon
Carcinogenesis
Colorectal Neoplasms
Neoplasms
Veterans
Colonic Neoplasms
Stem Cell Niche
Autophagy