Role of Claudin-2 in Colon Tumorigenesis

Claudin-2 在结肠肿瘤发生中的作用

• 批准号: 9026236
• 负责人: Amar B Singh
• 金额: --
• 依托单位: OMAHA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9026236
• 关键词: Affect; Antineoplastic Agents; Asses; Autophagocytosis; Biological Assay; Caco-2 Cells; Cancer Etiology; Cartoons; Cell Death; Cell Survival; Cells; Cellular Stress; Cessation of life; Clinical; Clinical Management; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Data; Disease; Disease Progression; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cell Proliferation; Event; Family member; Financial compensation; Fostering; Future; Goals; Growth; Immune; Immunologic Surveillance; Immunosuppression; In Vitro; Light; Messenger RNA; Military Personnel; Molecular; Mus; Mutation; Nature; Oncogenic; Outcome; Patients; Pharmaceutical Preparations; Phenotype; Population; Predisposition; Proteins; Quality of life; Regulation; Research; Resistance; Role; Signal Pathway; Signal Transduction; Stem cells; Stress; Testing; Therapeutic; Therapeutic Intervention; Tight Junctions; Tissues; Transgenic Mice; Undifferentiated; Up-Regulation; Veterans; beta catenin; cancer biomarkers; cancer cell; cancer stem cell; cell growth; colon cancer patients; colon carcinogenesis; colon tumorigenesis; in vivo; individualized medicine; mortality; neoplastic cell; novel; novel therapeutics; offspring; outcome forecast; overexpression; prevent; public health relevance; selective expression; stem cell niche; tumor; tumor growth; tumor progression; tumorigenic; villin

 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/β-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.