One of the major challenges in colorectal cancer includes poor understanding of the factors regulating its initiation and progression. Hyperactive Wnt signaling driven by excess active beta catenin due to either loss of the APC tumor suppressor gene or mutation of beta catenin is considered as an inciting event in vast majority of colorectal cancer patients. Although many of the components of this signaling pathway are known, the mechanisms that regulate the active beta catenin remain incompletely understood. We have recently described c-Cbl, a known tumor suppressor, as a novel inhibitor of Wnt signaling and an E3 ubiquitin ligase for active nuclear beta catenin. Leveraging the findings that in colorectal cancer cells, c-Cbl can also suppresses the phospho-resistant S33A mutant beta catenin and the active beta catenin resulting from APC inactivation, the crucial triggers for adenoma formation, this grant seeks to examine the role of c-Cbl in colorectal cancer tumorigenesis. Using biochemical, genetic, cellular and molecular biology approaches, we will examine how c- Cbl regulates the fundamental colorectal cancer cell biological functions and inhibits the beta catenin-mediated transcription in nucleus. We will validate these observations and gain further mechanistic understanding in the multistep colorectal cancer pathogenesis using mouse xenograft and knock out animal models. We will further validate our findings in human colorectal cancer tissues. This series of experiments will provide a window into the unique regulatory role of c-Cbl in colorectal cancer and pave the road for further translational studies.
Though there has been a significant progress in the diagnosis and treatment of colorectal cancer, we lack the markers to predict its predisposition and progression. In addition, the targeted therapeutic options in colorectal cancer remain limited. This proposal focuses on elucidating the role of c-Cbl, a newly described Wnt regulator and tumor suppressor in colorectal cancer initiation and progression. Multipronged approach as proposed in this grant will provide mechanistic understanding about the role of c-Cbl in colorectal cancer pathogenesis, which can be further developed as a prognostic marker and serve as a novel therapeutic target for colorectal cancer. This project investigates the role of c-Cbl, a novel inhibitor of colorectal cancer. Using molecula and biochemical techniques and disease models, we examine how c-Cbl regulates the fundamental functions of colorectal cancer cells to results in the reduction of tumor burden. This investigation will provide a deeper understanding about the molecular events involved in colorectal cancer pathogenesis as well will enable future development of both the diagnostic test to predict the risk of colon cancer and novel target to treat colon cancer.
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|Shashar, Moshe; Siwak, Jamaica; Tapan, Umit et al. (2016) c-Cbl mediates the degradation of tumorigenic nuclear ?-catenin contributing to the heterogeneity in Wnt activity in colorectal tumors. Oncotarget 7:71136-71150|
|Shivanna, Sowmya; Kolandaivelu, Kumaran; Shashar, Moshe et al. (2016) The Aryl Hydrocarbon Receptor is a Critical Regulator of Tissue Factor Stability and an Antithrombotic Target in Uremia. J Am Soc Nephrol 27:189-201|
|Arafa, Emad; Bondzie, Philip A; Rezazadeh, Kobra et al. (2015) TMIGD1 is a novel adhesion molecule that protects epithelial cells from oxidative cell injury. Am J Pathol 185:2757-67|
|Srinivasan, Srimathi; Chitalia, Vipul; Meyer, Rosana D et al. (2015) Hypoxia-induced expression of phosducin-like 3 regulates expression of VEGFR-2 and promotes angiogenesis. Angiogenesis 18:449-62|
|Shivanna, Sowmya; Harrold, Itrat; Shashar, Moshe et al. (2015) The c-Cbl ubiquitin ligase regulates nuclear ?-catenin and angiogenesis by its tyrosine phosphorylation mediated through the Wnt signaling pathway. J Biol Chem 290:12537-46|
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