Colorectal cancer is one of the most lethal of all cancers. One of the major drivers underlying the development of colorectal tumors is the Wnt/-catenin signaling pathway. We have previously established CRD-BP as a bona fide transcriptional target of Wnt signaling pathway and demonstrated that induction of CRD-BP is responsible for a variety of pleiotropic effects of Wnt/-catenin signaling in human colorectal cancer cells. We have demonstrated that: i) c-myc up-regulation by Wnt/-catenin signaling depends on CRD-BP; ii) CRD-BP facilitates cross-talk between Wnt and NF-?B pathways; iii) CRD-BP mediates activation of GLI1 transcriptional activity in response to Wnt signaling independently of Hh signaling pathway; iv) CRD-BP is transcriptionally regulated by c-myc and is involved in several functions of c-myc proto-oncogene, including regulation on translation, cell size, cell cycle progression, and cell proliferation; v) we have also uncovered a mechanism of CRD-BP-mediated stabilization of TrCP1 mRNA. We hypothesize that CRD-BP plays a central role in the modulation of Wnt/-catenin signaling in the oncogenic transformation of intestinal epithelia, including its role in the maintenance, self-renewal, differentiation, and transformation of intestinal epithelial stem cells (IESCs). We propose to study the mechanisms of CRD-BP involvement in intestinal tumorigenesis. Pursuant to these goals, our specific aims are: 1. To analyze the role of CRD-BP in the regulation of Wnt signaling in CRC cells. 2. To elucidate the mechanisms of CRD-BP function in intestinal tumorigenesis. Overall, the completion of the proposed studies will help elucidate the role of CRD-BP in colorectal carcinogenesis. It will also delineate the mechanisms of regulation and function of CRD-BP in these tumors. These studies may potentially lead to the design of agents capable of inhibiting CRD-BP that might be utilized in the therapy of CRC.
The major reason for the lack of satisfactory management of colorectal cancer is our poor understanding of the biology of colorectal tumorigenesis, especially the regulation of key signal transduction pathways and regulation of expression of oncogenes and tumor suppressors. Proposed studies on the role of CRD-BP in the regulation of Wnt signaling in intestinal tumorigenesis are highly significant not only for the understanding the biology of intestinal tumors, but also for the validation of a novel target for the therapy and/or prevention of intestinal tumorigenesis.
| Kim, TaeWon; Havighurst, Thomas; Kim, KyungMann et al. (2018) Targeting insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in metastatic melanoma to increase efficacy of BRAFV600E inhibitors. Mol Carcinog 57:678-683 |
| Poenitzsch Strong, Ashley M; Berry, Scott M; Beebe, David J et al. (2018) miFAST: A novel and rapid microRNA target capture method. Mol Carcinog 57:559-566 |
| Kim, TaeWon; Havighurst, Thomas; Kim, KyungMann et al. (2017) RNA-Binding Protein IGF2BP1 in Cutaneous Squamous Cell Carcinoma. J Invest Dermatol 137:772-775 |
| Goswami, Srikanta; Tarapore, Rohinton S; Poenitzsch Strong, Ashley M et al. (2015) MicroRNA-340-mediated degradation of microphthalmia-associated transcription factor (MITF) mRNA is inhibited by coding region determinant-binding protein (CRD-BP). J Biol Chem 290:384-95 |
| Hamilton, Kathryn E; Chatterji, Priya; Lundsmith, Emma T et al. (2015) Loss of Stromal IMP1 Promotes a Tumorigenic Microenvironment in the Colon. Mol Cancer Res 13:1478-86 |
