CRD-BP-mediated regulation of Wnt signaling in intestinal tumorigenesis

描述（申请人提供）：结直肠癌是所有癌症中最致命的癌症之一。结直肠肿瘤发展的主要驱动因素之一是Wnt/ß-catenin信号通路。我们之前已经确定了CRD-BP是Wnt信号通路的真正转录靶点，并证明了CRD-BP的诱导是人类结直肠癌细胞中Wnt/ß-catenin信号通路的多种多效作用的原因。我们已经证明：i) Wnt/ß-catenin信号对c-myc的上调依赖于CRD-BP；ii) CRD-BP促进Wnt和NF-κB通路之间的串扰；iii) CRD-BP独立于Hh信号通路介导Wnt信号激活GLI1转录活性；iv) crp - bp受c-myc的转录调控，参与c-myc原癌基因的多种功能，包括对翻译、细胞的调控

DESCRIPTION (provided by applicant): 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/ß-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/ß-catenin signaling in human colorectal cancer cells. We have demonstrated that: i) c-myc up-regulation by Wnt/ß-catenin signaling depends on CRD-BP; ii) CRD-BP facilitates cross-talk between Wnt and NF-κB 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 ßTrCP1 mRNA. We hypothesize that CRD-BP plays a central role in the modulation of Wnt/ß-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.