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。Wnt/？catenin信号通路是大肠肿瘤发生发展的主要驱动因素之一。我们先前已经建立了CRD-BP作为Wnt信号通路的真实转录靶点，并证明了CRD-BP的诱导与Wnt/？catenin信号在人结直肠癌细胞中的多种多效性有关。我们已经证明：i)c-myc的上调依赖于crd-BP；ii)crd-BP促进了wnt和nf-κB通路之间的串话；iii)crd-BP不依赖于HH信号途径而介导了转录活性的激活；iv)crd-BP受c-myc的转录调控，并参与了c-myc原癌基因的几个功能，包括对翻译、细胞和原癌基因的调节。 V)我们还发现了CRD-BP介导的？TrCP1mRNA稳定的机制。我们推测CRD-BP在肠上皮细胞癌变过程中Wnt/？-catenin信号的调控中起核心作用，包括其在维持、自我更新、分化和转化中的作用。 肠上皮干细胞(IESCs)。我们建议研究CRD-BP参与肠道肿瘤发生的机制。根据这些目标，我们的具体目标是：1.分析CRD-BP在结直肠癌细胞Wnt信号调控中的作用。2.阐明CRD-BP在肠道肿瘤发生中的作用机制。总体而言，拟议研究的完成将有助于阐明CRD-BP在结直肠癌发生中的作用。它还将描述CRD-BP在这些肿瘤中的调节和功能机制。这些研究可能导致能够抑制CRD-BP的药物的设计，这些药物可能用于结直肠癌的治疗。

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.