Gasgrins and Receptors in Colon Carcinogenesis

描述（由申请人提供）：结直肠癌是美国癌症相关死亡的主要原因之一，结肠上皮过度增生现在被认为是结直肠癌的一个危险因素。增加结肠上皮细胞增殖的因素被认为在结肠癌的发生中起作用。我们现在知道，完全加工的修饰胃泌素（G17）和未加工的非修饰胃泌素（gly-gastrin和progastrin， PG）对正常和癌变的肠细胞都有丝分裂作用。我们最近对过度表达PG或G17或缺乏功能性胃泌素基因（GAS-KO）的突变小鼠的研究表明，PG是一种新的致癌物质，而修饰的胃泌素抑制而不是刺激结肠癌的发生。修饰胃泌素（G17）与非修饰胃泌素（PG）在结肠癌发生中的差异作用是一项新发现，将在本应用中进一步研究。本研究的主要假设是PG在化学致癌物作用下增加结肠癌发生风险，而G17在化学致癌物作用下降低结肠癌发生风险。在Aim 1中，我们将使用更合适的突变小鼠模型，确认PG在生理浓度下是否具有同样的共致癌作用。通过增加PG浓度处理GAS-KO小鼠，将检验PG对结肠癌发生的可能剂量依赖性作用。在Aim 2中，我们将研究G17降低结肠癌发生风险的新可能性，方法是使用过表达G17的突变小鼠模型，增加G17浓度处理GAS-KO小鼠及其野生型（WT）幼崽，或降低WT小鼠内源性胃泌素水平。在Aim 3中，我们将研究胃泌素受体亚型在介导PG与G17的差异效应中的作用（如果有的话）。我们最近报道了一项新的发现，PG可能是结肠癌细胞和肠上皮细胞的抗凋亡因子。在Aim 4中，我们将研究PG和G17对结肠粘膜细胞凋亡潜能的相对影响，这可能有助于解释两种肽之间的差异作用。四个目标的研究结果将使我们能够确认我们的新假设，并提供重要的机制线索，这将构成未来资助期研究的基础。这些结果有望影响结肠癌患者的诊断、预后和临床管理。

DESCRIPTION (provided by applicant): Colorectal cancer represents one of the leading causes of cancer-related mortality in the U.S. Hyperproliferation of colonic epithelium is now recognized as a risk factor for colorectal cancer. Factors that increase proliferation of colonic epithelium are believed to play a role in colon carcinogenesis. We now know that fully processed amidated gastrins (G17) and unprocessed non-amidated gastrins (gly-gastrin and progastrin, PG) are mitogenic for normal and cancerous intestinal cells. Our recent studies with mutant mice that over-express either PG or G17 or lack the functional gastrin gene (GAS-KO), suggest the novel possibility that PG is a co-carcinogen, while amidated gastrins inhibit rather than stimulate colon carcinogenesis. Differential effects of amidated (G17) vs non-amidated (PG) gastrins on colon carcinogenesis is a novel finding that will be further investigated in this application. The major hypothesis of this proposal is that PG increases the risk while G17 decreases the risk of colon carcinogenesis in response to chemical carcinogens. In Aim 1 we will confirm if PG is equally co-carcinogenic at physiological concentrations using more appropriate mutant mouse models. Possible dose-dependent effects of PG on colon carcinogenesis will be examined by treating GAS-KO mice with increasing concentrations of PG. In Aim 2 we will investigate the novel possibility that G17 reduces the risk of colon carcinogenesis, by either using mutant mouse models that over-express G17, treating GAS-KO mice and their wild type (WT) littermates with increasing concentrations of G17, or reducing endogenous levels of gastrins in WT mice. In Aim 3 we will investigate a role, if any, of gastrin receptor subtypes in mediating differential effects of PG vs G17. We recently reported a novel finding that PG may function as an anti-apoptotic factor for colon cancer cells and intestinal epithelial cells. In Aim 4, we will examine relative effects of PG vs G17 on apoptotic potential of colonic mucosal cells, that may help to explain differential effects between the two peptides. Results of the studies in the four Aims will allow us to confirm our novel hypotheses, and provide important mechanistic clues that will form the basis of studies in future funding periods. These results are expected to impact diagnosis, prognosis and clinical management of patients with colon cancer.