Gastrins 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率的主要原因之一。结肠上皮过度增殖现在被认为是结直肠癌的危险因素。增加结肠上皮细胞增殖的因素被认为在结肠癌发生中起作用。我们现在知道，完全加工的酰胺化胃泌素（G17）和未加工的非酰胺化胃泌素（gly-胃泌素和前胃泌素，PG）对正常和癌性肠细胞具有促有丝分裂作用。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是一种共致癌物，而酰胺化胃泌素抑制而不是刺激结肠癌发生。酰胺化（G17）与非酰胺化（PG）胃泌素对结肠癌发生的不同作用是一项新发现，将在本申请中进一步研究。该提议的主要假设是，PG增加了结肠癌发生的风险，而G17降低了结肠癌发生的风险。在目标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等的共致癌性。通过用增加浓度的PG处理GAS-KO小鼠，将检查PG对结肠癌发生的可能的剂量依赖性作用。在目的2中，我们将研究G17降低结肠癌发生风险的新的可能性，通过使用过表达G17的突变小鼠模型，用增加浓度的G17处理GAS-KO小鼠及其野生型（WT）同窝仔，或降低WT小鼠中胃泌素的内源性水平。在目标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）。我们最近报道了一个新的发现，PG可能作为一个抗凋亡因子的结肠癌细胞和肠上皮细胞。在目的4中，我们将检查PG与G17对结肠粘膜细胞凋亡潜力的相对影响，这可能有助于解释两种肽之间的差异效应。四个目标的研究结果将使我们能够证实我们的新假设，并提供重要的机制线索，这些线索将成为未来资助期内研究的基础。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.