Inorganic phosphate regulated proliferation, transformation and tumorigenesis

描述（由申请人提供）：无机磷酸盐在许多层面上对人体至关重要。在细胞水平上，它是能量代谢、激酶信号传导以及DNA和脂质的形成和功能的组成部分。传统上，无机磷酸盐被认为是这些过程中被动的、必需的离子，然而，最近的数据表明，这种离子在细胞功能调节中起着更积极的作用。已发表的和初步的体外实验结果表明，多种细胞类型暴露于高浓度的无机磷酸盐会改变生长特性、特定的信号转导途径和基因表达，包括与癌症和转移相关的因子，如骨桥蛋白、c-fos、Egr1和Cox-2。我们的体内初步结果证实了体外研究，并表明血清无机磷酸盐水平改变了两阶段皮肤癌模型的肿瘤发生。综上所述，结果表明，有效无机磷酸盐水平可能是细胞生长和转化潜力的重要易感危险因素。血清中无机磷酸盐的主要来源是饮食摄入，部分原因是由于加工食品消费量的增加，美国饮食中无机磷酸盐的含量继续上升，超过了FDA已经认定的高水平。尽管饮食对功能基因组学的深远影响越来越明显，但迄今为止，对血清磷酸盐水平变化的分子和细胞反应的研究才刚刚开始。这一提议将检验以下假设：可利用的无机磷酸盐的数量通过特定的细胞和分子调控信号改变细胞的生长和转化潜能。为了验证这一假设，我们将利用体外细胞培养转化模型进行机制研究，并结合已建立的两阶段皮肤癌发生模型来确定生理相关性。本文提出的研究将：1)确定无机磷酸盐调节增殖和转化的细胞和分子机制：这条研究路线将验证磷酸盐运输结合FGF受体激活调节小GTP结合蛋白、N-ras和随后的AP-1转录激活的假设，这是磷酸盐诱导的增殖和转化反应所必需的。2)明确饲粮中无机磷酸盐在体内增殖、转化和肿瘤发生中的作用：在DMBA/TPA两阶段皮肤癌模型中，验证减少饲粮中无机磷酸盐的摄入会减少肿瘤发生的假设。

DESCRIPTION (provided by applicant): Inorganic phosphate is critical to the human body on many levels. At the cellular level it is required as a component of energy metabolism, kinase signaling and in the formation and function of DNA and lipids. Traditionally, inorganic phosphate has been thought of as a passive, required ion for these processes, however, recent data suggests a more active role for this ion in the regulation of cell function. Published and preliminary in vitro results have revealed that exposure of a variety of cell types to elevated inorganic phosphate will alter growth properties, specific signal transduction pathways, and gene expression, including cancer and metastasis related factors such as osteopontin, c-fos, Egr1 and Cox-2. Our preliminary in vivo results corroborate the in vitro studies and suggest that the levels of serum inorganic phosphate alter tumorigenesis in the two-stage model of skin carcinogenesis. Taken together the results suggest that the level of available inorganic phosphate may be an important predisposing risk factor to the growth and transformation potential of cells. The main source of serum inorganic phosphate is from dietary intake and due, in part, to the increased consumption of processed foods, the amount of inorganic phosphate in the American diet continues to rise above levels already considered high by the FDA. Although it is becoming increasingly apparent that diet can have profound effects on functional genomics, however, to date the molecular and cellular responses to changes in serum phosphate levels have only begun to be investigated. This proposal will test the hypothesis that; the amount of available inorganic phosphate alters the growth and transformation potential of cells through specific cellular and molecular regulatory signals. To test the hypothesis we will utilize defined in vitro cell culture models of transformation for mechanistic studies in combination with the established two-stage model of skin carcinogenesis to determine physiological relevance. The studies propose herein will: 1) Determine the cellular and molecular mechanisms of inorganic phosphate regulated proliferation and transformation: This line of investigation will test the hypothesis that phosphate transport in combination with FGF receptor activation regulates the small GTP binding protein, N-ras and subsequent AP-1 transcriptional activation necessary for the phosphate-induced proliferation and transformation response. 2) Define the role of dietary inorganic phosphate on proliferation, transformation and tumorigenesis in vivo: This aim will test the hypothesis that reducing dietary inorganic phosphate consumption will decrease tumorigenesis in the DMBA/TPA two-stage skin carcinogenesis model. PUBLIC HEALTH RELEVANCE: Inorganic phosphate is a common dietary element and the amount in the American diet continues to rise above levels already considered high by the FDA. Inorganic phosphate has recently been demonstrated to alter gene expression and the growth phenotype of a variety of cell types however, there is little research regarding the affects of dietary phosphate intake on human health. This proposal will investigate the role of dietary inorganic phosphate in cancer initiation, promotion and progression.