Inorganic phosphate regulated proliferation, transformation and tumorigenesis

无机磷酸盐调节增殖、转化和肿瘤发生

• 批准号: 8240098
• 负责人: GEORGE R. BECK
• 金额: $ 31.2万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-24 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8240098
• 关键词: Affect; American; Anchorage-Independent Growth; Biochemical; Carcinoma; Cell Culture Techniques; Cell physiology; Cells; Consumption; Cyclin D1; DNA; Data; Diet; Dietary intake; Disease; Elements; Energy Metabolism; Event; FOS gene; Fibroblast Growth Factor Receptors; Fibroblasts; Food Processing; GTP-Binding Proteins; Gene Expression; Growth; Health; Human; Human body; In Vitro; Indium; Inorganic Phosphate Transporter; Intake; Investigation; Ions; Knockout Mice; Lipids; Modeling; Molecular; Monomeric GTP-Binding Proteins; Mus; Neoplasm Metastasis; Nutritional; Papilloma; Phenotype; Phosphotransferases; Physiological; Process; Property; Proteomics; Publishing; Receptor Activation; Receptor Signaling; Regulation; Research; Risk Factors; Role; Serum; Signal Transduction; Signal Transduction Pathway; Signaling Protein; Skin Carcinogenesis; Sodium; Source; Staging; Testing; Therapeutic; Tissues; Transcription Factor AP-1; Transcriptional Activation; Tumorigenicity; Vitamin D; cancer initiation; cell behavior; cell type; dimethylbenzanthracene; extracellular; functional genomics; human disease; in vitro Model; in vivo; inorganic phosphate; insight; keratinocyte; neglect; osteopontin; public health relevance; response; tumor; tumorigenesis; tumorigenic

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.

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所需的被动离子，然而，最近的数据表明该离子在细胞功能调节中发挥着更积极的作用。已发表的初步体外结果表明，多种细胞类型暴露于升高的无机磷酸盐会改变生长特性、特定信号转导途径和基因表达，包括癌症和转移相关因子，如骨桥蛋白、c-fos、Egr1 和 Cox-2。我们的初步体内结果证实了体外研究，并表明血清无机磷酸盐水平改变了皮肤癌发生的两阶段模型中的肿瘤发生。总而言之，这些结果表明，可用无机磷酸盐的水平可能是细胞生长和转化潜力的重要诱发风险因素。血清无机磷酸盐的主要来源是饮食摄入，部分原因是加工食品消费量的增加，美国饮食中无机磷酸盐的含量持续上升，超过 FDA 已经认为较高的水平。尽管饮食对功能基因组学产生深远影响这一点变得越来越明显，但迄今为止，对血清磷酸盐水平变化的分子和细胞反应才刚刚开始研究。该提案将检验以下假设：可用无机磷酸盐的量通过特定的细胞和分子调节信号改变细胞的生长和转化潜力。为了检验这一假设，我们将利用定义的体外细胞培养转化模型进行机制研究，并结合已建立的皮肤癌发生的两阶段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：这一研究方向将检验磷酸盐转运与 FGF 受体激活相结合调节磷酸盐诱导的增殖和转化反应所必需的小 GTP 结合蛋白、N-ras 和随后的 AP-1 转录激活的假设。 2) 定义膳食无机磷酸盐对体内增殖、转化和肿瘤发生的作用：该目标将检验以下假设：减少膳食无机磷酸盐消耗将减少 DMBA/TPA 两阶段皮肤癌发生模型中的肿瘤发生。 公众健康相关性：无机磷酸盐是一种常见的膳食元素，美国饮食中的含量持续上升，超过了 FDA 认为较高的水平。最近已证明无机磷酸盐可以改变多种细胞类型的基因表达和生长表型，然而，关于膳食磷酸盐摄入量对人类健康影响的研究很少。该提案将研究膳食无机磷酸盐在癌症发生、促进和进展中的作用。