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）：在许多层面上，无机磷酸盐对人体至关重要。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所必需的。传统上，无机磷酸盐被认为是一种被动的，对于这些过程所需的离子，但是，最近的数据表明，该离子在细胞功能调节中起着更活跃的作用。已发表和初步的体外结果表明，各种细胞类型暴露于升高的无机磷酸盐升高将改变生长特性，特定的信号转导途径以及基因表达，包括癌症和转移相关因素，例如骨桥蛋白骨，C-FOS，C-FOS，EGR1，EGR1和COX-2。我们的初步体内导致体外研究证实了体外研究，并表明血清无机磷酸盐的水平改变了皮肤致癌的两阶段模型中的肿瘤发生。总而言之，结果表明，可用的无机磷酸盐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量，部分是由于加工食品的消耗量增加，美国饮食中无机磷酸盐的量持续上升到FDA已经认为很高的水平以上。尽管越来越明显的是，饮食可以对功能基因组学产生深远的影响，但是迄今为止，尚未开始研究分子和细胞对血清磷酸盐水平变化的反应。该提案将检验以下假设。可用的无机磷酸盐量通过特定的细胞和分子调节信号改变了细胞的生长和转化潜力。为了检验假设，我们将利用定义的体外细胞培养模型进行机械研究，并结合确定的皮肤致癌的两阶段模型来确定生理相关性。 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）定义饮食中磷酸盐对体内增殖，转化和肿瘤发生的作用：此目的将检验以下假设：减少饮食中的无机磷酸盐消耗将减少DMBA/TPA两级皮肤癌变模型的肿瘤发生。 公共卫生相关性：无机磷酸盐是一种常见的饮食元素，美国饮食中的数量继续超过FDA已经认为很高的水平。最近已证明无机磷酸盐可以改变基因表达和各种细胞类型的生长表型，但是，关于饮食中磷酸盐摄入对人类健康的影响的研究很少。该建议将研究饮食中磷酸盐在癌症开始，促进和进展中的作用。