Elevated phosphate activates N-ras and promotes cell transformation and skin tumorigenesis.
Elevated phosphate activates N-ras and promotes cell transformation and skin tumorigenesis.
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DOI：
10.1158/1940-6207.capr-09-0068
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发表时间：
2010-03
期刊：
影响因子：
--
通讯作者：
Beck GR Jr
中科院分区：
文献类型：
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作者：
Camalier CE;Young MR;Bobe G;Perella CM;Colburn NH;Beck GR Jr
最近的研究结果表明，从将无机磷酸盐视为基本细胞功能的被动需求到细胞行为的主动调节剂的范式转变。我们之前已经证明，在成骨前细胞系中，磷酸盐浓度升高会增加细胞增殖和促肿瘤基因（如Fra-1和骨桥蛋白）的表达。因此，我们假设磷酸盐浓度升高会促进体外细胞转化和体内肿瘤发生。添加磷酸盐的培养基增加了Balb/C小鼠JB6表皮细胞的锚定独立转化和增殖，N-ras、ERK1/2和AP-1的激活，并以剂量依赖的方式增加了Fra-1、COX-2和骨桥蛋白的基因表达。这些体外实验结果导致了一种假设，即改变饮食中无机磷酸盐的水平会改变皮肤癌变小鼠模型中的肿瘤发生。雌性FVB/N小鼠分别给予7,12-二甲基苯[a]蒽/12- o -十四能多酚-13-乙酸酯（DMBA/TPA）治疗，并饲喂高磷或低磷饲粮（占饲粮的1.2%和0.2%）19周。在不改变采食量和体重的情况下，高磷饲粮使皮肤乳头瘤数量增加了约50%。高磷饲料增加血清磷酸盐、甲状旁腺激素和骨桥蛋白浓度，降低血清钙浓度。因此，我们得出结论，升高的磷酸盐促进细胞转化和皮肤肿瘤的发生，部分是通过增加磷酸盐激活N-ras及其下游靶点的可用性，这将膳食磷酸盐定义为化学预防的新靶点。
Recent results suggest a paradigm shift from viewing inorganic phosphate as a passive requirement for basic cell functions to an active regulator of cell behavior. We have previously demonstrated that elevated concentrations of phosphate increased cell proliferation and expression of pro-tumorigenic genes such as Fra-1 and osteopontin in a pre-osteoblast cell line. Therefore, we hypothesized that elevated phosphate concentrations would promote cell transformation in vitro and tumorigenesis in vivo. Supplementation of medium with phosphate increased anchorage independent transformation and proliferation of Balb/C mouse JB6 epidermal cells, activation of N-ras, ERK1/2, and AP-1, and increased gene expression of Fra-1, COX-2, and osteopontin in a dose-dependent manner. These in vitro results led to the hypothesis that varying the levels of dietary inorganic phosphate would alter tumorigenesis in the mouse model of skin carcinogenesis. Female FVB/N mice were treated with 7,12-dimethylbenz[a]anthracene/12-O-tetradecanolyphorbol-13-acetate (DMBA/TPA) and fed high or low phosphate diets (1.2 versus 0.2% of the diet) for 19 weeks. The high phosphate diet increased skin papilloma number by approximately 50% without changing feed intake and body weights. High dietary phosphate increased serum concentrations of phosphate, parathyroid hormone, and osteopontin and decreased serum concentrations of calcium. Thus, we conclude that elevated phosphate promotes cell transformation and skin tumorigenesis partly by increasing the availability of phosphate for activation of N-ras and its downstream targets, which defines dietary phosphate as a novel target for chemoprevention.