The Calcium-Sensing Receptor Is Necessary for the Rapid Development of Hypercalcemia in Human Lung Squamous Cell Carcinoma
The Calcium-Sensing Receptor Is Necessary for the Rapid Development of Hypercalcemia in Human Lung Squamous Cell Carcinoma
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DOI：
10.1593/neo.101620
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发表时间：
2011-05-01
期刊：
影响因子：
4.8
通讯作者：
Rosol, Thomas J.
中科院分区：
文献类型：
--
作者：
Lorch, Gwendolen;Viatchenko-Karpinski, Serge;Rosol, Thomas J.
钙敏感受体（CaR）负责调节细胞外钙（Ca-o（2+））稳态。CaR激活已被证明可以增加几种癌细胞系的增殖;然而，它的存在或功能在肺癌中从未被记录。我们报道了钙离子激活的CaR导致MAPK介导的人肺鳞状细胞癌（SCC）细胞系和恶性肿瘤体液高钙血症（HHM）中甲状旁腺相关蛋白（PTHrP）的产生。此外，从高钙血症诱导的肺SCC中鉴定的CaR单核苷酸多态性降低了受体的激活阈值，导致PTHrP表达和分泌增加。增加野生型CaR或胞质结构域中具有单核苷酸多态性的CaR变体的表达是肺SCC诱导HHM的必要和充分条件。由于肺癌患者经常发展HHM和PTHrP在肺癌中的表达仅得到部分解释，我们的研究结果的意义表明，CaR变体可能提供PTHrP和钙之间的正反馈，导致HHM综合征。
The calcium-sensing receptor (CaR) is responsible for the regulation of extracellular calcium (Ca-o(2+)) homeostasis. CaR activation has been shown to increase proliferation in several cancer cell lines; however, its presence or function has never been documented in lung cancer. We report that Ca-o(2+)-activated CaR results in MAPK-mediated stimulation of parathyroid hormone-related protein (PTHrP) production in human lung squamous cell carcinoma (SCC) lines and humoral hypercalcemia of malignancy (HHM) in vivo. Furthermore, a single nucleotide polymorphism in CaR identified from a hypercalcemia-inducing lung SCC reduced the receptor's activation threshold leading to increased PTHrP expression and secretion. Increasing the expression of either wild-type CaR or a CaR variant with a single nucleotide polymorphism in the cytoplasmic domain was both necessary and sufficient for lung SCC to induce HHM. Because lung cancer patients who frequently develop HHM and PTHrP expression in lung cancer has been only partially explained, the significance of our findings indicates that CaR variants may provide a positive feedback between PTHrP and calcium and result in the syndrome of HHM.