Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA.
Neoplasia. 2011 May;13(5):428-38. doi: 10.1593/neo.101620.
The calcium-sensing receptor (CaR) is responsible for the regulation of extracellular calcium (Ca(2+) (o)) 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(2+) (o)-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.
钙敏感受体 (CaR) 负责调节细胞外钙 (Ca(2+) (o)) 稳态。CaR 的激活已被证明可增加几种癌细胞系的增殖；然而，其在肺癌中的存在或功能从未被记录过。我们报告称，Ca(2+) (o) 激活的 CaR 导致人肺鳞癌细胞系 (SCC) 中 MAPK 介导的甲状旁腺激素相关蛋白 (PTHrP) 产生的刺激，以及体内恶性肿瘤所致高钙血症 (HHM)。此外，从诱导高钙血症的肺 SCC 中鉴定出的 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。野生型 CaR 或细胞质域中单核苷酸多态性的 CaR 变体的表达增加对于肺 SCC 诱导 HHM 都是必需且充分的。由于肺癌患者经常发生 HHM 和肺癌中 PTHrP 的表达仅部分得到解释，因此我们发现的意义表明 CaR 变体可能在 PTHrP 和钙之间提供正反馈，导致 HHM 综合征。
