The calcium-sensing receptor: A promising target for prevention of colorectal cancer.
The calcium-sensing receptor: A promising target for prevention of colorectal cancer.
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DOI：
10.1016/j.bbamcr.2015.02.011
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发表时间：
2015-09
期刊：
影响因子：
--
通讯作者：
Kállay E
中科院分区：
文献类型：
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作者：
Aggarwal A;Prinz-Wohlgenannt M;Tennakoon S;Höbaus J;Boudot C;Mentaverri R;Brown EM;Baumgartner-Parzer S;Kállay E
膳食钙摄入量与结直肠癌（CRC）风险之间的负相关性是众所周知的，但了解甚少。钙敏感受体（CaSR），一种钙结合G蛋白偶联受体的表达在CRC中下调，这使我们假设CaSR在结肠中具有肿瘤抑制作用。本研究的目的是了解CaSR表达的恢复是否可以减少CRC的恶性表型。在人类结直肠肿瘤中，CaSR的表达与增殖标志物呈负相关，而CaSR的缺失与肿瘤分化差和凋亡潜力降低相关。在体内，缺乏CaSR显著增加了CaSR/PTH双敲除小鼠结肠中增殖标志物的表达，降低了分化和凋亡标志物的水平，证实了CaSR的肿瘤抑制功能。稳定过表达野生型CaSR的体外CRC细胞显示出增殖的显著降低，以及分化和凋亡潜力的增加。CaSR的正向别构调节剂CaSR-568进一步增强了这些作用，而用负向别构调节剂CaSR-2143处理则抑制了这些功能。有趣的是，显性负突变体（R185 Q）能够消除这些影响。我们的研究结果证明了CaSR在结肠中的关键肿瘤抑制作用。CaSR表达和功能的恢复与增殖、分化和凋亡之间平衡的调节有关，并为CRC治疗的新策略提供了理论基础。CaSR是结肠中的肿瘤抑制剂，抑制癌症的几个标志。CaSR表达和功能的恢复降低了CRC的恶性表型。我们的数据为开发针对CaSR的CRC治疗策略提供了理论基础。具有失活CaSR突变的人可能代表CRC的新风险组。
The inverse correlation between dietary calcium intake and the risk of colorectal cancer (CRC) is well known, but poorly understood. Expression of the calcium-sensing receptor (CaSR), a calcium-binding G protein-coupled receptor is downregulated in CRC leading us to hypothesize that the CaSR has tumor suppressive roles in the colon. The aim of this study was to understand whether restoration of CaSR expression could reduce the malignant phenotype in CRC. In human colorectal tumors, expression of the CaSR negatively correlated with proliferation markers whereas loss of CaSR correlated with poor tumor differentiation and reduced apoptotic potential. In vivo, dearth of CaSR significantly increased expression of proliferation markers and decreased levels of differentiation and apoptotic markers in the colons of CaSR/PTH double knock-out mice confirming the tumor suppressive functions of CaSR. In vitro CRC cells stably overexpressing wild-type CaSR showed significant reduction in proliferation, as well as increased differentiation and apoptotic potential. The positive allosteric modulator of CaSR, NPS R-568 further enhanced these effects, whereas treatment with the negative allosteric modulator, NPS 2143 inhibited these functions. Interestingly, the dominant-negative mutant (R185Q) was able to abrogate these effects. Our results demonstrate a critical tumor suppressive role of CaSR in the colon. Restoration of CaSR expression and function is linked to regulation of the balance between proliferation, differentiation, and apoptosis and provides a rationale for novel strategies in CRC therapy. The CaSR is a tumor suppressor in the colon inhibiting several hallmarks of cancer. Restoration of CaSR expression and function reduces malignant phenotype in CRC. Our data provide a rationale to develop CRC therapy stratergies targeting the CaSR. Persons with inactivating CaSR mutations could represent a new risk group in CRC.