Shah Girish V, Thomas Shibu, Muralidharan Anbalagan, Liu Yong, Hermonat Paul L, Williams Jill, Chaudhary Jaideep
Division of Pharmacology, University of Louisiana College of Pharmacy, 700 University Avenue, Monroe, Louisiana 71209, USA.
Endocr Relat Cancer. 2008 Dec;15(4):953-64. doi: 10.1677/ERC-08-0136. Epub 2008 Sep 10.
Expression of calcitonin (CT) and its receptor (CTR) is elevated in advanced prostate cancer (PC). Although the significance of CT-CTR axis in PC cell growth, invasion, and epithelial to mesenchymal transition has been established, its role in tumor metastasis has not been examined. To examine the role of CT-CTR axis in tumor metastasis, we employed stable CT-CTR activated and silenced system of three PC cell lines, LNCaP cells that lack endogenous CT, PC-3 cells that lack endogenous CTR, and PC-3M cells that co-express CT and CTR. Enforced expression of CT in LNCaP cells and CTR in PC-3 cells increased their ability to form orthotopic tumors and distant metastases in multiple organs. By contrast, silencing of CT expression in PC-3M cells not only reduced their tumorigenicity, but also completely abrogated their metastatic potential. To investigate the effect of in vivo silencing of CT expression on tumor growth, we employed recombinant adeno-associated virus (rAAV) to deliver anti-CT ribozymes in preexisting tumors of nude mice and large probasin promoter (LPB)-Tag transgenic mice. rAAV-CT(-) treatment not only abrogated the growth of pre-implanted tumors in nude mice, but also significantly reduced the growth of spontaneous tumors in LPB-Tag mice. Analysis of CT upregulated and silenced PC-3M transcriptomes revealed 105 genes affected by the modulation of CT expression. These CT signature genes generated survival, adhesion, pro-inflammatory, and pro-metastatic pathways. Added together, these data indicate a pivotal role for CT-CTR axis in PC metastasis and may serve as a potential therapeutic target for advanced PC.
降钙素（CT）及其受体（CTR）在晚期前列腺癌（PC）中的表达升高。尽管CT-CTR轴在PC细胞生长、侵袭及上皮-间质转化中的意义已得到证实，但其在肿瘤转移中的作用尚未得到研究。为了研究CT-CTR轴在肿瘤转移中的作用，我们构建了三种PC细胞系（缺乏内源性CT的LNCaP细胞、缺乏内源性CTR的PC-3细胞以及共表达CT和CTR的PC-3M细胞）的CT-CTR稳定激活和沉默系统。在LNCaP细胞中强制表达CT以及在PC-3细胞中强制表达CTR，增强了它们在多个器官中形成原位肿瘤和远处转移的能力。相比之下，沉默PC-3M细胞中的CT表达不仅降低了它们的致瘤性，还完全消除了它们的转移潜能。为了研究体内沉默CT表达对肿瘤生长的影响，我们使用重组腺相关病毒（rAAV）将抗CT核酶递送至裸鼠和大前列腺素启动子（LPB）-Tag转基因小鼠的现有肿瘤中。rAAV-CT(-)治疗不仅消除了裸鼠中预先植入肿瘤的生长，还显著降低了LPB-Tag小鼠中自发肿瘤的生长。对CT上调和沉默的PC-3M转录组分析显示，有105个基因受CT表达调节的影响。这些CT特征基因产生了生存、黏附、促炎和促转移途径。综上所述，这些数据表明CT-CTR轴在PC转移中起关键作用，可能成为晚期PC的潜在治疗靶点。
