Novel role of thromboxane receptors β isoform in bladder cancer pathogenesis
Novel role of thromboxane receptors β isoform in bladder cancer pathogenesis
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DOI：
10.1158/0008-5472.can-07-6560
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发表时间：
2008-06-01
期刊：
影响因子：
11.2
通讯作者：
Watson, Dennis K.
中科院分区：
文献类型：
--
作者：
Moussa, Omar;Ashton, Anthony W.;Watson, Dennis K.
这些研究是为了确定血栓素受体(TP)在膀胱癌中的潜在作用。本文报道的数据显示，在膀胱癌患者的组织中，TP-β受体蛋白的表达增加，并与显著不良的预后相关(P<；0.005)。膀胱癌细胞株表达TP-β亚型，不同于永生化的未转化的尿路上皮细胞(SV-Huc)，后者只表达TP-α亚型。在体外，TP-β受体的表达促进了细胞的增殖、迁移和侵袭，在体内也导致了SV-Huc细胞的恶性转化。激动剂介导的细胞外信号调节激酶和FAK的磷酸化依赖于TP-β的表达。此外，TP-β通过G-蛋白α亚基12或β-arrestin 2信号转导多种生物学效应。TP受体拮抗剂GR32191单独或与顺铂联合治疗，与赋形剂或顺铂单独治疗相比，显著延迟TCC-SUP膀胱癌细胞移植小鼠的肿瘤发生和延长小鼠的生存时间。这些结果支持TP-β受体亚型在膀胱癌进展中发挥独特作用的模型，其表达可能具有预测价值，并提供新的治疗靶点。
These studies were undertaken to determine the potential role of thromboxane receptors (TP) in bladder cancer. The data reported herein show that expression of the TP-beta receptor protein is increased in tissue obtained from patients with bladder cancer and associated with a significantly poorer prognosis (P < 0.005). Bladder cancer cell lines express the TP-beta isoform, unlike immortalized nontransformed urothelial cells (SV-HUC) that express only the TP-alpha isoform. TP-beta receptor expression, but not TP-alpha, promoted cell proliferation, migration, and invasion in vitro, and also resulted in malignant transformation of SV-HUC cells in vivo. Agonist-mediated phosphorylation of extracellular signal-regulated kinase and FAK was dependent on the expression of TP-beta. Furthermore, TP-beta mediated multiple biological effects by signaling through either G-protein alpha subunit 12 or beta-arrestin 2. Treatment of mice with the TP receptor antagonist GR32191, alone or in combination with cisplatin, significantly delayed tumor onset and prolonged survival of mice transplanted with TCC-SUP bladder cancer cells compared with vehicle or cisplatin alone. These results support the model that the TP-beta receptor isoform plays a unique role in bladder cancer progression and its expression may have predictive value and provide a novel therapeutic target.