Growth hormone-releasing hormone receptor antagonists inhibit human gastric cancer through downregulation of PAK1-STAT3/NF-κB signaling
Growth hormone-releasing hormone receptor antagonists inhibit human gastric cancer through downregulation of PAK1-STAT3/NF-κB signaling
复制标题
生长激素释放激素受体拮抗剂通过下调 PAK1-STAT3/NF-KB 信号传导抑制人胃癌
DOI：
10.1073/pnas.1618582114
复制
发表时间：
2016-12-20
影响因子：
11.1
通讯作者：
Zhang, Hao
中科院分区：
文献类型：
--
作者：
Gan, Jinfeng;Ke, Xiurong;Zhang, Hao
胃癌是世界范围内发病率第四高、死亡率第二高的恶性肿瘤。迫切需要制定有效的治疗方法。生长激素释放激素（GHRH）及其受体（GHRH-R）广泛存在于多种肿瘤组织和细胞系中。因此，GHRH-R的抑制被认为是治疗这些癌症的有希望的方法。然而，很少有人知道GHRH-R和相关的治疗人类胃癌。通过对多组胃癌患者的生存分析，我们发现肿瘤标本中GHRH-R的增加与生存不良相关，并且是患者预后的独立预测因子。我们接下来表明，MIA-602，一种高效的GHRH-R拮抗剂，有效地抑制培养细胞中的GC生长。此外，在异种移植到裸鼠中的人GC细胞系的多个模型中验证了这种抑制作用。从机制上讲，GHRH-R拮抗剂靶向GHRH-R并下调p21激活激酶1（PAK 1）介导的信号转导和转录激活因子3（STAT 3）/核因子-κ B（NF-κ B）炎症通路。总之，我们的研究确立了GHRH-R作为人类GC的潜在分子靶点，并建议用GHRH-R拮抗剂治疗作为这种癌症的有希望的治疗干预。
Gastric cancer (GC) ranks as the fourth most frequent in incidence and second in mortality among all cancers worldwide. The development of effective treatment approaches is an urgent requirement. Growth hormone-releasing hormone (GHRH) and GHRH receptor (GHRH-R) have been found to be present in a variety of tumoral tissues and cell lines. Therefore the inhibition of GHRH-R was proposed as a promising approach for the treatment of these cancers. However, little is known about GHRH-R and the relevant therapy in human GC. By survival analyses of multiple cohorts of GC patients, we identified that increased GHRH-R in tumor specimens correlates with poor survival and is an independent predictor of patient prognosis. We next showed that MIA-602, a highly potent GHRH-R antagonist, effectively inhibited GC growth in cultured cells. Further, this inhibitory effect was verified in multiple models of human GC cell lines xenografted into nude mice. Mechanistically, GHRH-R antagonists target GHRH-R and down-regulate the p21-activated kinase 1 (PAK1)-mediated signal transducer and activator of transcription 3 (STAT3)/nuclear factor-kappa B (NF-kappa B) inflammatory pathway. Overall, our studies establish GHRH-R as a potential molecular target in human GC and suggest treatment with GHRH-R antagonist as a promising therapeutic intervention for this cancer.