The G protein-coupled receptor GALR2 promotes angiogenesis in head and neck cancer.
The G protein-coupled receptor GALR2 promotes angiogenesis in head and neck cancer.
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DOI：
10.1158/1535-7163.mct-13-0904
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发表时间：
2014-05
影响因子：
5.7
通讯作者：
D'Silva NJ
中科院分区：
文献类型：
--
作者：
Banerjee R;Van Tubergen EA;Scanlon CS;Vander Broek R;Lints JP;Liu M;Russo N;Inglehart RC;Wang Y;Polverini PJ;Kirkwood KL;D'Silva NJ
头颈部鳞状细胞癌（SCCHN）是一种侵袭性疾病，患者生存率低。甘丙肽受体2（GALR 2）是一种G蛋白偶联受体（GPCR），可诱导SCCHN中的侵袭性肿瘤生长。本研究的目的是研究GALR 2促进血管生成的机制，血管生成是肿瘤生长所需的关键致癌表型。通过ELISA和体外血管生成测定研究了GALR 2表达对多种SCCHN细胞系中促血管生成细胞因子分泌的影响。化学抑制剂和基因敲除策略被用来了解关键的调节子。在小鼠异种移植物、鸡绒毛尿囊膜（CAM）和临床相关的小鼠原位口底模型中研究了GALR 2对血管生成的体内影响。GALR 2通过p38-MAPK介导的促血管生成细胞因子VEGF和IL-6的分泌诱导血管生成。此外，GALR 2激活小GTP蛋白，RAP 1B，从而诱导p38介导的三曲脯氨酸（TTP）失活，其功能是使细胞因子转录物不稳定。这导致促血管生成细胞因子的分泌增强以及体外和体内血管生成。在过度表达GALR 2的SCCHN细胞中，TTP的失活增加了IL-6和VEGF的分泌，而p38的抑制激活了TTP并减少了细胞因子的分泌。在这里，我们报告说，GALR 2刺激肿瘤血管生成SCCHN通过p38介导的抑制TTP，从而增强细胞因子分泌。鉴于p38抑制剂在临床上用于炎性疾病，GALR 2/p38介导的细胞因子分泌可能是SCCHN新辅助治疗的极好靶点。
Squamous cell carcinoma of the head and neck (SCCHN) is an aggressive disease with poor patient survival. Galanin Receptor 2 (GALR2) is a G-protein coupled receptor (GPCR) that induces aggressive tumor growth in SCCHN. The objective of this study was to investigate the mechanism by which GALR2 promotes angiogenesis, a critical oncogenic phenotype required for tumor growth. The impact of GALR2 expression on secretion of pro-angiogenic cytokines in multiple SCCHN cell lines was investigated by ELISA and in-vitro angiogenesis assays. Chemical inhibitor and genetic knockdown strategies were used to understand the key regulators. The in-vivo impact of GALR2 on angiogenesis was investigated in mouse xenograft, chick chorioallantoic membrane (CAM) and the clinically-relevant mouse orthotopic floor-of-mouth models. GALR2 induced angiogenesis via p38-MAPK-mediated secretion of pro-angiogenic cytokines, VEGF and IL-6. Moreover, GALR2 activated small-GTP-protein, RAP1B, thereby inducing p38-mediated inactivation of tristetraprolin (TTP), which functions to destabilize cytokine transcripts. This resulted in enhanced secretion of pro-angiogenic cytokines and angiogenesis in-vitro and in-vivo. In SCCHN cells overexpressing GALR2, inactivation of TTP increased secretion of IL-6 and VEGF, whereas inhibition of p38 activated TTP and decreased cytokine secretion. Here we report that GALR2 stimulates tumor angiogenesis in SCCHN via p38-mediated inhibition of TTP with resultant enhanced cytokine secretion. Given that p38 inhibitors are in clinical use for inflammatory disorders, GALR2/p38-mediated cytokine secretion may be an excellent target for new adjuvant therapy in SCCHN.