Authors' Affiliations: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry; Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan; Department of Craniofacial Biology, The Medical University of South Carolina, Columbia, South Carolina.
Mol Cancer Ther. 2014 May;13(5):1323-33. doi: 10.1158/1535-7163.MCT-13-0904. Epub 2014 Feb 25.
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 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 proangiogenic 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, and the clinically relevant mouse orthotopic floor-of-mouth models. GALR2 induced angiogenesis via p38-MAPK-mediated secretion of proangiogenic cytokines, VEGF, and interleukin-6 (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 proangiogenic 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.
头颈部鳞状细胞癌 (SCCHN) 是一种侵袭性疾病，患者生存状况较差。甘丙肽受体 2 (GALR2) 是一种 G 蛋白偶联受体，可诱导 SCCHN 中侵袭性肿瘤生长。本研究旨在探讨 GALR2 促进血管生成的机制，血管生成是肿瘤生长所必需的关键致癌表型。通过 ELISA 和体外血管生成试验研究了 GALR2 表达对多种 SCCHN 细胞系中促血管生成细胞因子分泌的影响。使用化学抑制剂和基因敲低策略来理解关键调节因子。通过小鼠异种移植、鸡绒毛尿囊膜和临床相关的小鼠原位口腔底模型研究了 GALR2 对血管生成的体内影响。GALR2 通过 p38-MAPK 介导的促血管生成细胞因子、VEGF 和白细胞介素-6 (IL-6) 的分泌诱导血管生成。此外，GALR2 激活小 GTP 蛋白 RAP1B，从而诱导 p38 介导的 tristetraprolin (TTP) 失活，TTP 的作用是使细胞因子转录物不稳定。这导致体外和体内促血管生成细胞因子和血管生成的增强。在过表达 GALR2 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 GALR2 通过 p38 介导的 TTP 抑制刺激 SCCHN 中的肿瘤血管生成，从而导致细胞因子分泌增强。鉴于 p38 抑制剂用于炎症性疾病的临床治疗，GALR2/p38 介导的细胞因子分泌可能是 SCCHN 新辅助治疗的一个极好靶点。
