Division of Surgical Science, Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Cancer Res. 2010 Jul 1;70(13):5628-38. doi: 10.1158/0008-5472.CAN-10-0595. Epub 2010 Jun 22.
Receptor for advanced glycation end products (RAGE) and its ligands are overexpressed in multiple cancers. RAGE has been implicated in tumorigenesis and metastasis, but little is known of the mechanisms involved. In this study, we define a specific functional role for an alternate splice variant termed RAGE splice variant 1 (RAGEv1), which encodes a soluble endogenous form of the receptor that inhibits tumorigenesis. RAGEv1 was downregulated in lung, prostate, and brain tumors relative to control matched tissues. Overexpressing RAGEv1 in tumor cells altered RAGE ligand stimulation of several novel classes of genes that are critical in tumorigenesis and metastasis. Additionally, RAGEv1 inhibited tumor formation, cell invasion, and angiogenesis induced by RAGE ligand signaling. Analysis of signal transduction pathways underlying these effects revealed marked suppression of c-jun-NH(2)-kinase (JNK) pathway signaling, and JNK inhibition suppressed signaling through the RAGE pathway. Tumors expressing RAGEv1 were significantly smaller than wild-type tumors and displayed prominently reduced activation of JNK. Our results identify RAGEv1 as a novel suppressor, the study of which may offer new cancer therapeutic directions.
晚期糖基化终产物受体（RAGE）及其配体在多种癌症中过度表达。RAGE 已被牵涉到肿瘤发生和转移中，但涉及的机制知之甚少。在这项研究中，我们确定了一个称为 RAGE 剪接变体 1（RAGEv1）的特殊功能，它编码一种可溶性内源性受体，可抑制肿瘤发生。与对照匹配组织相比，RAGEv1 在肺癌、前列腺癌和脑肿瘤中下调。在肿瘤细胞中过表达 RAGEv1 改变了 RAGE 配体对几种新型基因的刺激，这些基因在肿瘤发生和转移中至关重要。此外，RAGEv1 抑制了由 RAGE 配体信号诱导的肿瘤形成、细胞侵袭和血管生成。对这些作用的信号转导途径的分析表明，c-jun-NH(2)-kinase（JNK）途径信号明显受到抑制，而 JNK 抑制抑制了 RAGE 途径的信号转导。表达 RAGEv1 的肿瘤明显小于野生型肿瘤，并且 JNK 的激活显著降低。我们的结果将 RAGEv1 鉴定为一种新型的抑制剂，对其研究可能为癌症治疗提供新的方向。
