Wagner Nikolaus B, Weide Benjamin, Reith Maike, Tarnanidis Kathrin, Kehrel Coretta, Lichtenberger Ramtin, Pflugfelder Annette, Herpel Esther, Eubel Jana, Ikenberg Kristian, Busch Christian, Holland-Letz Tim, Naeher Helmut, Garbe Claus, Umansky Viktor, Enk Alexander, Utikal Jochen, Gebhardt Christoffer
Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
Int J Cancer. 2015 Dec 1;137(11):2607-17. doi: 10.1002/ijc.29619. Epub 2015 Jul 14.
RAGE is a central driver of tumorigenesis by sustaining an inflammatory tumor microenvironment. This study links the soluble forms of RAGE (sRAGE and esRAGE) with clinical outcome of melanoma patients. Moreover, tissue expression of RAGE was analyzed using immunohistochemistry on two independent tissue microarrays (TMA) containing 35 or 257 primary melanomas, and 41 or 22 benign nevi, respectively. Serum concentrations of sRAGE and esRAGE were measured in 229 Stage III-IV patients using ELISA and plasma concentrations of sRAGE were analyzed in an independent second cohort with 173 samples of Stage I-IV patients. In this cohort, three well-described SNPs in the RAGE gene were analyzed. RAGE protein expression was highly upregulated in primary melanomas compared to benign nevi in the two TMA (p < 0.001 and p = 0.005) as well as in sun-exposed melanomas (p = 0.046). sRAGE and esRAGE were identified as prognostic markers for survival as diminished sRAGE (p = 0.034) and esRAGE (p = 0.012) serum levels correlated with poor overall survival (OS). Multivariate Cox regression analysis showed that diminished serum sRAGE was independently associated with poor survival (p = 0.009). Moreover, diminished sRAGE was strongly associated with impaired OS in the second cohort (p < 0.001). Multivariate Cox regression analysis including the investigated SNPs revealed an independent correlation of the two interacting promoter SNPs with impaired OS. In conclusion, the soluble forms of RAGE and variants in its genetic locus are prognostic markers for survival in melanoma patients with high risk for progression.
RAGE通过维持炎症性肿瘤微环境，成为肿瘤发生的核心驱动因素。本研究将RAGE的可溶性形式（sRAGE和esRAGE）与黑色素瘤患者的临床结局联系起来。此外，利用免疫组织化学方法，在两个分别包含35例或257例原发性黑色素瘤以及41例或22例良性痣的独立组织微阵列（TMA）上分析了RAGE的组织表达。使用酶联免疫吸附测定法（ELISA）测定了229例III-IV期患者血清中sRAGE和esRAGE的浓度，并在一个包含173例I-IV期患者样本的独立第二队列中分析了sRAGE的血浆浓度。在该队列中，分析了RAGE基因中三个已充分描述的单核苷酸多态性（SNP）。在两个TMA中，与良性痣相比，原发性黑色素瘤中RAGE蛋白表达显著上调（p < 0.001和p = 0.005），在暴露于阳光的黑色素瘤中也是如此（p = 0.046）。sRAGE和esRAGE被确定为生存的预后标志物，因为sRAGE（p = 0.034）和esRAGE（p = 0.012）血清水平降低与总体生存期（OS）较差相关。多变量Cox回归分析表明，血清sRAGE降低与生存期差独立相关（p = 0.009）。此外，在第二队列中，sRAGE降低与OS受损密切相关（p < 0.001）。包括所研究SNP的多变量Cox回归分析显示，两个相互作用的启动子SNP与OS受损存在独立相关性。总之，RAGE的可溶性形式及其基因位点的变异是进展风险高的黑色素瘤患者生存的预后标志物。
