Down-regulation of the receptor for advanced glycation end-products (RAGE) supports non-small cell lung carcinoma
Down-regulation of the receptor for advanced glycation end-products (RAGE) supports non-small cell lung carcinoma
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DOI：
10.1093/carcin/bgh333
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发表时间：
2005-02-01
期刊：
影响因子：
4.7
通讯作者：
Simm, A
中科院分区：
文献类型：
--
作者：
Bartling, B;Hofmann, HS;Simm, A
晚期糖基化终末产物受体 (RAGE) 是免疫球蛋白超家族的跨膜受体。已鉴定出多种与 RAGE 结合的配体，包括两性蛋白。实验研究引发了这样的讨论：RAGE 及其与两性蛋白的相互作用有助于肿瘤生长和转移。然而，当比较肿瘤中的 RAGE 与组织学正常组织时，没有一项研究考虑到癌症中的差异转录谱可能会改变对研究结果的解释。在这里，我们发现与正常肺组织相比，非小细胞肺癌中 RAGE 的 mRNA 显着降低，蛋白质水平更是如此。 RAGE 的下调与较高的肿瘤 (TNM) 分期相关，但不依赖于组织学亚型、鳞状细胞肺癌和腺癌。随后，全长人 RAGE 在肺癌细胞 (NCI-H358) 中的过度表达显示在某些条件下肿瘤生长减弱。虽然在单层培养物中表达 RAGE 的细胞的增殖低于表达细胞质结构域缺失突变体 DeltacytoRAGE 或模拟转染的 NCI-H358 的细胞，但与 DeltacytoRAGE 细胞相比，RAGE 细胞在球状培养物和无胸腺小鼠体内也形成更小的肿瘤。此外，我们观察到胶原层上表达 RAGE 的细胞和表达 DeltacytoRAGE 的细胞有更多的上皮生长，而模拟 NCI-H358 细胞保持其肿瘤形态。这一观察结果得到了免疫荧光分析的支持，表明 RAGE 优先定位于细胞间接触位点，与细胞质结构域的表达无关。因此，RAGE 的下调可能被认为是组织重组和肺肿瘤形成的关键步骤。
The receptor for advanced glycation end-products (RAGE) is a transmembrane receptor of the immunoglobulin superfamily. Several ligands binding to RAGE have been identified, including amphoterin. Experimental studies have given rise to the discussion that RAGE and its interaction with amphoterin contribute to tumour growth and metastasis. However, none of the studies considered a differential transcription profile in cancer that might change the interpretation of the study results when comparing RAGE in tumours with histologically normal tissues. Here we show that RAGE is strongly reduced at the mRNA and even more so at the protein level in non-small cell lung carcinomas compared with normal lung tissues. Down-regulation of RAGE correlates with higher tumour (TNM) stages but does not depend on the histological subtypes, squamous cell lung carcinoma and adenocarcinoma. Subsequent overexpression of full-length human RAGE in lung cancer cells (NCI-H358) showed diminished tumour growth under some conditions. While proliferation of RAGE-expressing cells was less than that of cells expressing the cytoplasmic domain deletion mutant DeltacytoRAGE or mock-transfected NCI-H358 in monolayer cultures, RAGE cells also formed smaller tumours in spheroid cultures and in vivo in athymic mice compared with DeltacytoRAGE cells. Moreover, we observed a more epithelial growth of RAGE-expressing, but also of DeltacytoRAGE-expressing, cells on collagen layers, whereas mock NCI-H358 cells kept their tumour morphology. This observation was supported by immunofluorescence analyses demonstrating that RAGE preferentially localizes at intercellular contact sites, independent of expression of the cytoplasmic domain. Thus, down-regulation of RAGE may be considered as a critical step in tissue reorganization and the formation of lung tumours.