Leja Justyna, Essaghir Ahmed, Essand Magnus, Wester Kenneth, Oberg Kjell, Tötterman Thomas H, Lloyd Ricardo, Vasmatzis George, Demoulin Jean-Baptiste, Giandomenico Valeria
Division of Clinical Immunology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Mod Pathol. 2009 Feb;22(2):261-72. doi: 10.1038/modpathol.2008.174. Epub 2008 Oct 24.
The gene expression profile of metastasizing serotonin-producing neuroendocrine carcinomas, which arise from enterochromaffin cells in the jejunum and ileum, is still largely unknown. The aim of this study was to identify genes and proteins, which are preferentially expressed by neuroendocrine carcinoma and enterochromaffin cells and therefore potential novel biomarkers and/or therapeutic targets. Six carcinoma specimens and six normal ileal mucosas were profiled by Affymetrix microarrays. Advanced bioinformatics identified differentially and specifically expressed genes, which were validated by quantitative real-time-PCR on tumor cells extracted by laser capture microdissection and normal enterochromaffin cells extracted by immunolaser capture microdissection. We identified six novel marker genes for neuroendocrine carcinoma cells: paraneoplastic antigen Ma2 (PNMA2), testican-1 precursor (SPOCK1), serpin A10 (SERPINA10), glutamate receptor ionotropic AMPA 2 (GRIA2), G protein-coupled receptor 112 (GPR112) and olfactory receptor family 51 subfamily E member 1 (OR51E1). GRIA2 is specifically expressed by neuroendocrine carcinoma cells whereas the others are also expressed by normal enterochromaffin cells. GPR112 and OR51E1 encode proteins associated with the plasma membrane and may therefore become targets for antibody-based diagnosis and therapy. Hierarchical clustering shows high similarity between primary lesions and liver metastases. However, chemokine C-X-C motif ligand 14 (CXCL14) and NK2 transcription factor related locus 3 Drosophila (NKX2-3) are expressed to a lower level in liver metastases than in primary tumors and normal enterochromaffin cells, which implies a role in neuroendocrine carcinoma differentiation. In conclusion, this study provides a list of genes, which possess relatively specific expression to enterochromaffin and neuroendocrine carcinoma cells and genes with differential expression between primary tumors and metastases. We verified six novel marker genes that may be developed as biomarkers and/or therapeutic targets.
起源于空肠和回肠嗜铬细胞的转移性产血清素神经内分泌癌的基因表达谱仍 largely 未知。本研究的目的是鉴定那些优先由神经内分泌癌和嗜铬细胞表达的基因和蛋白质，因此是潜在的新型生物标志物和/或治疗靶点。通过 Affymetrix 微阵列对六个癌组织标本和六个正常回肠黏膜进行了分析。先进的生物信息学鉴定出差异表达和特异性表达的基因，这些基因通过对激光捕获显微切割提取的肿瘤细胞和免疫激光捕获显微切割提取的正常嗜铬细胞进行定量实时 PCR 得到验证。我们鉴定出六个神经内分泌癌细胞的新型标记基因：副肿瘤抗原 Ma2（PNMA2）、睾丸蛋白聚糖 -1 前体（SPOCK1）、丝氨酸蛋白酶抑制剂 A10（SERPINA10）、离子型 AMPA 谷氨酸受体 2（GRIA2）、G 蛋白偶联受体 112（GPR112）和嗅觉受体家族 51 亚家族 E 成员 1（OR51E1）。GRIA2 由神经内分泌癌细胞特异性表达，而其他基因也由正常嗜铬细胞表达。GPR112 和 OR51E1 编码与质膜相关的蛋白质，因此可能成为基于抗体的诊断和治疗靶点。层次聚类显示原发性病变和肝转移灶之间具有高度相似性。然而，趋化因子 C-X-C 基序配体 14（CXCL1 的14）和果蝇 NK2 转录因子相关位点 3（NKX2-3）在肝转移灶中的表达水平低于原发性肿瘤和正常嗜铬细胞，这暗示其在神经内分泌癌分化中的作用。总之，本研究提供了一份对嗜铬细胞和神经内分泌癌细胞具有相对特异性表达的基因清单，以及原发性肿瘤和转移灶之间差异表达的基因清单。我们验证了六个可能被开发为生物标志物和/或治疗靶点的新型标记基因。
