Gene expression profiles in primary ovarian serous papillary tumors and normal ovarian epithelium: Identification of candidate molecular markers for ovarian cancer diagnosis and therapy
Gene expression profiles in primary ovarian serous papillary tumors and normal ovarian epithelium: Identification of candidate molecular markers for ovarian cancer diagnosis and therapy
复制标题
DOI：
10.1002/ijc.20408
复制
发表时间：
2004-10-20
影响因子：
6.4
通讯作者：
Pecorelli, S
中科院分区：
文献类型：
--
作者：
Santin, AD;Zhan, FH;Pecorelli, S
为了鉴定卵巢浆液性乳头状癌（OSPC）和正常卵巢（NOVA）上皮之间具有差异表达模式的基因，并利用这些知识开发卵巢癌的新型诊断和治疗标志物，我们使用具有探针集的寡核苷酸微阵列与12，533个基因互补，分析10个原代OSPC细胞系的基因表达谱，2个已建立的OSPC细胞系（UCI-101、UCI-107）和5个原代NOVA上皮培养物。基因表达数据的无监督分析鉴定了129和170个基因，与NOVA相比，其在原发性OSPC中分别表现出>5倍的上调和下调。在已建立的OSPC细胞系中过表达的基因与原代OSPC中过表达的基因几乎没有相关性，这突出了由于长期体外生长而发生的基因表达的分歧。表达数据的层次聚类容易区分正常组织和原发性OSPC。与NOVA相比，层粘连蛋白、密蛋白3、密蛋白4、肿瘤相关钙信号转导子1和2（TR 0 P-1/Ep-CAM、TR 0 P-2）、ladinin 1、S100 A2、SERPIN 2（派-2）、CD 24、脂质运载蛋白2、骨桥蛋白、激肽释放酶6（蛋白酶M）、激肽释放酶10、间质蛋白酶（TADG-15）和分层蛋白是OSPC中最高度过表达的基因。OSPC中下调的基因包括转化生长因子β受体III、血小板衍生生长因子受体α、SEMACAP 3、ras同源基因家族成员I（ARHI）、血小板反应蛋白2和卵巢癌中失能/差异表达基因2（Dab 2/DOC 2）。通过定量RT-PCR和流式细胞术验证了这些基因中的一些基因（包括claudin 3、claudin 4、TROP-1和CD 24）在原代OSPC和NOVA上的差异表达。福尔马林固定、石蜡包埋的肿瘤标本的免疫组织化学染色进一步证实了CD 24和TR 0 P-1/Ep-CAM标志物在OSPC与NOVA上的差异表达。这些结果，获得了高度纯化的原代培养的卵巢癌，突出了重要的分子特征的OSPC，并可能提供一个基础，为开发新的类型特异性治疗这种疾病。(C)2004 Wiley-Liss，Inc.
With the goal of identifying genes with a differential pattern of expression between ovarian serous papillary carcinomas (OSPCs) and normal ovarian (NOVA) epithelium and using this knowledge for the development of novel diagnostic and therapeutic markers for ovarian cancer, we used oligonucleotide microarrays with probe sets complementary to 12,533 genes to analyze the gene expression profiles of 10 primary OSPC cell lines, 2 established OSPC cell lines (UCI-101, UCI-107) and 5 primary NOVA epithelial cultures. Unsupervised analysis of gene expression data identified 129 and 170 genes that exhibited >5-fold upregulation and downregulation, respectively, in primary OSPC compared to NOVA. Genes overexpressed in established OSPC cell lines had little correlation with those overexpressed in primary OSPC, highlighting the divergence of gene expression that occurs as a result of long-term in vitro growth. Hierarchical clustering of the expression data readily distinguished normal tissue from primary OSPC. Laminin, claudin 3, claudin 4, tumor-associated calcium signal transducers 1 and 2 (TROP-1/Ep-CAM, TROP-2), ladinin 1, S100A2, SERPIN2 (PAI-2), CD24, lipocalin 2, osteopontin, kallikrein 6 (protease M), kallikrein 10, matriptase (TADG-15) and stratifin were among the most highly overexpressed genes in OSPC compared to NOVA. Downregulated genes in OSPC included transforming growth factor-beta receptor III, platelet-derived growth factor receptor alpha, SEMACAP3, ras homolog gene family member I (ARHI), thrombospondin 2 and disabled-2/differentially expressed in ovarian carcinoma 2 (Dab2/DOC2). Differential expression of some of these genes, including claudin 3, claudin 4, TROP-1 and CD24, was validated by quantitative RT-PCR and flow cytometry on primary OSPC and NOVA. Immunohistochemical staining of formalin-fixed, paraffin-embedded tumor specimens from which primary OSPC cultures were derived further confirmed differential expression of CD24 and TROP-1/Ep-CAM markers on OSPC vs. NOVA. These results, obtained with highly purified primary cultures of ovarian cancer, highlight important molecular features of OSPC and may provide a foundation for the development of new type-specific therapies against this disease. (C) 2004 Wiley-Liss, Inc.