Capurso G, Lattimore S, Crnogorac-Jurcevic T, Panzuto F, Milione M, Bhakta V, Campanini N, Swift S M, Bordi C, Delle Fave G, Lemoine N R
Digestive and Liver Disease Unit, II Medical School, University La Sapienza, Rome, Italy.
Endocr Relat Cancer. 2006 Jun;13(2):541-58. doi: 10.1677/erc.1.01153.
The intrinsic nature of tumour behaviour (stable vs progressive) and the presence of liver metastases are key factors in determining the outcome of patients with a pancreatic endocrine tumour (PET). Previous expression profile analyses of PETs were limited to non-homogeneous groups or to primary lesions only. The aim of this study was to investigate the gene expression profiles of a more uniform series of sporadic, non-functioning (NF) PETs with progressive disease and, for the first time, their liver metastases, on the Affymetrix human genome U133A and B GeneChip set. Thirteen NF PET samples (eight primaries and five liver metastases) from ten patients with progressive, metastatic disease, three cell lines (BON, QGP and CM) and four purified islet samples were analysed. The same samples were employed for confirmation of candidate gene expression by means of quantitative RT-PCR, while a further 37 PET and 15 carcinoid samples were analysed by immunohistochemistry. Analysis of genes differentially expressed between islets and primaries and metastases revealed 667 up- and 223 down-regulated genes, most of which have not previously been observed in PETs, and whose gene ontology molecular function has been detailed. Overexpression of bridging integrator 1 (BIN1) and protein Z dependent protease inhibitor (SERPINA10) which may represent useful biomarkers, and of lymphocyte specific protein tyrosine kinase (LCK) and bone marrow stromal cell antigen (BST2) which could be used as therapeutic targets, has been validated. When primary tumours were compared with metastatic lesions, no significantly differentially expressed genes were found, in accord with cluster analysis which revealed a striking similarity between primary and metastatic lesions, with the cell lines clustering separately. We have provided a comprehensive list of differentially expressed genes in a uniform set of aggressive NF PETs. A number of dysregulated genes deserve further in-depth study as potentially promising candidates for new diagnostic and treatment strategies. The analysis of liver metastases revealed a previously unknown high level of similarity with the primary lesions.
肿瘤行为的内在本质（稳定型与进展型）以及肝转移的存在是决定胰腺内分泌肿瘤（PET）患者预后的关键因素。先前对PET的表达谱分析仅限于非同质组或仅针对原发性病变。本研究的目的是在Affymetrix人类基因组U133A和B基因芯片组上，研究一系列更均匀的散发性、无功能（NF）PET伴疾病进展的基因表达谱，以及首次研究其肝转移灶的基因表达谱。分析了来自10例进展期转移性疾病患者的13个NF PET样本（8个原发性肿瘤和5个肝转移灶）、3个细胞系（BON、QGP和CM）以及4个纯化的胰岛样本。通过定量RT-PCR对相同样本进行候选基因表达的确认，同时通过免疫组织化学分析另外37个PET样本和15个类癌样本。对胰岛、原发性肿瘤和转移灶之间差异表达基因的分析显示，有667个基因上调和223个基因下调，其中大多数基因此前在PET中未被观察到，并且其基因本体分子功能已被详细描述。桥联整合素1（BIN1）和蛋白Z依赖性蛋白酶抑制剂（SERPINA10）的过表达可能代表有用的生物标志物，淋巴细胞特异性蛋白酪氨酸激酶（LCK）和骨髓基质细胞抗原（BST2）的过表达可作为治疗靶点，这些已得到验证。当将原发性肿瘤与转移灶进行比较时，未发现明显差异表达的基因，这与聚类分析结果一致，聚类分析显示原发性肿瘤和转移灶之间有显著相似性，而细胞系单独聚类。我们提供了一组侵袭性NF PET中差异表达基因的综合列表。一些失调基因作为新诊断和治疗策略的潜在有前景的候选基因值得进一步深入研究。对肝转移灶的分析揭示了其与原发性病变之间此前未知的高度相似性。
