Serpin peptidase inhibitor cladeA member1 as a potential marker for malignancy in insulinomas
Serpin peptidase inhibitor cladeA member1 as a potential marker for malignancy in insulinomas
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DOI：
10.1158/1078-0432.ccr-06-1477
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发表时间：
2007-09-15
影响因子：
11.5
通讯作者：
Giannella-Neto, Daniel
中科院分区：
文献类型：
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作者：
de Sa, Sandra Valeria;Correa-Giannella, Maria Lucia;Giannella-Neto, Daniel
目的：胰岛素瘤的生物学行为不能根据组织病理学标准来预测，在组织病理学标准中，恶性肿瘤的诊断是通过转移的存在来证实的。本研究采用微阵列技术和实时定量反转录- PCR技术鉴定恶性和非恶性胰岛素瘤之间的差异表达基因，寻找有用的生物标志物来识别胰岛素瘤的转移潜力。实验设计：采用CodeLink人体生物阵列分析6例表现为良性的高分化内分泌肿瘤与1例高分化内分泌癌（WDEC）和3例内分泌癌转移瘤（MEC）之间近2万个基因的差异。采用实时定量反转录PCR技术对35例散发性胰岛素瘤中5个基因的差异表达进行了验证。丝氨酸肽酶抑制剂cladeA成员1 （SERPINA1; a-l-antitrypsin）在恶性胰岛素瘤中表达上调，并通过免疫组织化学进行评估。结果：微阵列数据分析得到230个差异表达基因。基因本体分析发现丝氨酸型内肽酶活性和丝氨酸型内肽酶抑制剂活性是表现出显著差异表达的途径。蛋白酶丝氨酸2和补体因子B（来自丝氨酸型内肽酶活性途径）分别在良性行为高分化内分泌肿瘤（WDET）和wdec /MEC中上调。血管紧张素原和SERPINA1（丝氨酸型内肽酶抑制剂活性途径）在WDEC/MEC中被证实上调。免疫组化结果显示，恶性胰岛素瘤中有85.7%表达SERPINA1，而非恶性胰岛素瘤中有14.3%表达SERPINA1。结论：我们的数据与SERPINA1是胰岛素瘤恶性标记物的可能性是一致的。鉴于抗α -1-抗胰蛋白酶抗体在病理服务中的广泛应用，SERPINA1表达评估可能在识别更有可能发展为侵袭性表现的患者方面具有临床应用价值。
Purpose: The biological behavior of insulinomas cannot be predicted based on histopathologic criteria in which the diagnosis of malignancy is confirmed by the presence of metastases. In this study, microarray and quantitative real-time reverse transcription- PCR were applied to identify differentially expressed genes between malignant and nonmalignant insulinomas to search for useful biomarkers to recognize the metastatic potential of insulinomas.Experimental Design: CodeLink human bioarrays were used to analyze differences in similar to 20,000 genes between six well- differentiated endocrine tumors of benign behavior compared with one well-differentiated endocrine carcinoma (WDEC) and three metastases of endocrine carcinomas (MEC). Quantitative real-time reverse transcription- PCR was used to validate differential expressions of five genes in a series of 35 sporadic insulinomas. Serpin peptidase inhibitor cladeA member 1 (SERPINA1; a-l-antitrypsin) expression, identified as up-regulated in malignant insulinomas, was also evaluated by immunohistochemistry.Results: Analysis of microarray data resulted in 230 differentially expressed genes. Gene Ontology analysis identified serine-type endopeptidase activity and serine-type endopeptidase inhibitor activity as pathways presenting significant differential expression. Protease serine 2 and complement factor B (from serine-type endopeptidase activity pathway) were respectively confirmed as up-regulated in well -differentiated endocrine tumors of benign behavior (WDET) and inWDEC/MEC. Angiotensinogen and SERPINA1 (from serine-type endopeptidase inhibitor activity pathway) were confirmed as up-regulated in WDEC/MEC. SERPINA1 was shown to be expressed in 85.7 % of malignant versus 14.3 % of nonmalignant insulinomas by immunohistochemistry.Conclusions: Our data are consistent to the possibility that SERPINA1 is a marker of malignancy in insulinomas. Given the widespread availability of antibody anti-alpha-1-antitrypsin in pathology services, SERPINA1 expression evaluation might be of clinical utility in recognizing patients more likely to develop an aggressive presentation.