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Serpin Peptidase Inhibitor Clade A Member 1 as a Potential Marker for Malignancy in Insulinomas

Authors' Affiliations: ¹ Laboratory for Cellular and Molecular Endocrinology LIM-25, ² Division of Transplant and Liver Surgery, ³ Division of Endocrinology, and ⁴ Division of Pathology, University of Sao Paulo Medical School; and ⁵ Department of Biochemistry, Chemistry Institute, University of Sao Paulo, Sao Paulo, Brazil

Requests for reprints: Daniel Giannella-Neto, Laboratory for Cellular and Molecular Endocrinology (LIM-25), University of Sao Paulo Medical School, Av. Dr. Arnaldo 455 #4307, 01246-903 São Paulo, Brazil. Phone: 55-11-3061-7253; Fax: 55-11-3061-7253; E-mail: dgiannella{at}terra.com.br.

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 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 clade A member 1 (SERPINA1; -1-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 in WDEC/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--1-antitrypsin in pathology services, SERPINA1 expression evaluation might be of clinical utility in recognizing patients more likely to develop an aggressive presentation.

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