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Aberrant Expression of a Disintegrin and Metalloproteinase 17/Tumor Necrosis Factor- Converting Enzyme Increases the Malignant Potential in Human Pancreatic Ductal Adenocarcinoma

¹ Department of Medicine II, Mannheim Medical Faculty, University of Heidelberg; ² Division of Molecular Gastroenterology, German Cancer Research Center, Heidelberg, Germany; ³ Department of Medicine A, University of Greifswald, Greifswald, Germany; ⁴ Department of Biochemistry and Molecular Biology and Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska; and ⁵ Department of Pathology, University of Kiel, Kiel, Germany

Requests for reprints: Matthias Löhr, Division of Molecular Gastroenterology (Deutsches Krebsforschungszentrum E180), German Cancer Research Center and Departments of Medicine II, Mannheim Medical Faculty, University of Heidelberg, Heidelberg, Germany. Phone: 49-621-383-2900; Fax: 49-621-383-1986; E-mail: matthias.loehr{at}med.ma.uni-heidelberg.de.

A disintegrin and metalloproteinase (ADAM) molecules are known for their unique potential to combine adhesion, proteolysis, and signaling. To understand the role of ADAM17/tumor necrosis factor- (TNF-) converting enzyme (TACE) in pancreatic ductal adenocarcinoma (PDAC), we investigated its expression, function, and in vitro regulation. ADAM17/TACE mRNA was expressed in 3 of 10 normal pancreatic tissues, 6 of 8 samples from patients with chronic pancreatitis, 10 of 10 PDAC tissues, and 9 of 9 pancreatic cancer cell lines, but it was absent in primary duct epithelial cells. Immunohistochemical staining revealed positive cancer cells in 8 of 10 PDACs but no staining of ducts in normal pancreas. ADAM17/TACE was found in 0 of 16 pancreatic intraepithelial neoplasia (PanIN)-1A lesions, 1 of 30 PanIN-1B lesions, 2 of 13 PanIN-2 lesions but, in 13 of 15 PanIN-3 lesions, associated with PDAC. Western blot, flow cytometry, and confocal microscopy analyses showed the aberrant expression of ADAM17/TACE protein in pancreatic cancer cell lines. The proteolytic activity of ADAM17/TACE, assessed by the release of TNF-, was inhibited by TNF- protease inhibitor. ADAM17/TACE gene silencing using small interfering RNA technique in vitro reduced invasion behavior dramatically, whereas proliferation was unaffected. Furthermore, ADAM17/TACE mRNA expression was down-regulated in pancreatic cancer cells arrested in G₂-M phase as well as in a time-dependent manner after TNF- and interleukin-6 incubation. In conclusion, our findings provide evidence of aberrant expression of the proteolytically active ADAM17/TACE in advanced precursor lesions (PanIN-3) and PDAC while identifying its critical involvement in the invasion process. (Cancer Res 2006; 66(18): 9045-53)

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