Aberrant expression of a disintegrin and metalloproteinase 17/tumor necrosis factor-α converting enzyme increases the malignant potential in human pancreatic ductal adenocarcinoma

Jörg Ringel, Ralf Jesnowski, Nicolas Moniaux, Jutta Lüttges, Jens Ringel, Amit Choudhury, Surinder K. Batra, Günter Klöppel, Matthias Löhr

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

A disintegrin and metalloproteinase (ADAM) molecules are known for their unique potential to combine adhesion, proteolysis, and signaling. To understand the role of ADAM 17/tumor necrosis factor-α (TNF-α) 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 ADAM 17/TACE protein in pancreatic cancer cell lines. The proteolytic activity of ADAM17/TACE, assessed by the release of TNF-α, was inhibited by TNF-α 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-α 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.

Original languageEnglish (US)
Pages (from-to)9045-9053
Number of pages9
JournalCancer Research
Volume66
Issue number18
DOIs
StatePublished - Sep 15 2006

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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