ORIGINAL ARTICLE

Overexpression of cellular inhibitor of apoptosis protein 2 is an early event in the progression of pancreatic cancer

Irene Esposito¹, Jörg Kleeff², Ivane Abiatari², Xined Shi², Nathalia Giese², Frank Bergmann¹, Wilfried Roth¹, Helmut Friess² and Peter Schirmacher¹

¹ Institute of Pathology, University of Heidelberg, Heidelberg, Germany
² Department of General Surgery, University of Heidelberg, Heidelberg, Germany

Correspondence to:
Correspondence to:
Dr I Esposito
Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220, 69120 Heidelberg, Germany; irene_esposito{at}med.uni-heidelberg.de

Aim: To determine the role of two antiapoptotic proteins of the inhibitor of apoptosis protein family, cellular inhibitor of apoptosis protein 1 (cIAP1) and cellular inhibitor of apoptosis protein 2 (cIAP2), in human pancreatic carcinogenesis.

Methods: mRNA levels were measured in pancreatic tissues and pancreatic cancer cell lines by quantitative reverse transcriptase PCR. Protein expression was assessed in pancreatic cancer cell lines by immunoblotting and in pancreatic tissues by immunohistochemistry, and correlated with pathological and survival data.

Results: cIAP1 expression was constantly high in non-neoplastic pancreatic tissues, in pancreatic intraepithelial neoplasia (PanIN) lesions, as well as in a subset of primary and metastatic pancreatic ductal adenocarcinomas (PDAC), and a preferential cytoplasmatic localisation was observed in the tumour tissues. cIAP1 expression was rare in a cohort of cystic tumours. cIAP2 mRNA levels were significantly higher (2.4 fold) in PDAC than in normal tissues. cIAP2 protein was overexpressed in PDAC, and was detectable in low- and high-grade PanIN lesions. Moreover, cIAP2 was often expressed in pancreatic cystic tumours. cIAP1 and cIAP2 mRNA and protein were detected in all the examined cell lines. Survival analysis revealed a shorter survival in patients with cIAP1/cIAP2-positive tumours.

Conclusions: cIAP1 might contribute to the regulation of the apoptotic process in the normal and in the neoplastic pancreas, depending on its subcellular localisation. Overexpression of cIAP2 is a common and early event in the progression of pancreatic cancer, and could therefore potentially influence the important pathophysiological aspects of PDAC, such as anoikis or chemoresistance.

Abbreviations: BIR, baculovirus iap repeat; cIAP1, cellular inhibitor of apoptosis protein 1; cIAP2, cellular inhibitor of apoptosis protein 2; CP, chronic pancreatitis; EGFR, epidermal growth factor receptor; ESPAC, European Study Group for Pancreatic Cancer; IAP, inhibitor of apoptosis protein; IPMN, intraductal papillary-mucinous neoplasm; PanIN, pancreatic intraepithelial neoplasia; PDAC, pancreatic ductal adenocarcinoma; TNF, tumour necrosis factor; XIAP, X-linked inhibitor of apoptosis

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