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Clinical Study

Hypoxia-inducible proto-oncogene Pim-1 is a prognostic marker in pancreatic ductal adenocarcinoma

Carolin Reiser-Erkan, Mert Erkan, Zheng Pan, Sandor Bekasi, Nathalia A. Giese, Sylvia Streit, Christoph W. Michalski, Helmut Friess and Jörg Kleeff

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Background: Pim-1 is a proto-oncogene involved in cell survival, differentiation and proliferation in several hematologic and epithelial malignancies. Clinical, absence of Pim-1 expression correlates with poor prognosis in prostate cancer. In the present study, the expression of Pim-1 is analyzed in pancreatic cancer and correlated to clinicopathological parameters. Methods: Pim-1 mRNA and protein was evaluated with quantitative real-time RT-PCR, immunofluorescence and immunocytochemistry analyses. Ex vivo expression analysis using semi-quantitative immunohistochemistry was performed using human pancreatic tissues of the normal pancreas (n=10), chronic pancreatitis (n=30), pancreatic ductal adenocarcinoma (n=59) and other pancreatic tumors (n=42). In consecutive sections HIF1-alpha was used as a marker of hypoxia. Survival of patients (n=35) was compared using the Kaplan-Meier method and a log-rank test. In vitro analyses were performed using cultured pancreatic cancer cell lines (n=8) and primary human pancreatic stellate cells. Results: Compared to benign, inflammatory and pre-malignant conditions (i.e., the normal pancreas, chronic pancreatitis and benign intraductal papillary mucinous neoplasm), expression of Pim-1 mRNA and protein increased significantly in pancreatic malignancies. Absence of Pim-1 immunopositivity in cancer cells strongly correlated with a poor prognosis (median survival 13.8 vs. 23.4 months, p=0.0016). In vitro, rapidly dividing (high versus low serum concentrations) and hypoxic cells displayed higher Pim-1 mRNA and protein levels. Conclusion: Hypoxia is a novel inducer of Pim-1 expression. Compared to non-malignant tissues Pim-1 significantly increases in pancreatic cancer. However, the presence of Pim-1 in cancer cells has a positive prognostic impact.

Authors

Carolin Reiser-Erkan

Department of Surgery, Technische Universität München, Munich, Germany

Mert Erkan

Department of Surgery, Technische Universität München, Munich, Germany

Zheng Pan

Sandor Bekasi

Department of General Surgery, University of Heidelberg, Heidelberg, Germany

Nathalia A. Giese

Department of General Surgery, University of Heidelberg, Heidelberg, Germany

Sylvia Streit

Department of Surgery, Technische Universität München, Munich, Germany

Christoph W. Michalski

Department of Surgery, Technische Universität München, Munich, Germany

Helmut Friess

Department of Surgery, Technische Universität München, Munich, Germany

Jörg Kleeff

Department of Surgery, Technische Universität München, Munich, Germany

Purchase article for $19

Subscribe to this journal for $129/year