Hypoxia-inducible proto-oncogene Pim-1 is a prognostic marker in pancreatic ductal adenocarcinoma.
BACKGROUND
Pim-1 is a proto-oncogene involved in cell survival, differentiation and proliferation in several hematologic and epithelial malignancies. Clinically, 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.


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.


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.


CONCLUSIONS
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.
Reiser-Erkan
Carolin
C
Department of Surgery, Technische Universität München, Munich, Germany.
Erkan
Mert
M
Pan
Zheng
Z
Bekasi
Sandor
S
Giese
Nathalia A
NA
Streit
Sylvia
S
Michalski
Christoph W
CW
Friess
Helmut
H
Kleeff
Jörg
J
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000090063:Proto-Oncogene Mas; D051573:Proto-Oncogene Proteins c-pim-1 / Q000032:analysis*
D014408:Biomarkers, Tumor; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1