Expression of nuclear Notch3 in pancreatic adenocarcinomas is associated with adverse clinical features, and correlates with the expression of STAT3 and phosphorylated Akt.
OBJECTIVE
Reactivation of the Notch signalling pathway occurs in a range of human malignancies. Previous research suggests that Notch3 is expressed in pancreatic adenocarcinomas, but neither cellular location nor association with clinical parameters has been described. The relationship between Notch3, clinical endpoints, and other proteins with potential to interact with Notch was therefore examined.


METHODS
An immunohistochemical study was performed on human pancreatic adenocarcinoma (n = 23) and normal pancreas (n = 12), to assess expression of Notch3, cyclin D1, pAkt, STAT3 and pSTAT3. Immunohistochemical data were then correlated with clinicopathological characteristics.


RESULTS
Notch3 was significantly overexpressed in the cytoplasm of 73.9% of tumours. Nuclear expression was not observed in normal pancreatic ductal tissue, but was noted in 43.5% of tumours. No tumour expressing nuclear Notch3 was resectable. There were significant correlations between expression and intracellular location of Notch3 and each of STAT3, pSTAT3 and pAkt, but not cyclin D1.


CONCLUSIONS
The presence of Notch3 in tumour nuclei is likely to represent functional activation of the protein, and is clearly linked to a more aggressive tumour phenotype. The correlation with STAT3, pSTAT3 and pAkt expression has not previously been described and the concurrent intracellular localisation of these proteins suggests a functional relationship between them.
Doucas
Helena
H
Cancer Biomarkers and Prevention Group, Department of Cancer Studies and Molecular Medicine, University of Leicester, Biocentre, Leicester, UK.
Mann
Christopher D
CD
Sutton
Christopher D
CD
Garcea
Guiseppe
G
Neal
Christopher P
CP
Berry
David P
DP
Manson
Margaret M
MM
D021581:Active Transport, Cell Nucleus; D000230:Adenocarcinoma / Q000737:chemistry* / Q000401:mortality; D000368:Aged; D056741:Cyclin D; D016213:Cyclins / Q000032:analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D010190:Pancreatic Neoplasms / Q000737:chemistry* / Q000401:mortality; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis*; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000032:analysis* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000032:analysis*; D015996:Survival Rate
D056741:Cyclin D; D016213:Cyclins; C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051057:Proto-Oncogene Proteins c-akt