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Carcinogenesis Advance Access published online on April 8, 2004
Carcinogenesis, doi:10.1093/carcin/bgh159
© 2004 by Oxford University Press
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© 2004 Oxford University Press

CANCER BIOLOGY

Enhanced expression of 14-3-3sigma in pancreatic cancer and its role in cell cycle regulation and apoptosis

Ahmed Guweidhi 1, Jörg Kleeff 1, Nathalia Giese 1, Jamael El Fitori 1, Knut Ketterer 2, Thomas Giese 3, Markus W. Büchler 1, Murray Korc 4, and Helmut Friess 1*

1 Department of General Surgery, University of Heidelberg, Germany
2 Department of General Surgery, University of Heidelberg, Germany; Department of Medicine, Dartmouth Hitchcock Medical Center, Dartmouth Medical School, Lebanon, NH, 03756, USA; Department of Pharmacology, Dartmouth Hitchcock Medical Center, Dartmouth Medical School, Lebanon, NH, 03756, USA; Department of Toxicology, Dartmouth Hitchcock Medical Center, Dartmouth Medical School, Lebanon, NH, 03756, USA
3 Department of Immunology, University of Heidelberg, Germany
4 Department of Medicine, Dartmouth Hitchcock Medical Center, Dartmouth Medical School, Lebanon, NH, 03756, USA; Department of Pharmacology, Dartmouth Hitchcock Medical Center, Dartmouth Medical School, Lebanon, NH, 03756, USA; Department of Toxicology, Dartmouth Hitchcock Medical Center, Dartmouth Medical School, Lebanon, NH, 03756, USA

* Corresponding author. E-mail: helmut_friess{at}med.uni-heidelberg.de.

Received 2 December 2003 ; revised 24 February 2004 ; accepted 31 March 2004

Abstract

Background: 14-3-3sigma belongs to the 14-3-3 family of proteins, which are involved in the modulation of diverse signal transduction pathways. Loss of 14-3-3sigma expression has been observed in a number of human cancers, suggesting that it may have a role as a tumor suppressor gene. Aim: To investigate the expression and the functional role of 14-3-3sigma in pancreatic ductal adenocarcinoma. Methods: Expression of 14-3-3sigma was analyzed using laser capture microdissection (LCM), quantitative real-time PCR (QRT-PCR), DNA arrays, immunohistochemistry, and Western blot analysis. The role of 14-3-3sigma in apoptosis and cell cycle regulation was evaluated by Western blotting, immunoprecipitation, and FACS analysis. Results: By QRT-PCR, 14-3-3sigma mRNA levels were 54-fold increased in pancreatic adenocarcinoma in comparison to normal pancreatic samples and localized in pancreatic cancer cells as determined by LCM. In pancreatic cancer cells, the degree of 14-3-3sigma expression was not decisive for the maintenance of G2/M cell cycle checkpoint or induction of apoptosis. Responses to radiation or apoptosis-inducing agents were neither accompanying by a significant 14-3-3sigma accumulation nor by a change in association of 14-3-3sigma with cdc2, bad and bax. Conclusion: The marked overexpression of 14-3-3sigma in PDAC together with multiple known genetic and epigenetic alterations of potential 14-3-3sigma interacting partners suggests an important role of aberrant 14-3-3sigma downstream signaling in pancreatic cancer.

14-3-3 sigma, cell cycle, apoptosis, pancreatic cancer
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