Research Papers:

Rac1b negatively regulates TGF-β1-induced cell motility in pancreatic ductal epithelial cells by suppressing Smad signalling

Hendrik Ungefroren _, Susanne Sebens, Klaudia Giehl, Ole Helm, Stephanie Groth, Fred Faendrich, Christoph Roecken, Bence Sipos, Hendrik Lehnert and Frank Gieseler

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Oncotarget. 2014; 5:277-290. https://doi.org/10.18632/oncotarget.1696

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Hendrik Ungefroren1,2, Susanne Sebens3, Klaudia Giehl4, Ole Helm3, Stephanie Groth2,7, Fred Fändrich2, Christoph Röcken5, Bence Sipos6, Hendrik Lehnert1, Frank Gieseler1

1 First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), Campus Lübeck, Lübeck, Germany

2 Clinic for Applied Cellular Medicine, University Hospital Schleswig-Holstein (UKSH) Campus Kiel, Kiel, Germany

3 Institute for Experimental Medicine, Group Inflammatory Carcinogenesis, University Hospital Schleswig-Holstein (UKSH) Campus Kiel, Kiel, Germany

4 Molecular Oncology of Solid Tumors, Internal Medicine V, Justus-Liebig-University Giessen, Giessen, Germany

5 Institute of Pathology, University Hospital Schleswig-Holstein (UKSH) Campus Kiel, Kiel, Germany

6 Institute of Pathology, Institute of General Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany

7 Current address: Department of Dermatology, UKSH, Campus Lübeck, Lübeck, Germany


Hendrik Ungefroren, email:

Keywords: Rac1b, Rac1, Smad, TGF-β1, pancreatic ductal adenocarcinoma, cell migration

Received: December 13, 2013 Accepted: December 23, 2013 Published: December 23, 2013


Transforming growth factor (TGF)-β1 promotes progression of pancreatic ductal adenocarcinoma (PDAC) by enhancing epithelial-mesenchymal transition, cell migration/invasion, and metastasis, in part by cooperating with the small GTPase Rac1. Prompted by the observation of higher expression of Rac1b, an alternatively spliced Rac1 isoform, in pancreatic ductal epithelial cells and in patients with chronic pancreatitis vs. PDAC, as well as in long-time vs. short-time survivors among PDAC patients, we asked whether Rac1b might negatively affect TGF-β1 prometastatic function. Interestingly, the non-malignant pancreatic ductal epithelial cell line H6c7 exhibited a higher ratio of active Rac1b to total Rac1b than the TGF-β1-responsive PDAC cell lines Panc-1 and Colo357. Notably, siRNA-mediated silencing of Rac1b increased TGF-β1/Smad-dependent migratory activities in H6c7, Colo357, and Panc-1 cells, while ectopic overexpression of Rac1b in Panc-1 cells attenuated TGF-β1-induced cell motility. Depletion of Rac1b in Panc-1 cells enhanced TGF-β1/Smad-dependent expression of promoter-reporter genes and of the endogenous Slug gene. Moreover, Rac1b depletion resulted in a higher and more sustained C-terminal phosphorylation of Smad3 and Smad2, suggesting that Rac1b is involved in Smad2/3 dephosphorylation/inactivation. Since pharmacologic or siRNA-mediated inhibition of Smad3 but not Smad2 was able to alleviate the Rac1b siRNA effect on TGF-β1-induced cell migration, our results suggests that Rac1b inhibits TGF-β1-induced cell motility in pancreatic ductal epithelial cells by blocking the function of Smad3. Moreover, Rac1b may act as an endogenous inhibitor of Rac1 in TGF-β1-mediated migration and possibly metastasis. Hence, it could be exploited for diagnostic/prognostic purposes or even therapeutically in late-stage PDAC as an antimetastatic agent.

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