Retinoic Acid Receptor Antagonists Inhibit miR-10a Expression and Block Metastatic Behavior of Pancreatic Cancer
Received 24 July 2008; accepted 24 August 2009. published online 11 September 2009.
Background & Aims
The infiltrating ductal adenocarcinoma of the pancreas is among the most lethal of all solid malignancies, largely owing to a high frequency of early metastasis. We identified microRNA-10a (miR-10a) as an important mediator of metastasis formation in pancreatic tumor cells and investigated the upstream and downstream regulatory mechanisms of miR-10a.
Methods
Northern blot analysis revealed increased expression levels of miR-10a in metastatic pancreatic adenocarcinoma. The role of miR-10a was analyzed by Morpholino and short interfering RNA transfection of pancreatic carcinoma cell lines and resected specimens of human pancreatic carcinoma. Metastatic behavior of primary pancreatic tumors and cancer cell lines was tested in xenotransplantation experiments in zebrafish embryos.
Results
We show that miR-10a expression promotes metastatic behavior of pancreatic tumor cells and that repression of miR-10a is sufficient to inhibit invasion and metastasis formation. We further show that miR-10a is a retinoid acid target and that retinoic acid receptor antagonists effectively repress miR-10a expression and completely block metastasis. This antimetastatic activity can be prevented by specific knockdown of HOX genes, HOXB1 and HOXB3. Interestingly, suppression of HOXB1 and HOXB3 in pancreatic cancer cells is sufficient to promote metastasis formation.
Conclusions
These findings suggest that miR-10a is a key mediator of metastatic behavior in pancreatic cancer, which regulates metastasis via suppression of HOXB1 and HOXB3. Inhibition of miR-10a expression (with retinoic acid receptor antagonists) or function (with specific inhibitors) is a promising starting point for antimetastatic therapies.
⁎Universitätsklinikum Greifswald, Klinik für Innere Medizin A, Greifswald, Germany
§Universitätsklinikum Greifswald Abteilung für Allgemein-, Viszeral-, Thorax- und Gefäβchirurgie, Greifswald, Germany
‡Institute of Biology, Department of Integrative Zoology, University of Leiden, AL Leiden, The Netherlands
Reprint requests Address requests for reprints to: Christoph P. Bagowski, MD, Institute of Biology, University of Leiden, Wassenaarseweg 64, 2333 AL Leiden, The Netherlands. fax: (31) (0)71-527-4999
Conflicts of interest The authors disclose no conflicts.
Funding This work was supported by grants from the Portuguese foundation for Science and Technology (SFRH/BD/27262/2006), the Deutsche Krebshilfe (10-2031-Le), (FVMM) University Greifswald, and by the Alfried Krupp Graduate School of Tumorbiology.
ABSTRACT
Retinoic Acid Receptor Antagonists Inhibit miR-10a Expression and Block Metastatic Behavior of Pancreatic Cancer