Role of BCL9L in transforming growth factor-β (TGF-β)-induced epithelial-to-mesenchymal-transition (EMT) and metastasis of pancreatic cancer
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Giuseppina Sannino1,6, Nicole Armbruster1,7, Mona Bodenhöfer1, Ursula Haerle1, Diana Behrens2, Malte Buchholz3, Ulrich Rothbauer4, Bence Sipos5, Christian Schmees1
1Natural and Medical Sciences Institute (NMI) at the University of Tuebingen, Tumor Biology Group, Reutlingen, Germany
2Experimental Pharmacology and Oncology GmbH, Berlin, Germany
3Department of Medicine, Division of Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Marburg, Germany
4Pharmaceutical Biotechnology, University of Tuebingen, Tuebingen, Germany
5Institute of Pathology, University of Tuebingen, Tuebingen, Germany
6Current address: Institute of Pathology, Laboratory of Pediatric Sarcoma Biology, Ludwig-Maximilians-Universität Munich, Munich, Germany
7Current address: Department of Internal Medicine II, University of Tuebingen, Tuebingen, Germany
Christian Schmees, email: [email protected]
Keywords: pancreatic cancer, BCL9L, β-catenin, E-cadherin, EMT
Received: August 20, 2015 Accepted: September 24, 2016 Published: October 04, 2016
Pancreatic ductal adenocarcinoma (PDAC) has a low overall survival rate, which is approximately 20% during the first year and decreases to less than 6% within five years of the disease. This is due to premature dissemination accompanied by a lack of disease-specific symptoms during the initial stages. Additionally, to date there are no biomarkers for an early prognosis available.
A growing number of studies indicate that epithelial to mesenchymal transition (EMT), triggered by WNT-, TGF-β- and other signaling pathways is crucial for the initiation of the metastatic process in PDAC. Here we show, that BCL9L is up-regulated in PDAC cell lines and patient tissue compared to non-cancer controls. RNAi-induced BCL9L knockdown negatively affected proliferation, migration and invasion of pancreatic cancer cells. On a molecular basis, BCL9L depletion provoked an increment of E-cadherin protein levels, with concomitant increase of β-catenin retention at the plasma membrane. This is linked to the induction of a strong epithelial phenotype in pancreatic cancer cells upon BCL9L knockdown even in the presence of the EMT-inducer TGF-β. Finally, xenograft mouse models of pancreatic cancer revealed a highly significant reduction in the number of liver metastases upon BCL9L knockdown. Taken together, our findings underline the key importance of BCL9L for EMT and thus progression and metastasis of pancreatic cancer cells. Direct targeting of this protein might be a valuable approach to effectively antagonize invasion and metastasis of PDAC.
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