title: Role of BCL9L in transforming growth factor-β (TGF-β)-induced epithelial-to-mesenchymal-transition (EMT) and metastasis of pancreatic cancer.
abstract: 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.
authors.affiliation: Natural and Medical Sciences Institute (NMI) at the University of Tuebingen, Tumor Biology Group, Reutlingen, Germany.|Current address: Institute of Pathology, Laboratory of Pediatric Sarcoma Biology, Ludwig-Maximilians-Universität Munich, Munich, Germany.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Sannino
authors.affiliation: Natural and Medical Sciences Institute (NMI) at the University of Tuebingen, Tumor Biology Group, Reutlingen, Germany.|Current address: Department of Internal Medicine II, University of Tuebingen, Tuebingen, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Armbruster
authors.affiliation: Natural and Medical Sciences Institute (NMI) at the University of Tuebingen, Tumor Biology Group, Reutlingen, Germany.
authors.forename: Mona
authors.initials: M
authors.lastname: Bodenhöfer
authors.affiliation: Natural and Medical Sciences Institute (NMI) at the University of Tuebingen, Tumor Biology Group, Reutlingen, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Haerle
authors.affiliation: Experimental Pharmacology and Oncology GmbH, Berlin, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Behrens
authors.affiliation: Department of Medicine, Division of Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Marburg, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Buchholz
authors.affiliation: Pharmaceutical Biotechnology, University of Tuebingen, Tuebingen, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Rothbauer
authors.affiliation: Institute of Pathology, University of Tuebingen, Tuebingen, Germany.
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
authors.affiliation: Natural and Medical Sciences Institute (NMI) at the University of Tuebingen, Tumor Biology Group, Reutlingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schmees
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D021381:Protein Transport; D014157:Transcription Factors; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C111180:BCL9 protein, human; D015820:Cadherins; D009363:Neoplasm Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D051176:beta Catenin
keywords: BCL9L; E-cadherin; EMT; pancreatic cancer; β-catenin