title: CUX1: a modulator of tumour aggressiveness in pancreatic neuroendocrine neoplasms.
abstract: Pancreatic neuroendocrine neoplasms (PNENs) constitute a rare tumour entity, and prognosis and treatment options depend on tumour-mediating hallmarks such as angiogenesis, proliferation rate and resistance to apoptosis. The molecular pathways that determine the malignant phenotype are still insufficiently understood and this has limited the use of effective combination therapies in the past. In this study, we aimed to characterise the effect of the oncogenic transcription factor Cut homeobox 1 (CUX1) on proliferation, resistance to apoptosis and angiogenesis in murine and human PNENs. The expression and function of CUX1 were analysed using knockdown and overexpression strategies in Ins-1 and Bon-1 cells, xenograft models and a genetically engineered mouse model of insulinoma (RIP1Tag2). Regulation of angiogenesis was assessed using RNA profiling and functional tube-formation assays in HMEC-1 cells. Finally, CUX1 expression was assessed in a tissue microarray of 59 human insulinomas and correlated with clinicopathological data. CUX1 expression was upregulated during tumour progression in a time- and stage-dependent manner in the RIP1Tag2 model, and associated with pro-invasive and metastatic features of human insulinomas. Endogenous and recombinant CUX1 expression increased tumour cell proliferation, tumour growth, resistance to apoptosis, and angiogenesis in vitro and in vivo. Mechanistically, the pro-angiogenic effect of CUX1 was mediated via upregulation of effectors such as HIF1α and MMP9. CUX1 mediates an invasive pro-angiogenic phenotype and is associated with malignant behaviour in human insulinomas.
authors.affiliation: Departments of GastroenterologyEndocrinology and MetabolismSurgeryPhilipps-University Marburg, Baldingerstraße, 35043 Marburg, GermanyDepartment of PathologyEberhard-Karls-University Tübingen, Tübingen, GermanyDepartment of PathologyUniversity Hospital Zurich, Zurich, Switzerland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Krug
authors.affiliation: Departments of GastroenterologyEndocrinology and MetabolismSurgeryPhilipps-University Marburg, Baldingerstraße, 35043 Marburg, GermanyDepartment of PathologyEberhard-Karls-University Tübingen, Tübingen, GermanyDepartment of PathologyUniversity Hospital Zurich, Zurich, Switzerland.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kühnemuth
authors.affiliation: Departments of GastroenterologyEndocrinology and MetabolismSurgeryPhilipps-University Marburg, Baldingerstraße, 35043 Marburg, GermanyDepartment of PathologyEberhard-Karls-University Tübingen, Tübingen, GermanyDepartment of PathologyUniversity Hospital Zurich, Zurich, Switzerland.
authors.forename: Heidi
authors.initials: H
authors.lastname: Griesmann
authors.affiliation: Departments of GastroenterologyEndocrinology and MetabolismSurgeryPhilipps-University Marburg, Baldingerstraße, 35043 Marburg, GermanyDepartment of PathologyEberhard-Karls-University Tübingen, Tübingen, GermanyDepartment of PathologyUniversity Hospital Zurich, Zurich, Switzerland.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Neesse
authors.affiliation: Departments of GastroenterologyEndocrinology and MetabolismSurgeryPhilipps-University Marburg, Baldingerstraße, 35043 Marburg, GermanyDepartment of PathologyEberhard-Karls-University Tübingen, Tübingen, GermanyDepartment of PathologyUniversity Hospital Zurich, Zurich, Switzerland.
authors.forename: Leonie
authors.initials: L
authors.lastname: Mühlberg
authors.affiliation: Departments of GastroenterologyEndocrinology and MetabolismSurgeryPhilipps-University Marburg, Baldingerstraße, 35043 Marburg, GermanyDepartment of PathologyEberhard-Karls-University Tübingen, Tübingen, GermanyDepartment of PathologyUniversity Hospital Zurich, Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Boch
authors.affiliation: Departments of GastroenterologyEndocrinology and MetabolismSurgeryPhilipps-University Marburg, Baldingerstraße, 35043 Marburg, GermanyDepartment of PathologyEberhard-Karls-University Tübingen, Tübingen, GermanyDepartment of PathologyUniversity Hospital Zurich, Zurich, Switzerland.
authors.forename: Juliane
authors.initials: J
authors.lastname: Kortenhaus
authors.affiliation: Departments of GastroenterologyEndocrinology and MetabolismSurgeryPhilipps-University Marburg, Baldingerstraße, 35043 Marburg, GermanyDepartment of PathologyEberhard-Karls-University Tübingen, Tübingen, GermanyDepartment of PathologyUniversity Hospital Zurich, Zurich, Switzerland.
authors.forename: Volker
authors.initials: V
authors.lastname: Fendrich
authors.affiliation: Departments of GastroenterologyEndocrinology and MetabolismSurgeryPhilipps-University Marburg, Baldingerstraße, 35043 Marburg, GermanyDepartment of PathologyEberhard-Karls-University Tübingen, Tübingen, GermanyDepartment of PathologyUniversity Hospital Zurich, Zurich, Switzerland.
authors.forename: Dominik
authors.initials: D
authors.lastname: Wiese
authors.affiliation: Departments of GastroenterologyEndocrinology and MetabolismSurgeryPhilipps-University Marburg, Baldingerstraße, 35043 Marburg, GermanyDepartment of PathologyEberhard-Karls-University Tübingen, Tübingen, GermanyDepartment of PathologyUniversity Hospital Zurich, Zurich, Switzerland.
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
authors.affiliation: Departments of GastroenterologyEndocrinology and MetabolismSurgeryPhilipps-University Marburg, Baldingerstraße, 35043 Marburg, GermanyDepartment of PathologyEberhard-Karls-University Tübingen, Tübingen, GermanyDepartment of PathologyUniversity Hospital Zurich, Zurich, Switzerland.
authors.forename: Juliane
authors.initials: J
authors.lastname: Friemel
authors.affiliation: Departments of GastroenterologyEndocrinology and MetabolismSurgeryPhilipps-University Marburg, Baldingerstraße, 35043 Marburg, GermanyDepartment of PathologyEberhard-Karls-University Tübingen, Tübingen, GermanyDepartment of PathologyUniversity Hospital Zurich, Zurich, Switzerland.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Gress
authors.affiliation: Departments of GastroenterologyEndocrinology and MetabolismSurgeryPhilipps-University Marburg, Baldingerstraße, 35043 Marburg, GermanyDepartment of PathologyEberhard-Karls-University Tübingen, Tübingen, GermanyDepartment of PathologyUniversity Hospital Zurich, Zurich, Switzerland michlp@med.uni-marburg.de.
authors.forename: Patrick
authors.initials: P
authors.lastname: Michl
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D007340:Insulinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C080632:CUX1 protein, human; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors
keywords: CUX1; RIP1Tag2; angiogenesis; insulinomas; pancreatic neuroendocrine neoplasms