title: RSUME is implicated in tumorigenesis and metastasis of pancreatic neuroendocrine tumors.
abstract: The factors triggering pancreatic neuroendocrine tumor (PanNET) progression are largely unknown. Here we investigated the role and mechanisms of the sumoylation enhancing protein RSUME in PanNET tumorigenesis. Immunohistochemical studies showed that RSUME is strongly expressed in normal human pancreas, in particular in β-cells. RSUME expression is reduced in insulinomas and is nearly absent in other types of PanNETs suggesting a role in PanNET tumorigenesis. In human pancreatic neuroendocrine BON1 cells, RSUME stimulates hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor-A (VEGF-A), which are key components of tumor neovascularisation. In contrast, RSUME suppresses nuclear factor-κB (NF-κB) and its target interleukin-8 (IL-8). Correspondingly, PanNET cells with RSUME knockdown showed decreased HIF-1α activity and increased NF-κB and IL-8 production leading to a moderate reduction of VEGF-A release as reduced HIF-1α/VEGF-A production is partly compensated by NF-κB/IL-8-induced VEGF-A. Notably, RSUME stabilizes the tumor suppressor PTEN, which is frequently lost in PanNETs and whose absence is associated with metastasis formation. In vivo orthotopic transplantation of PanNET cells with or without RSUME expression into nude mice showed that PanNETs without RSUME have reduced PTEN expression, grow faster and form multiple liver metastases. In sum, RSUME differentially regulates key components of PanNET formation suggesting that the observed loss of RSUME in advanced PanNETs is critically involved in PanNET tumorigenesis, particularly in metastasis formation.
authors: Department of Clinical Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany.|Current address: German Cancer Research Center, Heidelberg, Germany.
authors: Yonghe
authors: Y
authors: Wu
authors: Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA)-CONICET-Partner Institute of the Max Planck Society, Buenos Aires, Argentina.
authors: Lucas
authors: L
authors: Tedesco
authors: Department of Clinical Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany.
authors: Kristin
authors: K
authors: Lucia
authors: Institute of Pathology, Technical University of Munich, Munich, Germany.
authors: Anna M
authors: AM
authors: Schlitter
authors: Department of Clinical Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany.
authors: Jose Monteserin
authors: JM
authors: Garcia
authors: Institute of Pathology, Technical University of Munich, Munich, Germany.|Current address: Institute of Pathology, University of Düsseldorf, Düsseldorf, Germany.
authors: Irene
authors: I
authors: Esposito
authors: Department of Internal Medicine II, University-Hospital Campus Grosshadern, Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System (GEPNET-KUM), Ludwig-Maximilians-University of Munich, Munich, Germany.
authors: Christoph J
authors: CJ
authors: Auernhammer
authors: Department of Clinical Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany.
authors: Marily
authors: M
authors: Theodoropoulou
authors: Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA)-CONICET-Partner Institute of the Max Planck Society, Buenos Aires, Argentina.|Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors: Eduardo
authors: E
authors: Arzt
authors: Department of Clinical Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany.
authors: Ulrich
authors: U
authors: Renner
authors: Department of Clinical Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany.
authors: Günter K
authors: GK
authors: Stalla
mesh_terms: D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D016209:Interleukin-8 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D018358:Neuroendocrine Tumors / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D058207:Sumoylation; D014157:Transcription Factors / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C508606:CXCL8 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016209:Interleukin-8; D016328:NF-kappa B; C525338:RWDD3 protein, human; D014157:Transcription Factors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: PanNETs; RSUME; RWDD3; angiogenesis; metastasis