ECE2016 Eposter Presentations Endocrine tumours and neoplasia (68 abstracts)
RSUME regulates tumorigenesis and metastasis in pancreatic neuroendocrine tumors
Yonghe Wu 1, , Lucas Tedesco 3 , Kristin Lucia 1 , Anna M Schlitter 4 , Irene Esposito 5 , Christoph J Auernhammer 6 , Marily Theodoropoulou 1 , Eduardo Arzt 3, , Günter K Stalla 1 & Ulrich Renner 1
1Max Planck Institute of Psychiatry, Clinical Neuroendocrinology, Munich, Germany; 2German Cancer Research Center, Molecular Genetics, Heidelberg, Germany; 3Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, Argentina; 4Technical University of Munich, Institute of Pathology, Munich, Germany; 5University of Düsseldorf, Institute of Pathology, Düsseldorf, Germany; 6Department of Internal Medicine II, Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System, University of Munich, Munich, Germany; 7Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
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-kB (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 present 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.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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