Oncotarget

Research Papers:

RSUME is implicated in tumorigenesis and metastasis of pancreatic neuroendocrine tumors

Yonghe Wu, Lucas Tedesco, Kristin Lucia, Anna M. Schlitter, Jose Monteserin Garcia, Irene Esposito, Christoph J. Auernhammer, Marily Theodoropoulou, Eduardo Arzt, Ulrich Renner _ and Günter K. Stalla

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Oncotarget. 2016; 7:57878-57893. https://doi.org/10.18632/oncotarget.11081

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Abstract

Yonghe Wu1,6, Lucas Tedesco2, Kristin Lucia1, Anna M. Schlitter3, Jose Monteserin Garcia1, Irene Esposito3,7, Christoph J. Auernhammer4, Marily Theodoropoulou1, Eduardo Arzt2,5, Ulrich Renner1, Günter K. Stalla1

1Department of Clinical Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany

2Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA)-CONICET-Partner Institute of the Max Planck Society, Buenos Aires, Argentina

3Institute of Pathology, Technical University of Munich, Munich, Germany

4Department 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

5Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina

6Current address: German Cancer Research Center, Heidelberg, Germany

7Current address: Institute of Pathology, University of Düsseldorf, Düsseldorf, Germany

Correspondence to:

Ulrich Renner, email: [email protected]

Keywords: RSUME, RWDD3, PanNETs, angiogenesis, metastasis

Received: November 04, 2015     Accepted: July 17, 2016     Published: August 05, 2016

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.


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