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Wu, Y.; Tedesco, L.; Lucia, K.; Schlitter, A.M.; Garcia, J.M.; Esposito, I.; Auernhammer, C.J.; Theodoropoulou, M.; Arzt, E.; Renner, U.; Stalla, G.K. "RSUME is implicated in tumorigenesis and metastasis of pancreatic neuroendocrine tumors" (2016) Oncotarget. 7(36):57878-57893
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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 ß-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-1a (HIF-1a) 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-1a activity and increased NF-κB and IL-8 production leading to a moderate reduction of VEGF-A release as reduced HIF-1a/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.

Registro:

Documento: Artículo
Título:RSUME is implicated in tumorigenesis and metastasis of pancreatic neuroendocrine tumors
Autor:Wu, Y.; Tedesco, L.; Lucia, K.; Schlitter, A.M.; Garcia, J.M.; Esposito, I.; Auernhammer, C.J.; Theodoropoulou, M.; Arzt, E.; Renner, U.; Stalla, G.K.
Filiación:Department of Clinical Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany
Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA), CONICET-Partner Institute of the Max Planck Society, Buenos Aires, Argentina
Institute of Pathology, Technical University of Munich, Munich, Germany
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
Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
German Cancer Research Center, Heidelberg, Germany
Institute of Pathology, University of Düsseldorf, Düsseldorf, Germany
Palabras clave:Angiogenesis; Metastasis; PanNETs; RSUME; RWDD3; hypoxia inducible factor 1alpha; immunoglobulin enhancer binding protein; interleukin 8; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; regulator protein; RSUME protein; unclassified drug; vasculotropin A; HIF1A protein, human; hypoxia inducible factor 1alpha; IL8 protein, human; immunoglobulin enhancer binding protein; interleukin 8; RSUME protein, human; transcription factor; vasculotropin A; VEGFA protein, human; animal cell; animal experiment; animal model; animal tissue; Article; BON1 cell; cancer transplantation; controlled study; cytokine production; enzyme stability; female; growth rate; human; human cell; human tissue; immunohistochemistry; in vivo study; insulinoma; liver metastasis; lymph node metastasis; mouse; nonhuman; orthotopic transplantation; pancreas islet beta cell; pancreatic neuroendocrine tumor; protein expression; protein function; protein protein interaction; protein secretion; protein synthesis; sumoylation; transcription initiation; transcription regulation; tumor cell line; tumor growth; tumor vascularization; animal; Chlorocebus aethiops; CV-1 cell line; HEK293 cell line; metabolism; metastasis; neovascularization (pathology); neuroendocrine tumor; nude mouse; pancreas tumor; sumoylation; Animals; Cell Line, Tumor; Cercopithecus aethiops; COS Cells; Female; HEK293 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Interleukin-8; Mice; Mice, Nude; Neoplasm Metastasis; Neoplasm Transplantation; Neovascularization, Pathologic; Neuroendocrine Tumors; NF-kappa B; Pancreatic Neoplasms; Sumoylation; Transcription Factors; Vascular Endothelial Growth Factor A
Año:2016
Volumen:7
Número:36
Página de inicio:57878
Página de fin:57893
DOI: http://dx.doi.org/10.18632/oncotarget.11081
Título revista:Oncotarget
Título revista abreviado:Oncotarget
ISSN:19492553
CAS:interleukin 8, 114308-91-7; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase, 210488-47-4; vasculotropin A, 489395-96-2; HIF1A protein, human; Hypoxia-Inducible Factor 1, alpha Subunit; IL8 protein, human; Interleukin-8; NF-kappa B; RSUME protein, human; Transcription Factors; Vascular Endothelial Growth Factor A; VEGFA protein, human
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_19492553_v7_n36_p57878_Wu

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Citas:

---------- APA ----------
Wu, Y., Tedesco, L., Lucia, K., Schlitter, A.M., Garcia, J.M., Esposito, I., Auernhammer, C.J.,..., Stalla, G.K. (2016) . RSUME is implicated in tumorigenesis and metastasis of pancreatic neuroendocrine tumors. Oncotarget, 7(36), 57878-57893.
http://dx.doi.org/10.18632/oncotarget.11081
---------- CHICAGO ----------
Wu, Y., Tedesco, L., Lucia, K., Schlitter, A.M., Garcia, J.M., Esposito, I., et al. "RSUME is implicated in tumorigenesis and metastasis of pancreatic neuroendocrine tumors" . Oncotarget 7, no. 36 (2016) : 57878-57893.
http://dx.doi.org/10.18632/oncotarget.11081
---------- MLA ----------
Wu, Y., Tedesco, L., Lucia, K., Schlitter, A.M., Garcia, J.M., Esposito, I., et al. "RSUME is implicated in tumorigenesis and metastasis of pancreatic neuroendocrine tumors" . Oncotarget, vol. 7, no. 36, 2016, pp. 57878-57893.
http://dx.doi.org/10.18632/oncotarget.11081
---------- VANCOUVER ----------
Wu, Y., Tedesco, L., Lucia, K., Schlitter, A.M., Garcia, J.M., Esposito, I., et al. RSUME is implicated in tumorigenesis and metastasis of pancreatic neuroendocrine tumors. Oncotarget. 2016;7(36):57878-57893.
http://dx.doi.org/10.18632/oncotarget.11081