RSUME is implicated in tumorigenesis and metastasis of pancreatic neuroendocrine tumors

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 pancre...

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Publicado:	2016
Materias:	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 IL8 protein, human RSUME protein, human transcription factor 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 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
Acceso en línea:	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_19492553_v7_n36_p57878_Wu http://hdl.handle.net/20.500.12110/paper_19492553_v7_n36_p57878_Wu
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

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spelling	paper:paper_19492553_v7_n36_p57878_Wu2023-06-08T16:32:37Z RSUME is implicated in tumorigenesis and metastasis of pancreatic neuroendocrine tumors 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 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. 2016 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_19492553_v7_n36_p57878_Wu http://hdl.handle.net/20.500.12110/paper_19492553_v7_n36_p57878_Wu
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	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
spellingShingle	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 RSUME is implicated in tumorigenesis and metastasis of pancreatic neuroendocrine tumors
topic_facet	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
description	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.
title	RSUME is implicated in tumorigenesis and metastasis of pancreatic neuroendocrine tumors
title_short	RSUME is implicated in tumorigenesis and metastasis of pancreatic neuroendocrine tumors
title_full	RSUME is implicated in tumorigenesis and metastasis of pancreatic neuroendocrine tumors
title_fullStr	RSUME is implicated in tumorigenesis and metastasis of pancreatic neuroendocrine tumors
title_full_unstemmed	RSUME is implicated in tumorigenesis and metastasis of pancreatic neuroendocrine tumors
title_sort	rsume is implicated in tumorigenesis and metastasis of pancreatic neuroendocrine tumors
publishDate	2016
url	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_19492553_v7_n36_p57878_Wu http://hdl.handle.net/20.500.12110/paper_19492553_v7_n36_p57878_Wu
_version_	1768545348305813504

RSUME is implicated in tumorigenesis and metastasis of pancreatic neuroendocrine tumors

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