Epidrug-induced upregulation of functional somatostatin type 2 receptors in human pancreatic neuroendocrine tumor cells
| Autor: | Fadime Dogan, Leo J. Hofland, Richard A Feelders, Marije J. Veenstra, Steven W. J. Lamberts, Peter M. van Koetsveld, Wouter W. de Herder, Giovanni Vitale, William E. Farrell |
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| Přispěvatelé: | Internal Medicine |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Octreotide Neuroendocrine tumors pancreatic neuroendocrine tumor 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Internal medicine medicine Somatostatin receptor 2 Epigenetics Receptor epigenetics Somatostatin receptor business.industry somatostatin receptor type 2 BON-1 medicine.disease QGP-1 stomatognathic diseases 030104 developmental biology Endocrinology Somatostatin Oncology 030220 oncology & carcinogenesis business Research Paper medicine.drug |
| Zdroj: | Oncotarget, 9(19), 14791-14802. Impact Journals LLC Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Marije J. Veenstra 1 , Peter M. van Koetsveld 1 , Fadime Dogan 1 , William E. Farrell 2 , Richard A. Feelders 1 , Steven W.J. Lamberts 1 , Wouter W. de Herder 1 , Giovanni Vitale 3, 4 , Leo J. Hofland 1 1 Department of Internal Medicine, Division of Endocrinology, Erasmus MC, Rotterdam, The Netherlands 2 Department Human Disease and Genomics Group, Institute of Science and Technology in Medicine, School of Medicine, Keele University, Keele, United Kingdom 3 Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, Milan, Italy 4 Department of Clinical Sciences and Community Health (DISCCO), University of Milan, Milan, Italy Correspondence to: Leo J. Hofland, email: l.hofland@erasmusmc.nl Keywords: pancreatic neuroendocrine tumor, somatostatin receptor type 2, epigenetics, BON-1, QGP-1 Received: November 19, 2015 Accepted: April 24, 2016 Published: May 19, 2016 ABSTRACT Somatostatin receptors are a pivotal target for treatment of pancreatic neuroendocrine tumors (pNET), either with somatostatin analogues (SSA) or radiolabeled SSA. The highest affinity target for the most commonly used SSA is the somatostatin receptor type 2 ( sst 2 ). An important factor that may complicate treatment efficacy, is the variable number of receptors expressed on pNETs. Gene expression is subject to complex regulation, in which epigenetics has a central role. In this study we explored the possible role of epigenetic modifications in the variations in sst 2 expression levels in two human pNET cell lines, BON-1 and QGP-1. We found upregulation of sst 2 mRNA after treatment with the epidrugs 5-aza-2’-deoxycytidine (5-aza-dC) and valproic acid (VPA), an increased uptake of radiolabeled octreotide, as well as increased sensitivity to the SSA octreotide in functional cAMP inhibition. At epigenetic level we observed low methylation levels of the sst 2 gene promoter region irrespective of expression. Activating histone mark H3K9Ac can be regulated with epidrug treatment, with an angle of effect corresponding to the effect on mRNA expression. Repressive histone mark H3K27me3 is not regulated by either 5-aza-dC or VPA. We conclude that epidrug treatment, in particular with combined 5-aza-dC and VPA treatment, might hold promise for improving and adding to current SSA treatment strategies of patients with pNETs. |
| Databáze: | OpenAIRE |
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