Pancreatic Endocrine Tumourigenesis : Genes of potential importance
Understanding signalling pathways that control pancreatic endocrine tumour (PET) development and proliferation may reveal novel targets for therapeutic intervention. The pathogenesis for sporadic and hereditary PETs, apart from mutations of the MEN1 and VHL tumour suppressor genes, is still elusive....
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Uppsala universitet, Institutionen för medicinska vetenskaper
2008
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ndltd-UPSALLA1-oai-DiVA.org-uu-92942013-01-08T13:04:50ZPancreatic Endocrine Tumourigenesis : Genes of potential importanceengJohansson, Térèse A.Uppsala universitet, Institutionen för medicinska vetenskaperUppsala : Acta Universitatis Upsaliensis2008Pancreatic endocrine tumourMultiple endocrine neoplasia type 1TumourigenesisNotch signallingNotch1Hes1Neurog3Neurod1Men1Ascl1Pou3f4Pdx1Rpl10Dlk1Dkk1Tph1meninTumour biologyTumörbiologiUnderstanding signalling pathways that control pancreatic endocrine tumour (PET) development and proliferation may reveal novel targets for therapeutic intervention. The pathogenesis for sporadic and hereditary PETs, apart from mutations of the MEN1 and VHL tumour suppressor genes, is still elusive. The protein product of the MEN1 gene, menin, regulates many genes. The aim of this thesis was to identify genes involved in pancreatic endocrine tumourigenesis, with special reference to Notch signalling. Messenger RNA and protein expression of NOTCH1, HES1, HEY1, ASCL1, NEUROG3, NEUROD1, DLK1, POU3F4, PDX1, RPL10, DKK1 and TPH1 were studied in human PETs, sporadic and MEN 1, as well as in tumours from heterozygous Men1 mice. For comparison, normal and MEN1 non-tumourous human and mouse pancreatic specimens were used. Nuclear expression of HES1 was consistently absent in PETs. In mouse tumours this coincided with loss of menin expression, and there was a correlation between Men1 expression and several Notch signalling factors. A new phenotype consisting of numerous menin-expressing endocrine cell clusters, smaller than islets, was found in Men1 mice. Expression of NEUROG3 and NEUROD1 was predominantly localised to the cytoplasm in PETs and islets from MEN 1 patients and Men1 mice, whereas expression was solely nuclear in wt mice. Differences in expression levels of Pou3f4, Rpl10 and Dlk1 between islets of Men1 and wt mice were observed. In addition, combined RNA interference and microarray expression analysis in the pancreatic endocrine cell line BON1 identified 158 target genes of ASCL1. For two of these, DKK1 (a negative regulator of the WNT/β-catenin signalling pathway) and TPH1, immunohistochemistry was performed on PETs. In concordance with the microarray finding, DKK1 expression showed an inverse relation to ASCL1 expression. Altered subcellular localisation of HES1, NEUROD1 and NEUROG3 and down-regulation of DKK1 may contribute to tumourigenesis. Doctoral thesis, comprehensive summaryinfo:eu-repo/semantics/doctoralThesistexthttp://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-9294urn:isbn:978-91-554-7290-0Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 ; 379application/pdfinfo:eu-repo/semantics/openAccess |
collection |
NDLTD |
language |
English |
format |
Doctoral Thesis |
sources |
NDLTD |
topic |
Pancreatic endocrine tumour Multiple endocrine neoplasia type 1 Tumourigenesis Notch signalling Notch1 Hes1 Neurog3 Neurod1 Men1 Ascl1 Pou3f4 Pdx1 Rpl10 Dlk1 Dkk1 Tph1 menin Tumour biology Tumörbiologi |
spellingShingle |
Pancreatic endocrine tumour Multiple endocrine neoplasia type 1 Tumourigenesis Notch signalling Notch1 Hes1 Neurog3 Neurod1 Men1 Ascl1 Pou3f4 Pdx1 Rpl10 Dlk1 Dkk1 Tph1 menin Tumour biology Tumörbiologi Johansson, Térèse A. Pancreatic Endocrine Tumourigenesis : Genes of potential importance |
description |
Understanding signalling pathways that control pancreatic endocrine tumour (PET) development and proliferation may reveal novel targets for therapeutic intervention. The pathogenesis for sporadic and hereditary PETs, apart from mutations of the MEN1 and VHL tumour suppressor genes, is still elusive. The protein product of the MEN1 gene, menin, regulates many genes. The aim of this thesis was to identify genes involved in pancreatic endocrine tumourigenesis, with special reference to Notch signalling. Messenger RNA and protein expression of NOTCH1, HES1, HEY1, ASCL1, NEUROG3, NEUROD1, DLK1, POU3F4, PDX1, RPL10, DKK1 and TPH1 were studied in human PETs, sporadic and MEN 1, as well as in tumours from heterozygous Men1 mice. For comparison, normal and MEN1 non-tumourous human and mouse pancreatic specimens were used. Nuclear expression of HES1 was consistently absent in PETs. In mouse tumours this coincided with loss of menin expression, and there was a correlation between Men1 expression and several Notch signalling factors. A new phenotype consisting of numerous menin-expressing endocrine cell clusters, smaller than islets, was found in Men1 mice. Expression of NEUROG3 and NEUROD1 was predominantly localised to the cytoplasm in PETs and islets from MEN 1 patients and Men1 mice, whereas expression was solely nuclear in wt mice. Differences in expression levels of Pou3f4, Rpl10 and Dlk1 between islets of Men1 and wt mice were observed. In addition, combined RNA interference and microarray expression analysis in the pancreatic endocrine cell line BON1 identified 158 target genes of ASCL1. For two of these, DKK1 (a negative regulator of the WNT/β-catenin signalling pathway) and TPH1, immunohistochemistry was performed on PETs. In concordance with the microarray finding, DKK1 expression showed an inverse relation to ASCL1 expression. Altered subcellular localisation of HES1, NEUROD1 and NEUROG3 and down-regulation of DKK1 may contribute to tumourigenesis. |
author |
Johansson, Térèse A. |
author_facet |
Johansson, Térèse A. |
author_sort |
Johansson, Térèse A. |
title |
Pancreatic Endocrine Tumourigenesis : Genes of potential importance |
title_short |
Pancreatic Endocrine Tumourigenesis : Genes of potential importance |
title_full |
Pancreatic Endocrine Tumourigenesis : Genes of potential importance |
title_fullStr |
Pancreatic Endocrine Tumourigenesis : Genes of potential importance |
title_full_unstemmed |
Pancreatic Endocrine Tumourigenesis : Genes of potential importance |
title_sort |
pancreatic endocrine tumourigenesis : genes of potential importance |
publisher |
Uppsala universitet, Institutionen för medicinska vetenskaper |
publishDate |
2008 |
url |
http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-9294 http://nbn-resolving.de/urn:isbn:978-91-554-7290-0 |
work_keys_str_mv |
AT johanssonteresea pancreaticendocrinetumourigenesisgenesofpotentialimportance |
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1716508242469715968 |