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Reduced representation bisulfite sequencing of small intestinal neuroendocrine tumors identifies PTPRM as a novel candidate tumor suppressor gene
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. (Endocrine Surgery)
Karolinska Institutet, Karolinska University Hospital. (Department of Clinical Neuroscience, Center for Molecular Medicine)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. (Endocrine Surgery)
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(English)In: Article in journal (Refereed) Submitted
National Category
Cancer and Oncology Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-330794OAI: oai:DiVA.org:uu-330794DiVA: diva2:1146790
Available from: 2017-10-04 Created: 2017-10-04 Last updated: 2017-10-04
In thesis
1. Studies of epigenetic deregulation in parathyroid tumors and small intestinal neuroendocrine tumors
Open this publication in new window or tab >>Studies of epigenetic deregulation in parathyroid tumors and small intestinal neuroendocrine tumors
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Deregulation of the epigenome is associated with the initiation and progression of various types of human cancers. Here we investigated the level of 5-hydroxymethylcytosine (5hmC), expression and function of TET1 and TET2, and DNA methylation in parathyroid tumors and small intestinal neuroendocrine tumors (SI-NETs).

In Paper I, an undetectable/very low level of 5hmC in parathyroid carcinomas (PCs) compared to parathyroid adenomas with positive staining, suggested that 5hmC may represent a novel biomarker for parathyroid malignancy. Immunohistochemistry revealed that increased tumor weight in adenomas was associated with a more aberrant staining pattern of 5hmC and TET1. A growth regulatory role of TET1 was demonstrated in parathyroid tumor cells.

Paper II revealed that the expression of TET2 was also deregulated in PCs, and promoter hypermethylation was detected in PCs when compared to normal parathyroid tissues. 5-aza-2′-deoxycytidine treatment of a primary PC cell culture induced TET2 expression and further supported involvement of promoter hypermethylation in TET2 gene repression. TET2 knockout demonstrated a role for TET2 in cell growth and migration, and as a candidate tumor suppressor gene.

In Paper III, variable levels of 5hmC, and aberrant expression of TET1 and TET2 were observed in SI-NETs. We demonstrated a growth regulatory role for TET1, and cytoplasmic expression with absent nuclear localization for TET2 in SI-NETs. In vitro experiments supported the involvement of exportin-1 in TET2 mislocalization, and suggested that KPT-330/selinexor, an orally bioavailable selective inhibitor of exportin-1 and nuclear export, with anti-cancer effects, could be further investigated as a therapeutic option in patients with SI-NETs.

In Paper IV, DNA methylation was compared between SI-NET primary tumors and metastases by reduced representation bisulfite sequencing. Three differentially methylated regions (DMR) on chromosome 18 were detected and chosen for further analyses. The PTPRM gene, at 18p11, displayed low expression in SI-NETs with high levels of methylation in the presumed CpG island shores, and in the DMR rather than the promoter region or exon 1/intron 1 boundary. PTPRM overexpression resulted in inhibition of cell growth, proliferation, and induction of apoptosis in SI-NET cells, suggesting a role for PTPRM as an epigenetically deregulated candidate tumor suppressor gene in SI-NETs.  

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 53 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1377
Keyword
Epigenetics, 5hmC, TET1, TET2, parathyroid tumors, SI-NET, RRBS, PTPRM
National Category
Cancer and Oncology Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-330810 (URN)978-91-513-0097-9 (ISBN)
Public defence
2017-11-24, Fåhraeussalen, Rudbecklaboratoriet Hus 5, Dag Hammarskjölds väg 20, Uppsala, 13:15 (English)
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Supervisors
Available from: 2017-11-02 Created: 2017-10-04 Last updated: 2017-11-02

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