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TCEB3C a putative tumor suppressor gene of small intestine neuroendocrine tumors
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper. (Endokrinkirurgi, Endocrine Surgery)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper. (Endokrinkirurgi, Endocrine Surgery)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
Vise andre og tillknytning
2014 (engelsk)Inngår i: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 21, nr 2, s. 275-284Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Small intestinal neuroendocrine tumors (SI-NETs), formerly midgut carcinoids, are rare and slow-growing neoplasms. Frequent loss of one copy of chromosome 18 in primary tumors and metastases has been observed. The aim of the study was to investigate a possible role of TCEB3C (Elongin A3), currently the only imprinted gene on chromosome 18, as a tumor suppressor gene in SI-NETs, and whether its expression is epigenetically regulated. Primary tumors, metastases, the human SI-NET cell line CNDT2.5, and two other cell lines were included. Immunohistochemistry, gene copy number determination by PCR, colony formation assay, Western blotting, real-time quantitative RT-PCR, RNA interference, and quantitative CpG methylation analysis by pyrosequencing were performed. The large majority of tumors (33/43) showed very low to undetectable Elongin A3 expression and as expected 89% (40/45) displayed one TCEB3C gene copy. The DNA hypomethylating agent 5-aza-2'-deoxycytidine induced TCEB3C expression in CNDT2.5 cells, in primary SI-NET cells prepared directly after surgery, but not in two other cell lines. Also siRNA to DNMT1 and treatment with the general histone methyltransferase inhibitor 3-deazaneplanocin A induced TCEB3C expression in a cell type-specific way. CpG methylation at the TCEB3C promoter was observed in all analyzed tissues and thus not related to expression. Overexpression of TCEB3C resulted in a 50% decrease of clonogenic survival of CNDT2.5 cells, but not of control cells. The results support a putative role of TCEB3C as a tumor suppressor gene in SI-NETs. Epigenetic repression of TCEB3C seems to be tumor cell type-specific and involves both DNA and histone methylation.

sted, utgiver, år, opplag, sider
2014. Vol. 21, nr 2, s. 275-284
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-215816DOI: 10.1530/ERC-13-0419ISI: 000344787300017PubMedID: 24351681OAI: oai:DiVA.org:uu-215816DiVA, id: diva2:688550
Tilgjengelig fra: 2014-01-17 Laget: 2014-01-17 Sist oppdatert: 2017-12-06
Inngår i avhandling
1. Small Intestinal Neuroendocrine Tumours: Genetic and Epigenetic Studies and Novel Serum Biomarkers
Åpne denne publikasjonen i ny fane eller vindu >>Small Intestinal Neuroendocrine Tumours: Genetic and Epigenetic Studies and Novel Serum Biomarkers
2014 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Small intestinal neuroendocrine tumours (SI-NETs) are rare, hormone producing and proliferate slowly. Patients usually display metastases at time of diagnosis, the tumours are difficult to cure, and the disease course is unpredictable.

The gene expression pattern was investigated in paper I, with emphasis on aggressive disease and tumour progression. Expression microarrays were performed on 42 tumours. Unsupervised hierarchal clustering revealed three clusters that were correlated to clinical features, and expression changes from primary tumour to metastasis. Eight novel genes, ACTG2, GREM2, REG3A, TUSC2, RUNX1, TGFBR2, TPH1 and CDH6 may be of importance for tumour progression.

In paper II, expression of ACTG2 was detected in a fraction of SI-NETs, but not in normal enterochromaffin cells. Inhibition of histone methyltransferase and transfection of miR-145 induced expression and no effect was seen after DNA methylation or selective EZH2 inhibition in vitro. miR-145 expression was reduced in metastases compared to primary tumours. Overexpression of ACTG2 inhibited cell growth, and inducing ACTG2 may have therapeutic effects.

TCEB3C (Elongin A3) is located on chromosome 18 and is imprinted in some tissues. In paper III a reduced protein expression was detected. The gene was epigenetically repressed by both DNA and histone methylation in a tumour tissue specific context. The expression was also induced in primary cell cultures after DNA demethylation and pyrosequencing revealed promoter region hypermethylation. Overexpression of TCEB3C inhibited cell growth by 50%, suggesting TCEB3C to be a tumour suppressor gene.

In paper IV, 69 biomarkers were analysed in blood serum using multiplex proximity ligation assay. Nineteen markers displayed different levels between patients and controls. In an extended cohort, ELISA analysis showed elevated serum levels of Mindin, DcR3 and TFF3 in patients and protein expression in tumour cells. High levels of DcR3 and TFF3 were associated with poor survival, and DcR3 may be a marker for liver metastases. Mindin, DcR3, and TFF3 are potential novel diagnostic biomarkers for SI-NETs.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2014. s. 51
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 975
Emneord
SI-NET, microarray, tumour suppressor gene, epigenetic, serum biomarkers
HSV kategori
Forskningsprogram
Kirurgi
Identifikatorer
urn:nbn:se:uu:diva-219136 (URN)978-91-554-8887-1 (ISBN)
Disputas
2014-04-11, Rosénsalen, Akademiska Sjukhuset, Ing 95, Uppsala, 09:15 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2014-03-20 Laget: 2014-02-22 Sist oppdatert: 2018-01-11

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