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A Plausible Role for Actin Gamma Smooth Muscle 2 (ACTG2) in Small Intestinal Neuroendocrine Tumorgenesis
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper. (Endokrinkirurgi)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper. (Endokrinkirurgi)
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. (Endokrinkirurgi, Endocrine Surgery)
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nyckelord [en]
ACTG2, SI-NET, epigenetic, microRNA-145
Nationell ämneskategori
Medicin och hälsovetenskap Medicinska och farmaceutiska grundvetenskaper
Identifikatorer
URN: urn:nbn:se:uu:diva-219270OAI: oai:DiVA.org:uu-219270DiVA, id: diva2:698918
Tillgänglig från: 2014-02-25 Skapad: 2014-02-25 Senast uppdaterad: 2018-01-11
Ingår i avhandling
1. Small Intestinal Neuroendocrine Tumours: Genetic and Epigenetic Studies and Novel Serum Biomarkers
Öppna denna publikation i ny flik eller fönster >>Small Intestinal Neuroendocrine Tumours: Genetic and Epigenetic Studies and Novel Serum Biomarkers
2014 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2014. s. 51
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 975
Nyckelord
SI-NET, microarray, tumour suppressor gene, epigenetic, serum biomarkers
Nationell ämneskategori
Medicin och hälsovetenskap Medicinska och farmaceutiska grundvetenskaper
Forskningsämne
Kirurgi
Identifikatorer
urn:nbn:se:uu:diva-219136 (URN)978-91-554-8887-1 (ISBN)
Disputation
2014-04-11, Rosénsalen, Akademiska Sjukhuset, Ing 95, Uppsala, 09:15 (Svenska)
Opponent
Handledare
Tillgänglig från: 2014-03-20 Skapad: 2014-02-22 Senast uppdaterad: 2018-01-11

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Edfeldt, KatarinaHellman, PerWestin, GunnarStålberg, Peter

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Edfeldt, KatarinaHellman, PerWestin, GunnarStålberg, Peter
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