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Functional role of miR-196a in neuroendocrine tumor cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
Royal Free Hosp, London NW3 2QG, England.
Royal Free Hosp, London NW3 2QG, England.
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2015 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 102, no 1-2, 87-87 p.Article in journal, Meeting abstract (Refereed) Published
Place, publisher, year, edition, pages
S. Karger, 2015. Vol. 102, no 1-2, 87-87 p.
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-233206DOI: 10.1159/000431385ISI: 000361683500030OAI: oai:DiVA.org:uu-233206DiVA: diva2:750991
Conference
12th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, Barcelona, SPAIN, MAR 11-13, 2015
Available from: 2014-09-30 Created: 2014-09-30 Last updated: 2017-12-05Bibliographically approved
In thesis
1. Small Intestinal Neuroendocrine Tumor Analyses: Somatostatin Analog Effects and MicroRNA Profiling
Open this publication in new window or tab >>Small Intestinal Neuroendocrine Tumor Analyses: Somatostatin Analog Effects and MicroRNA Profiling
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Small intestinal neuroendocrine tumors (SI-NETs) originate from serotonin-producing enterochromaffin (EC) cells in the intestinal mucosa. Somatostatin analogs (SSAs) are mainly used to control hormonal secretion and tumor growth. However, the molecular mechanisms leading to the control of SI-NETs are unknown. Although microRNAs (miRNAs) are post transcriptional regulators deeply studied in many cancers, are not well-defined in SI-NETs. We adopted a two-pronged strategy to investigate SSAs and miRNAs: first, to provide novel insights into how SSAs control NET cells, and second, to identify an exclusive SI-NET miRNA expression, and investigate the biological functions of miRNA targets.

To accomplish the first aim, we treated CNDT2.5 cells with octreotide for 16 months. Affymetrix microarray was performed to study gene variation of CNDT2.5 cells in the presence or absence of octreotide. The study revealed that octreotide induces six genes, ANXA1, ARHGAP18, EMP1, GDF15, TGFBR2 and TNFSF15.

To accomplish the second aim, SI-NET tissue specimens were used to run genome-wide Affymetrix miRNA arrays. The expression of five miRNAs (miR-96, -182, -183, -196a and -200a) was significantly upregulated in laser capture microdissected (LCM) tumor cells versus LCM normal EC cells, whereas the expression of four miRNAs (miR-31, -129-5p, -133a and -215) was significantly downregulated in LCM tumor cells. We also detected nine tissue miRNAs in serum samples, showing that the expression of five miRNAs is significantly increased in SSA treated patients versus untreated patients. Conversely, SSAs do not change miRNA expression of four low expressed miRNAs. Silencing miR-196a expression was used to investigate functional activities in NET cells. This experimental approach showed that four miR-196a target genes, HOXA9, HOXB7, LRP4 and RSPO2, are significantly upregulated in silenced miR-196a NET cells.

In conclusion, ANXA1, ARHGAP18, EMP1, GDF15, TGFBR2 and TNFSF15 genes might regulate cell growth and differentiation in NET cells, and play a role in an innovative octreotide signaling pathway. The global SI-NET miRNA profiling revealed that nine selected miRNAs might be involved in tumorigenesis, and play a potential role as novel markers for follow-up. Indeed, silencing miR-196a demonstrated that HOXA9, HOXB7, LRP4 and RSPO2 genes are upregulated at both transcriptional and translational levels.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 48 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1039
Keyword
Small intestinal neuroendocrine tumors, Somatostatin analogs, Laser-capture microdissection, Microarray profiling and microRNA profiling
National Category
Cell and Molecular Biology
Research subject
Biology with specialization in Molecular Biology
Identifiers
urn:nbn:se:uu:diva-233207 (URN)978-91-554-9058-4 (ISBN)
Public defence
2014-11-20, Enghoffsalen, Entrance 50, Uppsala University Hospital, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2014-10-30 Created: 2014-09-30 Last updated: 2015-01-23

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Li, Su-ChenÖberg, KjellGiandomenico, Valeria

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