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Genes 2015, 6(1), 1-21; doi:10.3390/genes6010001

Down-Regulation of miR-129-5p and the let-7 Family in Neuroendocrine Tumors and Metastases Leads to Up-Regulation of Their Targets Egr1, G3bp1, Hmga2 and Bach1

1
Center for Genomic Medicine, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark
2
Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark
3
Cluster for Molecular Imaging, Faculty of Health Sciences, Blegdamsvej 3B, 2100 Copenhagen, Denmark
4
The Bioinformatics Center, Department of Biology and Biotech and Research Innovation Centre, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark
5
Computational Biology Center, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA
6
DTU Informatics, Technical University of Denmark, Anker Engelunds Vej 1, 2800 Kongens Lyngby, Denmark
7
Department of Pathology, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark
8
Department of Surgical Gastroenterology C, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark
9
Department of Clinical Biochemistry Næstved Hospital Ringstedvej 61, 4700 Næstved, Denmark
*
Author to whom correspondence should be addressed.
Academic Editor: J. Peter W. Young
Received: 10 October 2014 / Accepted: 9 December 2014 / Published: 24 December 2014
(This article belongs to the Section Human Genomics and Genetic Diseases)
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Abstract

Expression of miRNAs in Neuroendocrine Neoplasms (NEN) is poorly characterized. We therefore wanted to examine the miRNA expression in Neuroendocrine Tumors (NETs), and identify their targets and importance in NET carcinogenesis. miRNA expression in six NEN primary tumors, six NEN metastases and four normal intestinal tissues was characterized using miRNA arrays, and validated by in-situ hybridization and qPCR. Among the down-regulated miRNAs miR-129-5p and the let-7f/let-7 family, were selected for further characterization. Transfection of miR-129-5p inhibited growth of a pulmonary and an intestinal carcinoid cell line. Analysis of mRNA expression changes identified EGR1 and G3BP1 as miR-129-5p targets. They were validated by luciferase assay and western blotting, and found robustly expressed in NETs by immunohistochemistry. Knockdown of EGR1 and G3BP1 mimicked the growth inhibition induced by miR-129-5p. let-7 overexpression inhibited growth of carcinoid cell lines, and let-7 inhibition increased protein content of the transcription factor BACH1 and its targets MMP1 and HMGA2, all known to promote bone metastases. Immunohistochemistry analysis revealed that let-7 targets are highly expressed in NETs and metastases. We found down-regulation of miR-129-5p and the let-7 family, and identified new neuroendocrine specific targets for these miRNAs, which contributes to the growth and metastatic potential of these tumors. View Full-Text
Keywords: neuroendocrine tumors; cancer; miR-129-5p; let-7; EGR1; G3BP1; HMGA2; BACH1; MMP1 neuroendocrine tumors; cancer; miR-129-5p; let-7; EGR1; G3BP1; HMGA2; BACH1; MMP1
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Døssing, K.B.V.; Binderup, T.; Kaczkowski, B.; Jacobsen, A.; Rossing, M.; Winther, O.; Federspiel, B.; Knigge, U.; Kjær, A.; Friis-Hansen, L. Down-Regulation of miR-129-5p and the let-7 Family in Neuroendocrine Tumors and Metastases Leads to Up-Regulation of Their Targets Egr1, G3bp1, Hmga2 and Bach1. Genes 2015, 6, 1-21.

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