DOI: 10.1530/ERC-16-0044 http://erc.endocrinology-journals.org © 2016 Society for Endocrinology Printed in Great Britain Published by Bioscientifca Ltd. Endocrine-Related Cancer 23:9 Research H C Miller, A E Frampton et al. MicroRNAs in SBNETs and their metastases MicroRNAs associated with small bowel neuroendocrine tumours and their metastases Helen C Miller 1, †, Adam E Frampton 1, †, Anna Malczewska 1,2 , Silvia Ottaviani 1 , Euan A Stronach 1 , Rashpal Flora 3 , Daniel Kaemmerer 4 , Gert Schwach 5 , Roswitha Pfragner 5 , Omar Faiz 6 , Beata Kos-Kudła 2 , George B Hanna 7 , Justin Stebbing 2,‡ , Leandro Castellano 2,‡ and Andrea Frilling 1,‡ 1 Department of Surgery and Cancer, Imperial College, Hammersmith Hospital Campus, London, UK 2 Department of Pathophysiology and Endocrinology, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland 3 Department of Histopathology, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, UK 4 Zentralklinik Bad Berka GmbH, Robert-Koch-Allee, Bad Berka, Germany 5 Institute of Pathophysiology, Center for Molecular Medicine, Medical University of Graz, Graz, Austria 6 St Mark’s Hospital, Harrow, UK 7 Academic Surgical Unit, Department of Surgery and Cancer, Imperial College, St Mary’s Campus, London, UK † (H C Miller and A E Frampton contributed equally as co-frst authors) ‡ (J Stebbing, L Castellano and A Frilling contributed equally as co-senior authors) Endocrine-Related Cancer (2016) 23, 711–726 711–726 Correspondence should be addressed to A Frilling Email a.frilling@imperial.ac.uk Key Words f microRNAs f small bowel f neuroendocrine tumour f biomarkers f metastasis Abstract Novel molecular analytes are needed in small bowel neuroendocrine tumours (SBNETs) to better determine disease aggressiveness and predict treatment response. In this study, we aimed to profle the global miRNome of SBNETs, and identify microRNAs (miRNAs) involved in tumour progression for use as potential biomarkers. Two independent miRNA profling experiments were performed (n = 90), including primary SBNETs (n = 28), adjacent normal small bowel (NSB; n = 14), matched lymph node (LN) metastases (n = 24), normal LNs (n = 7), normal liver (n = 2) and liver metastases (n = 15). We then evaluated potentially targeted genes by performing integrated computational analyses. We discovered 39 miRNAs signifcantly deregulated in SBNETs compared with adjacent NSB. The most upregulated (miR-204-5p, miR-7-5p and miR-375) were confrmed by qRT-PCR. Two miRNAs (miR-1 and miR-143-3p) were signifcantly downregulated in LN and liver metastases compared with primary tumours. Furthermore, we identifed upregulated gene targets for miR-1 and miR-143-3p in an existing SBNET dataset, which could contribute to disease progression, and show that these miRNAs directly regulate FOSB and NUAK2 oncogenes. Our study represents the largest global miRNA profling of SBNETs using matched primary tumour and metastatic samples. We revealed novel miRNAs deregulated during SBNET disease progression, and important miRNA–mRNA interactions. These miRNAs have the potential to act as biomarkers for patient stratifcation and may also be able to guide treatment decisions. Further experiments to defne molecular mechanisms and validate these miRNAs in larger tissue cohorts and in biofuids are now warranted. Downloaded from Bioscientifica.com at 06/10/2020 08:10:23AM via free access