MicroRNAs associated with small bowel neuroendocrine tumours and their metastases

Endocrine-Related Cancer - Tập 23 Số 9 - Trang 711-726 - 2016
H. Miller1, Adam E. Frampton1, Anna Malczewska2,1, Silvia Ottaviani1, Euan A. Stronach1, Rashpal Flora3, Daniel Kaemmerer4, Gert Schwach5, Roswitha Pfragner5, Omar Faiz6, Beata Kos‐Kudła2, George B. Hanna7, Justin Stebbing2, Leandro Castellano2, Andrea Frilling1
1Department of Surgery and Cancer, Imperial College, Hammersmith Hospital Campus, London, UK
2Department of Pathophysiology and Endocrinology, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland
3Department of Histopathology, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, UK
4Zentralklinik Bad Berka GmbH, Robert-Koch-Allee, Bad Berka, Germany
5Institute of Pathophysiology, Center for Molecular Medicine, Medical University of Graz, Graz, Austria
6St Mark’s Hospital, Harrow, UK
7Academic Surgical Unit, Department of Surgery and Cancer, Imperial College, St Mary's Campus, London, UK

Tóm tắt

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 profile the global miRNome of SBNETs, and identify microRNAs (miRNAs) involved in tumour progression for use as potential biomarkers. Two independent miRNA profiling 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 significantly deregulated in SBNETs compared with adjacent NSB. The most upregulated (miR-204-5p, miR-7-5p and miR-375) were confirmed by qRT-PCR. Two miRNAs (miR-1 and miR-143-3p) were significantly downregulated in LN and liver metastases compared with primary tumours. Furthermore, we identified 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 regulateFOSBandNUAK2oncogenes. Our study represents the largest global miRNA profiling 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 stratification and may also be able to guide treatment decisions. Further experiments to define molecular mechanisms and validate these miRNAs in larger tissue cohorts and in biofluids are now warranted.

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Endocrine-Related Cancer

Tập 23 Số 9

711-726

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