title: MicroRNAs associated with small bowel neuroendocrine tumours and their metastases.
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 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 regulate FOSB and NUAK2 oncogenes. 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.
authors.affiliation: Department of Surgery and CancerImperial College, Hammersmith Hospital Campus, London, UK.
authors.forename: Helen C
authors.initials: HC
authors.lastname: Miller
authors.affiliation: Department of Surgery and CancerImperial College, Hammersmith Hospital Campus, London, UK.
authors.forename: Adam E
authors.initials: AE
authors.lastname: Frampton
authors.affiliation: Department of Surgery and CancerImperial College, Hammersmith Hospital Campus, London, UK Department of Pathophysiology and EndocrinologySchool of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Malczewska
authors.affiliation: Department of Surgery and CancerImperial College, Hammersmith Hospital Campus, London, UK.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ottaviani
authors.affiliation: Department of Surgery and CancerImperial College, Hammersmith Hospital Campus, London, UK.
authors.forename: Euan A
authors.initials: EA
authors.lastname: Stronach
authors.affiliation: Department of HistopathologyImperial College Healthcare NHS Trust, Hammersmith Hospital, London, UK.
authors.forename: Rashpal
authors.initials: R
authors.lastname: Flora
authors.affiliation: Zentralklinik Bad Berka GmbHRobert-Koch-Allee, Bad Berka, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kaemmerer
authors.affiliation: Institute of PathophysiologyCenter for Molecular Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Gert
authors.initials: G
authors.lastname: Schwach
authors.affiliation: Institute of PathophysiologyCenter for Molecular Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Roswitha
authors.initials: R
authors.lastname: Pfragner
authors.affiliation: St Mark's HospitalHarrow, UK.
authors.forename: Omar
authors.initials: O
authors.lastname: Faiz
authors.affiliation: Department of Pathophysiology and EndocrinologySchool of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland.
authors.forename: Beata
authors.initials: B
authors.lastname: Kos-Kudła
authors.affiliation: Academic Surgical UnitDepartment of Surgery and Cancer, Imperial College, St Mary's Campus, London, UK.
authors.forename: George B
authors.initials: GB
authors.lastname: Hanna
authors.affiliation: Department of Pathophysiology and EndocrinologySchool of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland.
authors.forename: Justin
authors.initials: J
authors.lastname: Stebbing
authors.affiliation: Department of Pathophysiology and EndocrinologySchool of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland.
authors.forename: Leandro
authors.initials: L
authors.lastname: Castellano
authors.affiliation: Department of Surgery and CancerImperial College, Hammersmith Hospital Campus, London, UK a.frilling@imperial.ac.uk.
authors.forename: Andrea
authors.initials: A
authors.lastname: Frilling
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000473:pathology*; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000556:secondary; D008198:Lymph Nodes / Q000378:metabolism; D008207:Lymphatic Metastasis / Q000235:genetics; D035683:MicroRNAs; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs
keywords: biomarkers; metastasis; microRNAs; neuroendocrine tumour; small bowel