title: Overexpression of miR-210 is associated with SDH-related pheochromocytomas, paragangliomas, and gastrointestinal stromal tumours.
abstract: miR-210 is a key regulator of response to hypoxia. Pheochromocytomas (PCs) and paragangliomas (PGLs) with germline SDHx or VHL mutations have pseudohypoxic gene expression signatures. We hypothesised that PC/PGLs containing SDHx or VHL mutations, and succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumours (GISTs), would overexpress miR-210 relative to non-SDH or -VHL-mutated counterparts. miR-210 was analysed by quantitative PCR in i) 39 PC/PGLs, according to genotype (one SDHA, five SDHB, seven VHL, three NF1, seven RET, 15 sporadic, one unknown) and pathology (18 benign, eight atypical, 11 malignant, two unknown); ii) 18 GISTs, according to SDHB immunoreactivity (nine SDH-deficient and nine SDH-proficient) and iii) two novel SDHB-mutant neurosphere cell lines. miR-210 was higher in SDHx- or VHL-mutated PC/PGLs (7.6-fold) compared with tumours without SDHx or VHL mutations (P=0.0016). miR-210 was higher in malignant than in unequivocally benign PC/PGLs (P=0.05), but significance was lost when benign and atypical tumours were combined (P=0.08). In multivariate analysis, elevated miR-210 was significantly associated with SDHx or VHL mutation, but not with malignancy. In GISTs, miR-210 was higher in SDH-deficient (median 2.58) compared with SDH-proficient tumours (median 0.60; P=0.0078). miR-210 was higher in patient-derived neurosphere cell lines containing SDHB mutations (6.5-fold increase) compared with normal controls, in normoxic conditions (P<0.01). Furthermore, siRNA-knockdown of SDHB in HEK293 cells increased miR-210 by 2.7-fold (P=0.001) under normoxia. Overall, our results suggest that SDH deficiency in PC, PGL and GISTs induces miR-210 expression and substantiates the role of aberrant hypoxic-type cellular responses in the development of these tumours.
authors.affiliation: Cancer Genetics Laboratory, Kolling Institute of Medical Research Department of Endocrinology, Royal North Shore Hospital, The University of Sydney, Sydney, New South Wales 2065, Australia Department of Surgery, Faculty of Medical and Health Sciences, Waikato Clinical School, University of Auckland, Auckland 1142, New Zealand Department of Anatomical Pathology, Cancer Diagnosis and Oncology Group, Kolling Institute of Medical Research Department of Endocrine and Oncology Surgery, Neurogenetics Research Laboratory, Kolling Institute of Medical Research Department of ENT Surgery, Department of Neurology Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, Royal North Shore Hospital, The University of Sydney, Sydney, New South Wales 2065, Australia.
authors.forename: V H M
authors.initials: VH
authors.lastname: Tsang
authors.forename: T
authors.initials: T
authors.lastname: Dwight
authors.forename: D E
authors.initials: DE
authors.lastname: Benn
authors.forename: G Y
authors.initials: GY
authors.lastname: Meyer-Rochow
authors.forename: A J
authors.initials: AJ
authors.lastname: Gill
authors.forename: M
authors.initials: M
authors.lastname: Sywak
authors.forename: S
authors.initials: S
authors.lastname: Sidhu
authors.forename: D
authors.initials: D
authors.lastname: Veivers
authors.forename: C M
authors.initials: CM
authors.lastname: Sue
authors.forename: B G
authors.initials: BG
authors.lastname: Robinson
authors.forename: R J
authors.initials: RJ
authors.lastname: Clifton-Bligh
authors.forename: N R
authors.initials: NR
authors.lastname: Parker
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D002648:Child; D005260:Female; D005500:Follow-Up Studies; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D060787:Neoplasm Grading; D010235:Paraganglioma / Q000235:genetics* / Q000473:pathology; D010673:Pheochromocytoma / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013385:Succinate Dehydrogenase / Q000235:genetics*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C543800:MIRN210 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human
keywords: gastrointestinal stromal tumour; miR-210; paraganglioma; pheochromocytoma; succinate dehydrogenase