title: Integrative analysis of miRNA and mRNA expression profiles in pheochromocytoma and paraganglioma identifies genotype-specific markers and potentially regulated pathways.
abstract: Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine neoplasias of neural crest origin that can be part of several inherited syndromes. Although their mRNA profiles are known to depend on genetic background, a number of questions related to tumor biology and clinical behavior remain unanswered. As microRNAs (miRNAs) are key players in the modulation of gene expression, their comprehensive analysis could resolve some of these issues. Through characterization of miRNA profiles in 69 frozen tumors with germline mutations in the genes SDHD, SDHB, VHL, RET, NF1, TMEM127, and MAX, we identified miRNA signatures specific to, as well as common among, the genetic groups of PCCs/PGLs. miRNA expression profiles were validated in an independent series of 30 composed of VHL-, SDHB-, SDHD-, and RET-related formalin-fixed paraffin-embedded PCC/PGL samples using quantitative real-time PCR. Upregulation of miR-210 in VHL- and SDHB-related PCCs/PGLs was verified, while miR-137 and miR-382 were confirmed as generally upregulated in PCCs/PGLs (except in MAX-related tumors). Also, we confirmed overexpression of miR-133b as VHL-specific miRNAs, miR-488 and miR-885-5p as RET-specific miRNAs, and miR-183 and miR-96 as SDHB-specific miRNAs. To determine the potential roles miRNAs play in PCC/PGL pathogenesis, we performed bioinformatic integration and pathway analysis using matched mRNA profiling data that indicated a common enrichment of pathways associated with neuronal and neuroendocrine-like differentiation. We demonstrated that miR-183 and/or miR-96 impede NGF-induced differentiation in PC12 cells. Finally, global proteomic analysis in SDHB and MAX tumors allowed us to determine that miRNA regulation occurs primarily through mRNA degradation in PCCs/PGLs, which partially confirmed our miRNA-mRNA integration results.
authors: Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Centro Nacional de Investigaciones Oncológicas, Melchor Fernández Almagro 3, Madrid, Spain.
authors: Aguirre A
authors: AA
authors: de Cubas
authors: L Javier
authors: LJ
authors: Leandro-García
authors: Francesca
authors: F
authors: Schiavi
authors: Veronika
authors: V
authors: Mancikova
authors: Iñaki
authors: I
authors: Comino-Méndez
authors: Lucía
authors: L
authors: Inglada-Pérez
authors: Manuel
authors: M
authors: Perez-Martinez
authors: Nuria
authors: N
authors: Ibarz
authors: Pilar
authors: P
authors: Ximénez-Embún
authors: Elena
authors: E
authors: López-Jiménez
authors: Agnieszka
authors: A
authors: Maliszewska
authors: Rocío
authors: R
authors: Letón
authors: Alvaro
authors: A
authors: Gómez Graña
authors: Carmen
authors: C
authors: Bernal
authors: Cristina
authors: C
authors: Alvarez-Escolá
authors: Cristina
authors: C
authors: Rodríguez-Antona
authors: Giuseppe
authors: G
authors: Opocher
authors: Javier
authors: J
authors: Muñoz
authors: Diego
authors: D
authors: Megias
authors: Alberto
authors: A
authors: Cascón
authors: Mercedes
authors: M
authors: Robledo
mesh_terms: D000008:Abdominal Neoplasms / Q000235:genetics; D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000235:genetics*; D000328:Adult; D000368:Aged; D000818:Animals; D002648:Child; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D016716:PC12 Cells; D010235:Paraganglioma / Q000235:genetics*; D010673:Pheochromocytoma / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D051381:Rats; D013899:Thoracic Neoplasms / Q000235:genetics; D055815:Young Adult
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger
keywords: differentiation; microRNA; paraganglioma; pheochromocytoma