title: Overexpression of genes involved in miRNA biogenesis in medullary thyroid carcinomas with RET mutation.
abstract: Abnormal expression of non-coding micro RNA (miRNA) has been described in medullary thyroid carcinoma (MTC). Expression of genes encoding factors involved in miRNA biogenesis results often deregulated in human cancer and correlates with aggressive clinical behavior. In this study, expression of four genes involved in miRNA biogenesis (DICER, DROSHA, DCGR8, and XPO5) was investigated in 54 specimens of MTC. Among them, 33 and 13 harbored RET and RAS mutations, respectively. DICER, DGCR8, and XPO5 mRNA levels were significantly overexpressed in MTC harboring RET mutations, in particular, in the presence of RET634 mutation. When MTCs with RET and RAS mutations were compared, only DGCR8 displayed a significant difference, while MTCs with RAS mutations did not show significant differences with respect to non-mutated tumors. We then attempted to correlate expression of miRNA biogenesis genes with tumor aggressiveness. According to the TNM status, MTCs were divided in two groups and compared (N0 M0 vs. N1 and/or M1): for all four genes no significant difference was detected. Cell line experiments, in which expression of a RET mutation is silenced by siRNA, suggest the existence of a causal relationship between RET mutation and overexpression of DICER, DGCR8, and XPO5 genes. These findings demonstrate that RET- but not RAS-driven tumorigenic alterations include abnormalities in the expression of some important genes involved in miRNA biogenesis that could represent new potential markers for targeted therapies in the treatment of RET-mutated MTCs aimed to restore the normal miRNA expression profile.
authors.affiliation: Dipartimento di Scienze Mediche e Biologiche, Università di Udine, Piazzale Kolbe 4, 33100, Udine, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Puppin
authors.forename: Cosimo
authors.initials: C
authors.lastname: Durante
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Sponziello
authors.forename: Antonella
authors.initials: A
authors.lastname: Verrienti
authors.forename: Valeria
authors.initials: V
authors.lastname: Pecce
authors.forename: Elisa
authors.initials: E
authors.lastname: Lavarone
authors.forename: Federica
authors.initials: F
authors.lastname: Baldan
authors.forename: Antonio Francesco
authors.initials: AF
authors.lastname: Campese
authors.forename: Amelie
authors.initials: A
authors.lastname: Boichard
authors.forename: Ludovic
authors.initials: L
authors.lastname: Lacroix
authors.forename: Diego
authors.initials: D
authors.lastname: Russo
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Filetti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Damante
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018276:Carcinoma, Medullary / Q000235:genetics* / Q000473:pathology; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
chemical_list: D035683:MicroRNAs; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human