title: Clinical and functional impact of TARBP2 over-expression in adrenocortical carcinoma.
abstract: Deregulation of microRNA (miRNA) expression in adrenocortical carcinomas (ACCs) has been documented to have diagnostic, prognostic, as well as functional implications. Here, we evaluated the mRNA expression of DROSHA, DGCR8, DICER (DICER1), TARBP2, and PRKRA, the core components in the miRNA biogenesis pathway, in a cohort of 73 adrenocortical tumors (including 43 adenomas and 30 carcinomas) and nine normal adrenal cortices using a RT-qPCR approach. Our results show a significant over-expression of TARBP2, DICER, and DROSHA in the carcinomas compared with adenomas or adrenal cortices (P<0.001 for all comparisons). Using western blot and immunohistochemistry analyses, we confirmed the higher expression of TARBP2, DICER, and DROSHA at the protein level in carcinoma cases. Furthermore, we demonstrate that mRNA expression of TARBP2, but not DICER or DROSHA, is a strong molecular predictor to discriminate between adenomas and carcinomas. Functionally, we showed that inhibition of TARBP2 expression in human NCI-H295R ACC cells resulted in a decreased cell proliferation and induction of apoptosis. TARBP2 over-expression was not related to gene mutations; however, copy number gain of the TARBP2 gene was observed in 57% of the carcinomas analyzed. In addition, we identified that miR-195 and miR-497 could directly regulate TARBP2 and DICER expression in ACC cells. This is the first study to demonstrate the deregulation of miRNA-processing factors in adrenocortical tumors and to show the clinical and biological impact of TARBP2 over-expression in this tumor type.
authors.affiliation: Departments of Oncology-Pathology Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. stefano.caramuta@ki.se
authors.forename: Stefano
authors.initials: S
authors.lastname: Caramuta
authors.forename: Linkiat
authors.initials: L
authors.lastname: Lee
authors.forename: Deniz M
authors.initials: DM
authors.lastname: Ozata
authors.forename: Pinar
authors.initials: P
authors.lastname: Akçakaya
authors.forename: Hong
authors.initials: H
authors.lastname: Xie
authors.forename: Anders
authors.initials: A
authors.lastname: Höög
authors.forename: Jan
authors.initials: J
authors.lastname: Zedenius
authors.forename: Martin
authors.initials: M
authors.lastname: Bäckdahl
authors.forename: Catharina
authors.initials: C
authors.lastname: Larsson
authors.forename: Weng-Onn
authors.initials: WO
authors.lastname: Lui
mesh_terms: D000293:Adolescent; D000306:Adrenal Cortex Neoplasms / Q000235:genetics*; D018246:Adrenocortical Adenoma / Q000235:genetics*; D018268:Adrenocortical Carcinoma / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D053487:DEAD-box RNA Helicases / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics*; D043244:Ribonuclease III / Q000235:genetics; D055815:Young Adult; D000099253:Trans-Activation Responsive RNA-Binding Protein
chemical_list: D053487:DEAD-box RNA Helicases; D035683:MicroRNAs; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D043244:Ribonuclease III; D000099253:Trans-Activation Responsive RNA-Binding Protein; C552722:MIRN195 microRNA, human; C559640:MIRN497 microRNA, human; C408087:DICER1 protein, human; C517918:DROSHA protein, human
keywords: TARBP2; adrenocortical cancer; diagnostic; function; over-expression