MicroRNA signature in massive macronodular adrenocortical disease and implications for adrenocortical tumourigenesis.
OBJECTIVE
Massive macronodular adrenocortical disease (MMAD) may be caused by aberrant microRNA expression. To determine the microRNA profile in MMAD and identify putative microRNA-gene target pairs involved in adrenal tumourigenesis.


METHODS
We performed microRNA microarray analysis in 10 patients with ACTH-independent Cushing syndrome caused by MMAD (ages 39-60 years) and four normal adrenal cortex samples were used as controls. Microarray data were validated by real-time polymerase chain reaction (qRT-PCR). Identification of potential microRNA-gene target pairs implicated in MMAD pathogenesis has been performed by integrating our microRNA data with previously obtained cDNA microarray data. Experimental validation of specific microRNA gene targets was performed by transfection experiments and luciferase assay.


RESULTS
A total of 37 microRNAs were differentially expressed between MMAD and normal tissues; 16 microRNAs were down-regulated, including miR-200b and miR-203, whereas 21 microRNAs were up-regulated, miR-210 and miR-484 among them. Comparison of microRNA data with different clinicopathological parameters revealed miR-130a and miR-382 as putative diagnostic MMAD markers. Interestingly, we detected miR-200b targeting directly Matrin 3 (MATR3) expression in an adrenocortical cancer cell line (H295R).


CONCLUSIONS
MicroRNAs appear to have distinct regulatory effects in MMAD, including an association with clinical presentation and severity of the disease, expressed by the degree of hypercortisolism. This is the first investigation of microRNAs in MMAD, a disease with complex pathogenesis; the data indicate that specific microRNAs such as miR-200b may play a significant role in MMAD formation and/or progression.
Section on Endocrinology and Genetics (SEGEN), Program in Developmental Endocrinology and Genetics (PDEGEN), National Institute of Child Health and Human Development (NICHD), Bethesda, MD 20892, USA.
Eirini I
EI
Bimpaki
Dimitrios
D
Iliopoulos
Andreas
A
Moraitis
Constantine A
CA
Stratakis
D000303:Adrenal Cortex Diseases / Q000235:genetics* / Q000473:pathology; D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000473:pathology; D000328:Adult; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D003560:Cysts / Q000235:genetics / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology
D035683:MicroRNAs