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MicroRNA Signature of Primary Pigmented Nodular Adrenocortical Disease: Clinical Correlations and Regulation of Wnt Signaling

¹ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts and ² Section on Endocrinology and Genetics, Program in Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development, NIH, Bethesda, Maryland

Requests for reprints: Constantine A. Stratakis, Section on Endocrinology and Genetics/Program in Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development, NIH, Building 10, CRC (East Laboratories), Room 1-3330, 10 Center Drive, MSC1103, Bethesda, MD 20892. Phone: 301-496-4686, ext. 496-6683; Fax: 301-402-0574, ext. 480-0378; E-mail: stratakc{at}mail.nih.gov.

Key Words: Cushing's syndrome • adrenocortical tumors • primary pigmented adrenal hyperplasia • miR-449 • WISP2

MicroRNAs comprise a novel group of gene regulators implicated in the development of different types of cancer; however, their role in primary pigmented nodular adrenocortical disease (PPNAD) has not been investigated. PPNAD is a bilateral adrenal hyperplasia often associated with Carney complex, a multiple neoplasia syndrome; both disorders are caused by protein kinase A (PKA) regulatory subunit type 1A (PRKARIA)–inactivating mutations. We identified a 44-microRNA gene signature of PPNAD after comparing PPNAD with normal adrenal samples. Specifically, 33 microRNAs were up-regulated and 11 down-regulated in PPNAD relative to normal tissues. These results were validated by stem loop real-time PCR analysis. Comparison of microRNA microarray data with clinicopathologic variables revealed a negative correlation (r = –0.9499) between let-7b expression and cortisol levels in patients with PPNAD. Integration of microRNA microarray with serial analysis of gene expression data together with bioinformatic algorithm predictions revealed nine microRNA-gene target pairs with a potential role in adrenal pathogenesis. Using a PPNAD cell line, we showed that miR-449 was up-regulated and identified its direct target, WNT1-inducible signaling pathway protein 2 (WISP2); in addition, pharmacologic inhibition of PKA resulted in the up-regulation of miR-449 leading to the suppression of WISP2. Overall, we investigated, for the first time, the microRNA profile and its clinical significance in PPNAD; these data also suggest that PKA, via microRNA regulation, affects the Wnt signaling pathway, which through expression and clinical studies is suspected to be a primary mediator of PRKAR1A-related tumorigenesis. [Cancer Res 2009;69(8):3278–82]

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