The Role of MicroRNA Expression in the Diagnosis of Adrenocortical Carcinomas. A Marker of Poor Prognostic Tumors
Beatriz A Walter, Stephanie Barak, Antonio Fojo, Maria J Merino. NCI, NIH, Bethesda
Background: Adrenocortical carcinoma is an agressive tumor characterized by high metastatic potential and poor patient survival. However, little is known about molecular mechanisms involved in the pathogenesis of these lesions. MicroRNAs (miRNAs), short fragments of non-coding RNAs, have been shown to regulate the expression of genes related with oncogenesis in different tumor types. The aim of this study was therefore to identify miRNAs associated with this malignancy and their potential role in differentiating benign from malignant Adrenocortical lesions.
Design: Fifty one Adrenal lesions were studied: 16 Adrenocortical Carcinomas (AC); 7 metastasis from AC; 8 Adrenal Hyperplasias (AH); 10 Adrenal Adenomas (AA) and their Normal Adrenal (NA) cortex. Tumor and normal subpopulation of cells were microdissected and their RNA extracted. MiRNA expression level of 2 putatively important miRNAs (miRNA 483-5p and miRNA 195) was determined by qRT-PCR analysis of all lesions. Differentially expressed miRNAs for each of the histologic subtypes in comparison with normal adrenal cortex were defined as those with 2-fold change. Immunohistochemical analysis of IGF2 protein expression as a predictor of miR-483-5p target was also evaluated.
Results: In the group of ACs and metastasis, miRNA 483-5p was significantly up-regulated (median fold change 26.98 (p<0.001) and 6.15-fold (p=0.04), respectively). The higher levels of up-regulation were found in the more aggressive forms of AC. Adrenal Hyperplasia and Adrenal Adenomas showed lower miRNA 483-5p expression levels, (fold change 0.23 (p=0.13) and 0.21 (p=0.12), respectively). When samples were analyzed as groups (malignant vs. benign) the difference in miR-483-5p expression was highly significant (Fold-change 68.58, p<0.001). Inverse results were obtained for miR-195; it was down-regulated in the ACs, and showed very low expression in the metastatic lesions (0.03 (p<0.001)). Adenomas and Hyperplasia groups were also down regulated when compared with the normal samples (0.67 and 0.56-fold change). This down regulation was significant when the malignant tumors were compared with the benign group (p=0.05).
Conclusions: Our results suggest a relevant role of MiRNA-483-5p and MiRNA-195 in the pathogenesis and diagnosis of Adrenocortical carcinomas. This microRNA signature most likely reflects unique molecular changes for each group of lesions, and it may not only prove to be useful in diagnosis, but it can also have great impact in the development of new molecular targets and therapy.
Tuesday, March 20, 2012 1:00 PM
Poster Session IV # 45, Tuesday Afternoon