Altered expression of the IGF2‑H19 locus and mitochondrial respiratory complexes in adrenocortical carcinoma

Abnormalities of the insulin-like growth factor 2 (1GF2)-H19 locus with the overexpression of 1GF2 are frequent findings in adrenocortical carcinoma (ACC). The present study assessed the expression of RNAs and microRNAs (miRNAs/miRs) from the 1GF2-H19 locus using PCR-based methods in ACC and adrenocortical adenoma (ACA). The results were associated with proteomics data. 1GF2 was overexpressed in ACC, and its expression correlated with that of miR-483-3p and miR-483-5p hosted by 1GF2. The downregulated expression of H19 in ACC compared to ACA correlated with miR-675 expression hosted by H19. Several proteins exhibited an inverse correlation in expression and were predicted as targets of miR-483-3p, miR-483-5p or miR-675. Subsets of these proteins were differentially expressed between ACC and ACA. These included several proteins involved in mitochondrial metabolism. Among the mitochondrial respiratory complexes, complex I and IV were significantly decreased in ACC compared to ACA. The protein expression of NADH:ubiquinone oxidoreductase subunit C1 (NDUFC1), a subunit of mitochondrial respiratory complex I, was further validated as being lower in ACC compared to ACA and normal adrenals. The silencing of miR-483-5p increased NDUFC1 protein expression and reduced both oxygen consumption and glycolysis rates. On the whole, the findings of the present study reveal the dysregulation of the 1GF2-H19 locus and mitochondrial respiration in ACC. These findings may provide a basis for the further understanding of the pathogenesis of ACC and may have potential values for diagnostics and treatment. Key words: adrenal cortical tumors, insulin-like growth factor 2, H19, microRNAs, mitochondrial respiratory complexes