MiR-34a and miR-483-5p are candidate serum biomarkers for adrenocortical tumors

Abstract

Background Nonfunctioning adrenal incidentalomas are common and many patients undergo adrenalectomy to exclude adrenocortical carcinoma (ACC). Recent studies have shown dysregulated microRNA expression in ACC. The objective of this study was to determine the feasibility and diagnostic accuracy of measuring serum microRNAs in patients with benign and malignant adrenocortical tumors. Method Five microRNAs were selected from microRNA profiling studies in ACC (miR-let-7d, -34a, -195, -214, and 483-5p). Total microRNA was extracted from serum samples in patients with malignant and benign adrenal neoplasms. MicroRNAs levels were measured by quantitative RT-PCR and normalized to miR-16. To determine if microRNAs were secreted from ACC cells, we measured microRNA levels in culture. Results Serum samples from 22 patients with cortical adenomas and 17 patients with ACC were analyzed and all 5 microRNAs were detected. We found higher levels of miR-34a(p=0.001) and miR-483-5p(p=0.011) in patients with ACC. The AUC was 0.81 for miR-34a and 0.74 for miR-438-5p. MiR-34a and miR-483-5p levels in ACC cells were higher in the supernatant at 48 hours as compared to intracellular levels. Conclusions We show dysregulated microRNAs in ACC are detectable in human serum samples. MiR-34a and miR-483-5p are candidate serum biomarkers for distinguishing between benign and malignant adrenocortical tumors.

MicroRNA expression patterns in adrenocortical carcinoma variants and clinical pathologic correlations

“…A loss of heterozygosity of this chromosome region has been reported in 84% of adrenocortical carcinomas and 30% of adenomas [29,30]. Accordingly, miR-195 is down-regulated in adrenocortical carcinomas both at the tissue [15,17,19] and serum levels [20]. In our series, low miR-195 was a feature of functioning and β-catenin negative tumors, but no correlation was found with p53 protein expression.…”

“…In NCI-H295R adrenocortical carcinoma cell line, miR-483-5p promotes cell proliferation, but has no effect on apoptosis [18], while miR-483-3p, targeting the pro-apoptotic protein PUMA [25], protects cells from apoptosis [18]. They were consistently found to be over-expressed in comparison with adenomas [15][16][17][18][19][20] and reciprocally correlated [15]. As expected, we found a strong reciprocal correlation among miR-483-3p and miR-483-5p (r= 0.7380, p=<0.0001).…”

“…Three miRNA were selected since those most consistently reported to be deregulated in both tissue and serum of adrenocortical carcinoma patients: miR-483-3p and 5p, which are transcribed from an intronic sequence of IGF2 gene and are commonly over-expressed in adrenocortical carcinoma, and miR-195 which is conversely down-modulated in adrenocortical carcinoma [15][16][17][18][19][20]; moreover, due to the peculiar metabolic and ultrastructural features of oncocytic cells which are the hall-mark of the oncocytic variant, two additional miRNAs -significantly deregulated in adrenocortical cancer -were selected based on their involvement in the hypoxic pathway (miR-210) [21] or a peculiar mitochondrial localization (miR-1974) [22].…”

The next step: mechanisms driving adrenocortical carcinoma metastasis

“…Indeed, miR-483-5p has been demonstrated to be overexpressed both in the primary tumor (Soon et al 2009, Patterson et al 2011, Duregon et al 2014b) and the bloodstream (Chabre et al 2013, Patel et al 2013, Szabó et al 2014). Chabre and coworkers showed that high circulating serum levels of miR-483-5p and low circulating levels of miR-195 in 21 ACCs stratified into non-aggressive and aggressive cancers were associated with both shorter DFS and OS (Chabre et al 2013).…”

Keringő mikroRNS-ek az endokrin daganatok diagnosztikájában

“…A mellékvese daganatos állapotaiban felfedezett keringő mikroRNS-ek [29,30]. Kutatócsoportunk is vizsgálta korábban a mellékvesekéreg-carcinoma keringő mikro-RNS-mintázatát.…”