Abstract
Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis and limited therapeutic options. Over the last decade, pan-genomic analyses of genetic and epigenetic alterations and genome-wide expression profile studies allowed major advances in the understanding of the molecular genetics of ACC. Besides the well-known dysfunctional molecular pathways in adrenocortical tumors, such as the IGF2 pathway, the Wnt pathway, and TP53, high-throughput technologies enabled a more comprehensive genomic characterization of adrenocortical cancer. Integration of expression profile data with exome sequencing, SNP array analysis, methylation, and microRNA (miRNA) profiling led to the identification of subgroups of malignant tumors with distinct molecular alterations and clinical outcomes. miRNAs post-transcriptionally silence their target gene expression either by degrading mRNA or by inhibiting translation. Although our knowledge of the contribution of deregulated miRNAs to the pathogenesis of ACC is still in its infancy, recent studies support their relevance in gene expression alterations in these tumors. Some miRNAs have been shown to carry potential diagnostic and prognostic values, while others may be good candidates for therapeutic interventions. With the emergence of disease-specific blood-borne miRNAs signatures, analyses of small cohorts of patients with ACC suggest that circulating miRNAs represent promising non-invasive biomarkers of malignancy or recurrence. However, some technical challenges still remain, and most of the miRNAs reported in the literature have not yet been validated in sufficiently powered and longitudinal studies. In this review, we discuss the current knowledge regarding the deregulation of tumor-associated and circulating miRNAs in ACC patients, while emphasizing their potential significance in pathogenic pathways in light of recent insights into the role of miRNAs in shaping the tumor microenvironment.
Highlights
Adrenocortical cancer is a rare and aggressive malignancy
ACC, adrenocortical carcinoma; ACA, adrenocortical adenoma; NA, normal adrenal cortex. ↑ Upregulated, ↓ downregulated in ACC as compared to adenoma or normal adrenal cortices. aThe ACC group was composed of aggressive and non-aggressive ACC. bOverexpressed in aggressive versus non-aggressive ACC. cAssociated with shorter survival. id, idem refers to the line above
ACC, adrenocortical carcinoma; ACA, adrenocortical adenoma; NA, normal adrenal cortex. ↑ Upregulated, ↓ downregulated in the serum or plasma of patients with ACC as compared to patients with adenoma or healthy subjects. aThe ACC group was composed of aggressive and non-aggressive ACC. bOverexpressed in the serum from patients with aggressive versus patients with nonaggressive ACC. cAssociated with shorter survival and recurrence risk
Summary
Adrenocortical cancer is a rare and aggressive malignancy (with an incidence of 0.7–2.0 cases per million per year). An analysis of gene expression in a wide range of primary tumors revealed that the downregulation of miRNAs observed in cancer was due to a failure at the Drosha processing step the mechanisms underlying these dysregulations were not elucidated in this study [37]. NGS brought a new informative landscape on miRNA expression in adrenocortical cancer [26] (discussed below) Despite this rapid progress, many challenges related to miRNA biomarker development for ACC include variations in sample collection and processing, in quantification methods and normalization controls as well as in data analysis. Veronese et al showed that miR-483-3p inhibition could suppress tumorigenicity of HepG2 cells while no antitumor effect was elicited by inhibition of IGF2 [66] These results clearly indicate crucial oncogenic functions of miR-483 within IGF2 gene and might explain why transgenic animals for IGF2 overexpression did not develop tumors as IGF2 transgenes were lacking miR-483 locus. ACC, adrenocortical carcinoma; ACA, adrenocortical adenoma; NA, normal adrenal cortex. ↑ Upregulated, ↓ downregulated in ACC as compared to adenoma or normal adrenal cortices. aThe ACC group was composed of aggressive (poor prognosis) and non-aggressive (good prognosis) ACC. bOverexpressed in aggressive versus non-aggressive ACC. cAssociated with shorter survival. id, idem refers to the line above
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