microRNAs as Potential Biomarkers in Adrenocortical Cancer: Progress and Challenges

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.

Keywords: adrenocortical carcinoma; biomarker; circulating miRNA; diagnosis; prognosis; therapeutic targets.

Figure 1

Biogenesis and function of microRNAs. miRNA genes are transcribed as primary miRNAs (Pri-miRNA) by polymerase II (Pol II) in the nucleus. Pri-miRNAs are cleaved by the RNAse III endonuclease DROSHA and its proteins partners (DROSHA complex) to produce the 60- to 70-nt stem–loop precursor miRNAs (pre-miRNAs). The pre-miRNAs are then exported to the cytoplasm by exportin 5 and further processed by DICER1, a type III RNAse that produces the 22-nt mature miRNAs. One strand of the mature miRNA is selectively loaded into the miRNA-induced silencing complex (RISC), which contains DICER1, Argonaute (AGO) proteins, and the transactivation-responsive RNA-binding protein (TRBP). In the cytoplasm, mature miRNAs bind essentially to the 3′-UTR of the target mRNA and repress its expression through both translational repression and mRNA destabilization. Some miRNAs have been shown to bind to the open reading frame (ORF) and the 5′-UTR of the target mRNA, and to activate or repress its translation efficiency. In the nucleus, miRNAs were shown to bind to gene promoter to regulate gene expression. miRNAs are also released into the extracellular space and are possibly involved in intercellular communication when transferred to target cells. Extracellular miRNAs are encapsulated within microvesicles, such as exosomes, or bound to RNA-binding proteins, such as Ago2, or lipoproteins, such as HDL.

Figure 2

An overview of miRNA research tools for isolation, detection, target determination, regulation, and clinical applications.

Figure 3

Schematic representation of the potential cross-talk between adrenocortical cancer cells and cells of the tumor microenvironment (TME). By targeting cells of the TME, adrenocortical cancer cell-derived exosomes could favor stimulation of angiogenesis, production of pro-inflammatory cytokines, alterations of the extracellular matrix, and generation of a pre-metastatic niche. The TME-derived exosomes (dashed lines) could enhance growth and survival of cancer cells, promote invasion and induction of epithelial to mesenchymal transition, and also drug resistance. MBV, multivesicular body.