THE ROLE OF NONCODING RNAS IN THE PATHOGENESIS OF ADRENOCORTICAL CARCINOMA

Abstract

Adrenocortical cancer (ACC) has a poor prognosis and limited treatments. Noncoding RNAs are important regulators of gene expression and can function as oncogenes or tumour suppressors. Two classes of noncoding RNAs are microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). Aims: To establish lncRNA expression profiles of adrenocortical tumours and evaluate if lncRNA expression can be used to predict clinical outcomes. To evaluate whether the lncRNA - PRINS has a tumour suppressor role in ACC. To investigate miR-7 as a tumour suppressor in ACC in vitro and assess miR-7 replacement as a therapeutic in vivo. Methods: LncRNA profiles were established using the ArrayStar Human LncRNA V3.0 microarray. Differentially expressed lncRNAs were correlated with clinical outcomes. PRINS expression in ACC cells was restored using mammalian expression vector (pcDNA3.1[PRINS]) and compared to an empty vector (pcDNA3.1[Blank]). miR-7 was transfected in ACC cell lines and phenotypes compared to a negative control (miRNA scramble sequences). Mouse xenograft models were established and miR-7 was given intravenously by EGFR targeted EnGeneIC nanoparticle delivery vehicles (EDVs). Results: LncRNA expression of 21 samples (ten ACCs, five adrenocortical adenomas, six normal adrenal cortex) showed distinct lncRNA patterns by hierarchical clustering and heat mapping. The lncRNA PRINS was associated with ACC recurrence. Restoring PRINS expression in ACC cells increased rates of apoptosis and reduced expression of the anti-apoptotic TP53 related gene – TNFRSF11B. miR-7 transfected ACC cells reduced cell proliferation and G1 cell cycle arrest, and reduced expression of RAF1, EGFR and MTOR. Systemic miR-7 replacement caused a reduction in the rate of xenograft tumour growth. Conclusions: LncRNA expression profiles can classify ACC. miR-7 and PRINS act as tumour suppressors in ACC. Noncoding RNAs offer potential as biomarkers and therapeutics to improve treatment for ACC.