Downregulation of miR-216a-5p and miR-652-3p is associated with growth and invasion by targeting JAK2 and PRRX1 in GH-producing pituitary tumours.

ABSTRACT

Expression of aberrant microRNA (miRNA) is associated with tumour formation, migration, and invasion. However, there is limited information about the epigenetics of pituitary tumorigenesis. This study investigated the role of miRNA expression during the tumorigenesis of growth hormone (GH)-secreting pituitary tumours. miRNA profiling and real-time PCR were used to analyse the mRNA expression profile in sequential pituitary tissues of a unique animal model with a GH-producing pituitary tumour. Selected miRNAs were further validated in GH-producing cell lines and human pituitary tumour samples. The expression of significantly altered miRNAs and their predicted targets, as detected by microarray, was evaluated by real-time PCR, Western blotting, and immunohistochemistry using samples from mouse models and human pituitary tumours. The effect of miRNAs on tumour proliferation and invasion was examined in GH3 cells using the MTS and Matrigel invasion assays. Among the 14 miRNAs whose expression was significantly changed, miR-216a-5p (fold change = -5.638, P -value = 0.014) and miR-652-3p (fold change = -3.482, P -value = 0.010) were constantly and significantly downregulated. Transfection with mimics of miR-216a-5p and miR-652-3p inhibited GH3 proliferation and invasion, whereas inhibitors promoted them. The direct target genes of miR-216a-5p and miR-652-3p were Jak2 and Prrx1, respectively, which were downregulated in GH3 cells transfected with mimics and in serial pituitary gland tissues, including hyperplasic tissues and tumours of acromegalic animal models and pituitary tumour tissues of acromegalic patients. Downregulated miR-216a-5p and miR-652-3p expression may contribute to tumour progression by targeting JAK2 and PRRX1 on GH-producing pituitary tumours.