Differential expression of microRNAs in development of GH-secreting pituitary adenoma

Abstract

Recent studies have suggested that aberrant microRNA (miRNA) expression profiles are associated with tumor formation, migration, and invasion. However, the role of miRNA in the development of pituitary adenoma is limited. Herein, we analyzed the different miRNA expression profiles during the cascade of pituitary tumorigenesis, using of somatotroph-specific aryl hydrocarbon receptor interacting protein (AIP) knock-out (sAIPKO) mouse model. To explore possible oncogenic factors in sAIPKO, we used a miRNA microarray to profile changes in the expression of miRNAs. Top/significantly deregulated miRNAs were analyzed from 4 to 50 wks of pituitary adenoma progression (hyperplasia to tumor) by quantitative realtime-polymerase chain reaction (qRT-PCR) analyses. Candidate miRNAs were further validated in human tissue samples which had no AIP gene mutation. Clinical indicators for growth hormone (GH)-secreting pituitary adenoma were analyzed according to the different expression profile of each miRNAs, including basal and glucose-suppressed nadir GH, insulin-like Growth Factor 1 (IGF-1), tumor size, invasiveness, and Ki-67 labeling index. Target mRNAs of candidate miRNAs were also verified in GH3 cells and sAIPKO model. Fourteen miRNAs were significantly changed during GH-secreting pituitary tumorigenesis in sAIPKO mice. Through analysis of qRT-PCR using sAIPKO model during the mouse pituitary adenoma progression and their contemporary littermate animals, seven miRNAs that showed similar trends to miRNA microarray. miR-216a-5p and miR-652-3p were selected from those candidate miRNAs using human GH-secreting pituitary adenoma tissues. Direct target genes of candidate miRNAs were predicted and their expression regulation by binding miRNA was also verified in GH3 cells and sAIPKO mouse model. Finally, the effect of miR-216a-5p and miR-652-3p on proliferation and invasion in GH3 cells was observed. In conclusion, it is strongly suggested that miR-21a-5p and miR-652-3p may regulate GH-secreting pituitary adenoma tumorigenesis. Future studies will focus on their utilizing possibility as therapeutic targets in a larger number of human GH-secreting pituitary adenoma tissues.