MicroRNA-186 targets SKP2 to induce p27Kip1-mediated pituitary tumor cell cycle deregulation and modulate cell proliferation

摘要

Pituitary tumors are usually benign but can occasionally exhibit hormonal and proliferative behaviors. Dysregulation of the G1/S restriction point largely contributes to the over-proliferation of pituitary tumor cells. F-box protein S-phase kinase-interacting protein-2 (SKP2) reportedly targets and inhibits the expression of p27supKip1/sup, a well-known negative regulator of G1 cell cycle progression. In this study, SKP2 expression was found to be upregulated while p27supKip1/sup expression was determined to be downregulated in rat and human pituitary tumor cells. Furthermore, SKP2 knockdown induced upregulation of p27supKip1/sup and cell growth inhibition in rat and human pituitary tumor cells, while SKP2overexpression elicited opposite effects on p27supKip1/sup expression and cell growth. The expression of microRNA-186 (miR-186) was reported to be reduced in pituitary tumors. Online tools predicted SKP2 to be a direct downstream target of miR-186, which was further confirmed by luciferase reporter gene assays. Moreover, miR-186 could modulate the cell proliferation and p27supKip1/sup-mediated cell cycle alternation of rat and human pituitary tumor cells through SKP2. As further confirmation of these findings, miR-186 and p27supKip1/sup expression were downregulated, while SKP2 expression was upregulated in human pituitary tumor tissue samples; thus, SKP2 expression negatively correlated with miR-186 and p27supKip1/sup expression. In contrast, miR-186 expression positively associated with p27supKip1/sup expression. Taken together, we discovered a novel mechanism by which miR-186/SKP2 axis modulates pituitary tumor cell proliferation through p27supKip1/sup-mediated cell cycle alternation.