Dysregulated miR-137 and its target EGFR contribute to the progression of pituitary adenomas

摘要

Pituitary adenomas (PAs) hypersecrete hormones or cause mass effect symptoms, with 10%-35% patients showing resistance to standard therapies. Targeting epidermal growth factor receptor (EGFR) has significantly improved the clinical outcome in many cancers. In this study, immunochemistry results showed that EGFR associated H-scores in 116 PA samples were higher than those in pituitary glands, and that p21, p27-and Wif-1 associated H-scores were lower (P < 0.05 for all). Patients with high levels of EGFR had increased PA invasion, lower total resection, and lower p21 and p27 expression than those with low levels of EGFR expression. Dualluciferase reporter gene assays showed that EGFR was the target gene of miR-137, and miR-137 mimic could inhibit the cell proliferation of GH3 cells and induce apoptosis and G1-phase arrest of GH3 cells. A combination of miR-137 mimic and AZD9291 had stronger inhibition on GH3 cells compared with miR-137 mimic or AZD9291 alone; furthermore, miR-137 inhibitor partially reversed the inhibition of AZD9291. p21 and p27 were shown to be involved in the miR-137- and AZD9291-mediated effects on GH3 cells. In all, activation of EGFR in PAs was related to tumor invasive behavior, which reduced the total resection of PAs in patients. A combination of miR-137 and AZD9291 provided a potential treatment for PAs, especially for patients who show resistance to standard treatment.