Activation of the HIF1α/TIMP1/MT6-MMP pathway is associated with invasion in pituitary null cell adenomas.

Abstract

Non-functioning pituitary adenomas (NFPAs) are a highly heterogeneous group and often shows invasion, but few studies have explored the invasion mechanism and biomarkers for specific subtypes. This study was designed to describe the role of HIF1α and its downstream genes in specific subtypes of NFPAs. Specimens were classified into two subtypes of NFPAs: 46 null cell adenomas (28 invasive, 18 non-invasive) and 46 oncocytomas (11 invasive, 35 non-invasive). HIF1α, TIMP1, MT6-MMP, ECAD and NCAD were detected by qRT-PCR, western blot or immunohistochemistry in tumor tissue. The transwell assay was performed to measure the effects of HIF1α on tumor cell invasion in GH3 and GT1-1 cells. TIMP1, MT6-MMP, ECAD and NCAD were detected by western blot in HIF1α overexpressed GT1-1 cells. HIF1α mRNA and protein level was significantly up-regulated in invasive pituitary null cell adenomas but not in invasive pituitary oncocytoma. The TIMP1 mRNA and protein level was significantly down-regulated and MT6-MMP mRNA and protein level was significantly up-regulated in invasive pituitary null cell adenomas. Meanwhile, there were no significant differences in epithelial-mesenchymal transition (EMT) markers, ECAD and NCAD, between invasive and non-invasive pituitary null cell adenomas. The overexpression of HIF1α promoted the invasive capability of pituitary adenoma cells in vitro. Regarding the molecular mechanism, HIF1α overexpression could down-regulated TIMP1 and up-regulated MT6-MMP expression levels but not affected EMT markers expression. Our results suggested HIF1α might contribute to the invasion of pituitary null cell adenomas through activating HIF1α/TIMP1/MT6-MMP pathway but not EMT.