Yu Shengyuan, Duan Quanxi, Niu Changcun, Mu Chengzhi
Endocr Relat Cancer. 2025 Jan 10;32(2). doi: 10.1530/ERC-24-0146. Print 2025 Feb 1.
Non-functioning pituitary adenomas (NFPAs) are a highly heterogeneous group and often show 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 and 18 noninvasive) and 46 oncocytomas (11 invasive and 35 noninvasive). 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 upregulated in invasive pituitary null cell adenomas but not in invasive pituitary oncocytoma. The TIMP1 mRNA and protein level was significantly downregulated and MT6-MMP mRNA and protein level was significantly upregulated in invasive pituitary null cell adenomas. Meanwhile, there were no significant differences in epithelial-mesenchymal transition (EMT) markers, ECAD and NCAD, between invasive and noninvasive 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 downregulate TIMP1 and upregulate MT6-MMP expression levels but did not affect EMT markers' expression. Our results suggested that HIF1α might contribute to the invasion of pituitary null cell adenomas through activating HIF1α/TIMP1/MT6-MMP pathway but not EMT.
无功能垂体腺瘤（NFPAs）是一个高度异质性的群体，常表现出侵袭性，但很少有研究探讨其侵袭机制及特定亚型的生物标志物。本研究旨在描述缺氧诱导因子1α（HIF1α）及其下游基因在NFPAs特定亚型中的作用。标本被分为NFPAs的两种亚型：46例无颗粒细胞腺瘤（28例侵袭性和18例非侵袭性）和46例嗜酸细胞瘤（11例侵袭性和35例非侵袭性）。通过qRT-PCR、蛋白质免疫印迹法或免疫组织化学检测肿瘤组织中的HIF1α、基质金属蛋白酶组织抑制因子1（TIMP1）、基质金属蛋白酶6（MT6-MMP）、上皮钙黏蛋白（ECAD）和神经钙黏蛋白（NCAD）。进行Transwell实验以检测HIF1α对GH3和GT1-1细胞中肿瘤细胞侵袭的影响。通过蛋白质免疫印迹法检测HIF1α过表达的GT1-1细胞中的TIMP1、MT6-MMP、ECAD和NCAD。HIF1α mRNA和蛋白水平在侵袭性垂体无颗粒细胞腺瘤中显著上调，但在侵袭性垂体嗜酸细胞瘤中无显著上调。TIMP1 mRNA和蛋白水平在侵袭性垂体无颗粒细胞腺瘤中显著下调，而MT6-MMP mRNA和蛋白水平显著上调。同时，侵袭性和非侵袭性垂体无颗粒细胞腺瘤之间的上皮-间质转化（EMT）标志物ECAD和NCAD无显著差异。HIF1α的过表达促进垂体腺瘤细胞在体外的侵袭能力。关于分子机制，HIF1α的过表达可下调TIMP1并上调MT6-MMP的表达水平，但不影响EMT标志物的表达。我们的结果表明，HIF1α可能通过激活HIF1α/TIMP1/MT6-MMP途径而非EMT促进垂体无颗粒细胞腺瘤的侵袭。
