Qi Junhui, Ni Wei
Department of Neurosurgery, The Second Hospital of Yunnan Province, Kunming, People's Republic of China.
Department of Neurosurgery, The Third Affiliated Hospital of Kunming Medical University, No. 519, Kunzhou Road, Kunming, Yunnan Province, 650118, People's Republic of China.
Pathol Oncol Res. 2020 Apr;26(2):937-946. doi: 10.1007/s12253-019-00615-2. Epub 2019 Mar 25.
Gonadotroph pituitary adenomas (GPAs) constitute approximately 15-40% of pituitary tumors. Some GPAs can be highly infiltrative, making full surgical resection challenging and increasing the risk of recurrence. The transcriptional co-activator Mastermind-Like Domain Containing 1 (MAMLD1, CXorf6, F18) is involved in regulating signaling pathways important in pituitary tumorigenesis, including the Notch signaling pathway. However, MAMLD1's role in GPA remains unknown. GPA biopsies were collected from 96 patients following surgery, who were monitored until tumor recurrence. GPA tissue was used for immunohistochemistry. The murine GPA cell lines αT3 and LβT2 were used for in vitro experiments. Lentiviral constructs were employed for MAMLD1 knockdown (KD) and dominant negative (DN) mutant experiments. Quantitative real-time PCR (qPCR) and Western blotting of MAMLD1 and Notch2 were performed. MTT and Transwell assays were used to quantify proliferation and migration, respectively. An αT3 xenograft model was established in athymic nude mice followed by fluorescent IHC of xenograft tumors. MAMLD1 and Notch2 levels correlated positively with aggressive GPAs. Increased MAMLD1 levels correlated with shortened recurrence-free survival (RFS) in aggressive GPA patients. Moreover, MAMLD1 expression independently affected patient RFS according to multivariate Cox regression. In vitro, MAMLD1 KD in the murine GPA cell lines attenuated their proliferation and migration and Notch2 expression. Additionally, DN MAMLD1 lowered their proliferative and migratory capacity. MAMLD1 KD suppressed tumor growth and Notch2 expression in murine xenografts. MAMLD1 may serve as a predictor of GPA patient outcome and may also be leveraged as a possible therapeutic target for aggressive GPA tumors.
促性腺激素垂体腺瘤（GPA）约占垂体肿瘤的15%-40%。一些GPA具有高度浸润性，这使得完全手术切除具有挑战性，并增加了复发风险。转录共激活因子含类主脑结构域1（MAMLD1，CXorf6，F18）参与调节垂体肿瘤发生中重要的信号通路，包括Notch信号通路。然而，MAMLD1在GPA中的作用尚不清楚。从96例接受手术的患者中收集GPA活检样本，并对其进行监测直至肿瘤复发。GPA组织用于免疫组织化学。小鼠GPA细胞系αT3和LβT2用于体外实验。慢病毒构建体用于MAMLD1敲低（KD）和显性负性（DN）突变实验。对MAMLD1和Notch2进行定量实时PCR（qPCR）和蛋白质印迹分析。MTT和Transwell实验分别用于定量增殖和迁移。在无胸腺裸鼠中建立αT3异种移植模型，然后对异种移植肿瘤进行荧光免疫组织化学分析。MAMLD1和Notch2水平与侵袭性GPA呈正相关。侵袭性GPA患者中，MAMLD1水平升高与无复发生存期（RFS）缩短相关。此外，根据多变量Cox回归分析结果，MAMLD1表达独立影响患者的RFS。在体外，小鼠GPA细胞系中的MAMLD1 KD减弱了它们的增殖、迁移以及Notch2表达。此外，DN MAMLD1降低了它们的增殖和迁移能力。MAMLD1 KD抑制了小鼠异种移植瘤的生长和Notch2表达。MAMLD1可能作为GPA患者预后的预测指标，也可能作为侵袭性GPA肿瘤的潜在治疗靶点。
