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 MAMLD1L210X 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.
Keywords: CXorf6; MAMLD1; Notch; Pituitary adenoma.