Epithelial–Mesenchymal Transition Induced by SMAD4 Activation in Invasive Growth Hormone-Secreting Adenomas

Abstract

The detection and treatment of invasive growth hormone-secreting pituitary adenoma (GHPA) remains challenging. Several transcription factors promoting the epithelial–mesenchymal transition (EMT) can act as cofactors for the transforming growth factor-beta (TGF-ß)/SMAD4. The goal of this study was to investigate the association of SMAD4 expression and clinicopathologic features using a tissue microarray analysis (TMA). The levels of SMAD4 and the related genes of EMT in GHPAs were analyzed by q-PCR and western blot. SMAD4 was strongly expressed in 15/19 cases (78.9%) of invasive GHPA and 10/42 cases (23.8%) of noninvasive GHPA (χ2=10.887, p=0.000). In the high SMAD4 group, a headache was reported in 16/25 cases (64%) compared with 13/36 cases (36.1%) in the low SMAD4 group (χ2=4.565, p=0.032). The progression-free survival (PFS) in the high group was lower than that in the low group (p=0.026). qRT-PCR and western blot analysis further revealed a significant downregulation of E-cadherin and upregulation of N-cadherin and vimentin in the invasive GHPA group. SMAD4 was associated with increased levels of invasion of GH3 cells, as determined by a transwell test. SMAD4 downregulated E-cadherin levels and increased the levels of N-cadherin and vimentin. Our data provide evidence that SMAD4 is a potential prognosis biomarker and a therapeutic target for patients with invasive GHPA.

Keywords

• smad4
• growth hormone-secreting pituitary adenoma
• invasive
• epithelial–mesenchymal transition
• gh3 cells