The expression of TGF-β1, Smad3, phospho-Smad3 and Smad7 is correlated with the development and invasion of nonfunctioning pituitary adenomas

Abstract

BackgroundTransforming growth factor β (TGF-β) signaling functions as a suppressor or a promoter in tumor development, depending on the tumor stage and type. However, the role of TGF-β signaling in nonfunctioning pituitary adenomas (NFPAs) has not been explored.MethodsTGF-β1, Smad2, phospho-Smad2 (p-Smad2), Smad3, phospho-Smad3 (p-Smad3), Smad4, and Smad7 were detected in 5 cases of normal anterior pituitaries, 29 cases of invasive NFPAs, and 21 cases of noninvasive NFPAs by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blot, and immunohistochemical analysis.ResultsThe Smad3 and p-Smad3 protein levels gradually decreased from normal anterior pituitaries, noninvasive NFPAs, to invasive NFPAs. However, there were no significant differences in Smad2 (P = 0.122) and p-Smad2 protein levels (P = 0.101) or Smad2 mRNA level (P = 0.409). In addition, the TGF-β1 mRNA level gradually decreased while the Smad7 mRNA level gradually increased from normal anterior pituitaries, noninvasive NFPAs, to invasive NFPAs. Furthermore, proliferating cell nuclear antigen (PCNA) mRNA level was markedly increased in invasive NFPAs compared to noninvasive ones (P < 0.01), and its level was negatively correlated with Smad3 mRNA level (P < 0.01).ConclusionThe activity of TGF-β signaling may be restrained in NFPAs and is correlated with the development and invasion of NFPAs.

Limitations of high throughput methods for miRNA expression profiles in non-functioning pituitary adenomas

“…Several earlier studies, including ours, reported the possible involvement of this pathway in pituitary adenomagenesis [20,[32][33][34]. We showed the downregulation of the TGFβ pathway through miRNAs targeting Smad3 in NFPAs compared to NP, while Zhenye [34] reported that the activity of TGF-β signaling might be restrained in NFPAs and this result correlated with the development and invasion of NFPAs. The Smad3 and Phospho-Smad3 protein levels were found to be gradually decreased from normal anterior pituitaries, to non-invasive NFPAs and to invasive NFPAs [34].…”

“…We showed the downregulation of the TGFβ pathway through miRNAs targeting Smad3 in NFPAs compared to NP, while Zhenye [34] reported that the activity of TGF-β signaling might be restrained in NFPAs and this result correlated with the development and invasion of NFPAs. The Smad3 and Phospho-Smad3 protein levels were found to be gradually decreased from normal anterior pituitaries, to non-invasive NFPAs and to invasive NFPAs [34]. All these data may confirm that TGFβ signaling seems to be important in development of NFPA.…”

The role of TGF-β/Smad signaling in dopamine agonist-resistant prolactinomas

“…(Massague, 2008). When TGF-β becomes mutated it no longer regulates cell proliferation thus a cell can grow at an uncontrollable rate and cancer develops (Zhenye et al, 2014).…”

The pituitary TGFβ1 system as a novel target for the treatment of resistant prolactinomas

“…In humans the expression of several components of the TGFβ signaling pathway was recently compared in five normal human anterior pituitaries, 29 invasive nonfunctioning pituitary adenomas (NFPAs) and 21 noninvasive NFPAs (Zhenye et al 2014). This report demonstrated that TGFβ1 mRNA expression and p-Smad3 protein levels gradually decreased, while Smad7 mRNA levels gradually increased from normal anterior pituitaries to noninvasive NFPAs and invasive NFPAs.…”