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

Li Zhenye,Wu Youtu,Wang Hongyun,Wang Fei,Hong Lichuan,Cao Lei,Wu Yonggang,Zhang Yazhuo,Li Chuzhong,Lan Xiaolei

doi:10.1186/1479-5876-12-71

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.

Highlights

Transforming growth factor β (TGF-β) signaling functions as a suppressor or a promoter in tumor development, depending on the tumor stage and type
In this study, we examined the expression of TGF-β1, Smad2, phospho-Smad2 (p-Smad2), Smad3, phospho-Smad3 (p-Smad3), Smad4, and Smad7 in normal anterior pituitaries, invasive Nonfunctioning pituitary adenomas (NFPA), and noninvasive NFPAs and evaluated whether they were correlated with tumor development and invasion
Comparison of Smad3 and p-Smad3 levels in invasive NFPAs and noninvasive NFPAs Western blot analysis demonstrated that the Smad3 protein level was significantly less in invasive NFPAs (P < 0.01) and noninvasive NFPAs (P < 0.01) compared to normal anterior pituitaries (Figure 1A and B)

Summary

Introduction

Transforming growth factor β (TGF-β) signaling functions as a suppressor or a promoter in tumor development, depending on the tumor stage and type. The role of TGF-β signaling in nonfunctioning pituitary adenomas (NFPAs) has not been explored. Pituitary adenomas (PAs) account for up to 15% of intracranial tumors and have a prevalence of 80–90/100,000 people [1,2]. Approximately 0.2% of PAs with subarachnoid, brain, or systemic metastasis are considered to be malignant [3]. Nonfunctioning pituitary adenomas (NFPAs) consist of approximately 30% of all pituitary tumors, reflecting a very heterogeneous group [5]. As hormonal inactivity leads to delayed diagnosis compared with functioning PAs, NFPAs sometimes present with invasive macroadenomas that cause severe neurological symptoms [6]. NFPA therapy remains a challenge for clinicians

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