Correlation of IL-6R/STAT3 signaling with invasiveness of pituitary null cell adenomas: A study based on proteomics

Abstract

Objective To identify the relationship of IL-6R/STAT3 signaling to invasiveness of pituitary null cell adenomas by the study of proteomics. Methods In this study, specimens were collected from 45 cases of pituitary null cell adenomas which were surgical treated at Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University. Normal pituitary tissues were collected from 3 body donors who died from traffic accidents. Different proteins between invasive and non-invasive null cell adenomas were determined by nano liquid chromatography tandem mass spectrometry (nano LC-MS/MS) and quantitative proteomics analysis. The signaling pathway related to invasive of null cell adenomas was identified by bioinformatic analysis. The gene expression levels of the signaling pathway was confirmed by qPCR (quantitative polymerase chain reaction) and immunohistochemistry (IHC) in invasive pituitary tumors and non-invasive null cell adenomas. Results A total of 283 differentially expressed proteins (P<0.05) were identified between invasive and non-invasive pituitary null cell adenomas. Among those, 182 and 101 were up-regulated and down-regulated in invasive pituitary null cell adenomas, respectively. The bioinformatic analysis demonstrated that 8 canonical pathways were differentially expressed between normal pituitary glands and pituitary null cell adenomas. IL-6R/STAT3 signaling was related to invasiveness of pituitary null cell adenomas. The IL-6R, JAK2 and STAT3 mRNA expression levels in invasive null cell adenomas (2.2, 2.8 and 4.3, respectively) were significantly higher than those in non-invasive null cell adenomas (1.7, 1.7, 2.9, respectively) based on the results of qPCR (P<0.05). The values of staining intensity of IL-6R, JAK2, STAT3, p-STAT3 and MMP9 (9.2, 8.6, 9.7, 10.5 and 9.8, respectively) were significantly increased in invasive null cell adenomas compared with those in non-invasive null cell adenomas (5.8, 5.3, 5.7, 5.2 and 4.1, respectively) according to the IHC data. Conclusion The IL-6R/STAT3 signaling may play an important role in invasive null cell adenomas by enhancement of MMP9 expression. Key words: Pituitary adenoma; Neoplasm invasiveness; Proteomics; Signal pathways; IL-6R/STAT3