Abstract
Non-functional pituitary adenoma (NFPA) seriously affects hypothanamus-pituitary-target organ axis system, with a series of molecule alterations in the multiple levels of genome, transcriptome, proteome, and post-translational modifications, and those molecules mutually interact in a molecular-network system. Meta analysis coupled with IPA pathway-network program was used to comprehensively analyze nine sets of documented NFPA omics data, including NFPA quantitative transcriptomics data [280 differentially expressed genes (DEGs)], NFPA quantitative proteomics data [50 differentially expressed proteins (DEPs)], NFPA mapping protein data (218 proteins), NFPA mapping protein nitration data (9 nitroproteins and 3 non-nitrated proteins), invasive NFPA quantitative transriptomics data (346 DEGs), invasive NFPA quantitative proteomics data (57 DEPs), control mapping protein data (1469 proteins), control mapping protein nitration data (8 nitroproteins), and control mapping phosphorylation data (28 phosphoproteins). A total of 62 molecular-networks with 861 hub-molecules and 519 canonical-pathways including 54 cancer-related canonical pathways were revealed. A total of 42 hub-molecule panels and 9 canonical-pathway panels were identified to significantly associate with tumorigenesis. Four important molecular-network systems, including PI3K/AKT, mTOR, Wnt, and ERK/MAPK pathway-systems, were confirmed in NFPAs by PTMScan experiments with altered expression-patterns and phosphorylations. Nineteen high-frequency hub-molecules were also validated in NFPAs with PTMScan experiment with at least 2.5-fold changes in expression or phosphorylation, including ERK, ERK1/2, Jnk, MAPK, Mek, p38 MAPK, AKT, PI3K complex, p85, PKC, FAK, Rac, Shc, HSP90, NFκB Complex, histone H3, AP1, calmodulin, and PLC. Furthermore, mTOR and Wnt pathway-systems were confirmed in NFPAs by immunoaffinity Western blot analysis, with significantly decreased expression of PRAS40 and increased phosphorylation levels of p-PRAS40 (Thr246) in mTOR pathway in NFPAs compared to controls, and with the decreased protein expressions of GSK-3β and GSK-3β, significantly increased phosphorylation levels of p-GSK3α (Ser21) and p-GSK3β (Ser9), and increased expression level of β-catenin in Wnt pathway in NFPAs compared to controls. Those findings provided a comphrensive and large-scale pathway network data for NFPAs, and offer the scientific evidence for insights into the accurate molecular mechanisms of NFPA and discovery of the effective biomarkers for diagnosis, prognosis, and determination of therapeutic targets.
Highlights
Human non-functional pituitary adenoma (NFPA) is a common disease that occurs in the central regulatory organ pituitary, and seriously impacts on physiological functions and human health [1]
This study demonstrated that the activated PI3K/Akt signaling was substantially involved in stimulation of multiple cascades in NFPAs through the following pathways (Figure 3): (i) The activated Akt phosphorylated TSC2 and residue Thr246 in PRAS40 to inactivate these proteins and subsequently stimulated mTOR complex 1 (mTORC1) signaling; (ii) The functional loss of Akt consequentially activated canonical Wnt pathway by phosphorylation at residue Ser21 in GSK3α, and Ser9 in GSK3β; (iii) Akt activated NF-κB signaling through phosphorylating the upstream IκB kinase α; (iv) Akt blocked pro-apoptotic activity of BAD through phosphorylation and promoted cell survival; (v) PI3K/Akt signaling could interact with ERK, Jun N-terminal kinase (JNK), and p38 signaling from multiple levels; and (vi) Akt lead to degradation of the transcription factors NFAT and inhibited migration and invasion of a cancer
This study found that JNK, Jun, ATF2, NFAT, phospholipase C (PLC), PKC, CDC42, and NFκB were differentially expressed in non-canonical Wnt pathway in NFPAs compared to controls, which demonstrated non-canonical Wnt pathways were closely related to NFPAs
Summary
Human non-functional pituitary adenoma (NFPA) is a common disease that occurs in the central regulatory organ pituitary, and seriously impacts on physiological functions and human health [1]. Omics (genomics, transcriptomics, proteomics, peptidomics, metabolomics, and radiomics) and systems biology are promoting one to change paradigms from traditional single-factor strategy to multiparameter systematic strategy in pituitary adenoma studies and clinical practice [4, 7], in the model of predictive screening and prognostic assessment, which traditionally only depended on the changes of serum single-hormone change and pituitary imaging, and in the therapeutic model of cancer from the general radiotherapy and chemotherapy to personalized strategy [8, 9]. It is necessary to construct multiple omics data-based molecular networks for clarification of accurate molecular mechanisms of NFPAs, and discovery of tumor-specific biomarker pattern for efficient prediction screening, early diagnosis, prognostic assessment, and individualized prevention and therapy [12]
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