Heterogeneity analysis of the proteomes in clinically nonfunctional pituitary adenomas

BMC Medical Genomics, Dec 2014

Background Clinically nonfunctional pituitary adenomas (NFPAs) without any clinical elevation of hormone and with a difficulty in its early-stage diagnosis are highly heterogeneous with different hormone expressions in NFPA tissues, including luteinizing hormone (LH)-positive, follicle-stimulating hormone (FSH)-positive, LH/FSH-positive, and negative (NF). Elucidation of molecular mechanisms and discovery of biomarkers common and specific to those different subtypes of NFPAs will benefit NFPA patients in early-stage diagnosis and individualized treatment. Methods Two-dimensional gel electrophoresis (2DGE) and PDQuest image analyses were used to compare proteomes of different NFPA subtypes (NF-, LH-, FSH-, and LH/FSH-positive) relative to control pituitaries (Con). Differentially expressed proteins (DEPs) were characterized with mass spectrometry (MS). Each set of DEPs in four NFPA subtypes was evaluated with overlap analysis and signaling pathway network analysis with comparison to determine any DEP and pathway network that are common and specific to each NFPA subtype. Results A total of 93 differential protein-spots were determined with comparison of each NFPA type (NF-, LH-, FSH-, and LH/FSH-positive) versus control pituitaries. A total of 76 protein-spots were MS-identified (59 DEPs in NF vs. Con; 65 DEPs in LH vs. Con; 63 DEPs in FSH vs. Con; and 55 DEPs in LH/FSH vs. Con). A set of DEPs and pathway network data were common and specific to each NFPA subtype. Four important common pathway systems included MAPK-signaling abnormality, oxidative stress, mitochondrial dysfunction, and cell-cycle dysregulation. However, these pathway systems were, in fact, different among four NFPA subtypes with different protein-expression levels of most of nodes, different protein profiles, and different pathway network profiles. Conclusions These result data demonstrate that common and specific DEPs and pathway networks exist in four NFPA subtypes, and clarify proteome heterogeneity of four NFPA subtypes. Those findings will help to elucidate molecular mechanisms of NFPAs, and discover protein biomarkers to effectively manage NFPA patients towards personalized medicine.

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Heterogeneity analysis of the proteomes in clinically nonfunctional pituitary adenomas

Zhan et al. BMC Medical Genomics Heterogeneity analysis of the proteomes in clinically nonfunctional pituitary adenomas Xianquan Zhan 0 1 Xiaowei Wang 0 1 Ying Long 0 1 Dominic M Desiderio 0 Hunan Engineering Laboratory for Structural Biology and Drug Design, Xiangya Hospital, Central South University , 87 Xiangya Road, Changsha, Hunan 410008 , P. R. China 1 Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University , 87 Xiangya Road, Changsha, Hunan 410008 , P. R. China Background: Clinically nonfunctional pituitary adenomas (NFPAs) without any clinical elevation of hormone and with a difficulty in its early-stage diagnosis are highly heterogeneous with different hormone expressions in NFPA tissues, including luteinizing hormone (LH)-positive, follicle-stimulating hormone (FSH)-positive, LH/FSH-positive, and negative (NF). Elucidation of molecular mechanisms and discovery of biomarkers common and specific to those different subtypes of NFPAs will benefit NFPA patients in early-stage diagnosis and individualized treatment. Methods: Two-dimensional gel electrophoresis (2DGE) and PDQuest image analyses were used to compare proteomes of different NFPA subtypes (NF-, LH-, FSH-, and LH/FSH-positive) relative to control pituitaries (Con). Differentially expressed proteins (DEPs) were characterized with mass spectrometry (MS). Each set of DEPs in four NFPA subtypes was evaluated with overlap analysis and signaling pathway network analysis with comparison to determine any DEP and pathway network that are common and specific to each NFPA subtype. Results: A total of 93 differential protein-spots were determined with comparison of each NFPA type (NF-, LH-, FSH-, and LH/FSH-positive) versus control pituitaries. A total of 76 protein-spots were MS-identified (59 DEPs in NF vs. Con; 65 DEPs in LH vs. Con; 63 DEPs in FSH vs. Con; and 55 DEPs in LH/FSH vs. Con). A set of DEPs and pathway network data were common and specific to each NFPA subtype. Four important common pathway systems included MAPK-signaling abnormality, oxidative stress, mitochondrial dysfunction, and cell-cycle dysregulation. However, these pathway systems were, in fact, different among four NFPA subtypes with different protein-expression levels of most of nodes, different protein profiles, and different pathway network profiles. Conclusions: These result data demonstrate that common and specific DEPs and pathway networks exist in four NFPA subtypes, and clarify proteome heterogeneity of four NFPA subtypes. Those findings will help to elucidate molecular mechanisms of NFPAs, and discover protein biomarkers to effectively manage NFPA patients towards personalized medicine. Nonfunctional pituitary adenoma; Proteome; Heterogeneity; Two-dimensional gel electrophoresis; Mass spectrometry; Differentially expressed protein; Pathway network - Background Clinically nonfunctional pituitary adenomas (NFPAs) are a very challenging clinical problem in pituitary tumor patients relative to functional pituitary adenomas (FPAs) because an NFPA does not have any elevation of the corresponding hormone [1,2]. Thus, an NFPA commonly cannot be diagnosed until presentation of visual injuries and compression symptoms of neighboring tissues, when the tumor has progressed to the middle/late stage. An opportunity is lost for early-stage treatment, and central endocrine regulatory roles of the pituitary, are both lost. The use of proteomics to elucidate molecular mechanisms and discover tumor-related NFPA biomarkers is our long-term goal. Extensive proteomics studies of pituitary adenomas have been carried out in our, and other, research groups [3-10], including protein expression profiles [11-14], differentially expressed proteins (DEPs) [15,16], protein post-translational modifications (PTMs) that include tyrosine nitration [17-19] and phosphorylation [20,21], hormone isoforms [22], protein molecular pathway networks [16,23] from comparative proteomics and systems biology analyses between NFPA versus control tissues [15,23] and between invasive versus noninvasive NFPAs [16], and serum protein biomarkers in pituitary adenomas [6-8]. Moreover, a protein antibody array (n = 1,005 proteins) based on pituitary adenoma proteomics data was used to analyze human pituitary adenomas and identify a DEP profile [24]. A clinical proteomic method that was used to accurately stratify pituitary adenomas was based on multiplex immunoassays of peptide hormones extracted from formalin-fixed and paraffinembedded tissue [9,10]. Laser capture microdissection (LCM) coupled with proteomics was used to accurately identify the proteomic variation of an adenoma relative to control pituitary [25-27]. Proteomics data-based systems pathway network analysis revealed four important signal pathway network variations in NFPA pathophysiological processes, including mitochondrial dysfunction, oxidative stress, cell-cycle dysregulation, and MAPK-signaling syst (...truncated)


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Xianquan Zhan, Xiaowei Wang, Ying Long, Dominic M Desiderio. Heterogeneity analysis of the proteomes in clinically nonfunctional pituitary adenomas, BMC Medical Genomics, 2014, pp. 69, 7, DOI: 10.1186/s12920-014-0069-6