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Metabolism-Related Enzyme Alterations Identified by Proteomic Analysis in Human Renal Cell Carcinoma

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Metabolism-Related Enzyme Alterations Identified by Proteomic Analysis in Human Renal Cell Carcinoma Journal name: OncoTargets and Therapy Article Designation: Original Research Year: 2016 Volume: 9 OncoTargets and Therapy Dovepress Running head verso: Lu et al Running head recto: Protein disorders in human renal cell carcinoma by proteomic analysis open access to scientific and medical research DOI: http://dx.doi.org/10.2147/OTT.S91953 Open Access Full Text Article ORIGINAL RESEARCH Metabolism-related enzyme alterations identified by proteomic analysis in human renal cell carcinoma Zejun Lu1,* Abstract: The renal cell carcinoma (RCC) is one of the most common types of kidney neoplasia Yuqin Yao2,* in Western countries; it is relatively resistant to conventional chemotherapy and radiotherapy. Qi Song3 Metabolic disorders have a profound effect on the degree of malignancy and treatment resistance Jinliang Yang4 of the tumor. However, the molecular characteristics related to impaired metabolism leading Xiangfei Zhao1 to the initiation of RCC are still not very clear. In this study, two-dimensional electrophoresis Ping Yang1 (2-DE) and mass spectra (MS) technologies were utilized to identify the proteins involved in energy metabolism of RCC. A total of 73 proteins that were differentially expressed in con- Jingbo Kang1 ventional RCC, in comparison with the corresponding normal kidney tissues, were identified. 1 Department of Radiation Oncology, Bioinformatics analysis has shown that these proteins are involved in glycolysis, urea cycle, Naval General Hospital of People’s Liberation Army, Beijing, 2Research and the metabolic pathways of pyruvate, propanoate, and arginine/proline. In addition, some Center for Public Health and were also involved in the signaling network of p53 and FAS. These results provide some clues Preventive Medicine, West China for new therapeutic targets and treatment strategies of RCC. School of Public Health/No 4 West China Teaching Hospital, Sichuan Keywords: renal cell cancer, metabolism, two-dimensional electrophoresis, proteome University, Chengdu, 3Department of Gynaecology and Obstetrics, The General Hospital of Chinese Introduction People’s Armed Police Force, Beijing, The early stage diagnosis of renal cell carcinoma (RCC) in many countries is probably 4State Key Laboratory of Biotherapy/ Collaborative Innovation Center associated with the observed plateau in RCC mortality in the US and in many European for Biotherapy, West China Hospital, countries. Nevertheless, ∼50% of patients diagnosed across all stages of this disease die Sichuan University, Chengdu, People’s Republic of China within the first 5 years after diagnosis.1,2 Conventional chemotherapy and radiotherapy *These authors contributed equally does not exert a significant long-term benefit on RCC; instead, it has been found to to this work decrease the length or quality of life. RCC is not a single disease; rather, it is a compila- tion of several types of cancer that occur in the kidney. The poor prognosis of RCC is largely due to the effects of different oncogenes, each having a different histology and response to therapy.3 Metabolic control analysis is useful in assessing the influence of metabolic pathways on the course and treatment of complex diseases.4,5 Since the meta- bolic environment influences the rate-controlling steps of enzymes in metabolic pathways, the management of complex disease phenotypes is largely dependent on the expression of the entire collection of genes involved than on any particular gene or enzyme.6,7 This means that the management of complex disease phenotypes relies on a collection of system-wide interconnected processes that involve glycolysis and respiration. Success- ful manipulations of metabolic networks can lead to restoration of order and adaptive behavior in disordered states that involve complex gene–environment interactions.8,9 Metabolic control analysis is especially important in kidney cancer management, Correspondence: Jingbo Kang because disorder and abnormal energy metabolism are characteristics of RCC.10 Department of Radiation Oncology, Naval General Hospital of PLA, However, there are few specific studies that identify the tumor-related metabolic Fuchengmen Road, No. 6, Beijing 100048, proteins in RCC. In the present study, a comprehensive bioinformatics approach People’s Republic of China Email [email protected] was applied to tissue proteomic data to identify those metabolic steps and networks submit your manuscript | www.dovepress.com OncoTargets and Therapy 2016:9 1327–1337 1327 Dovepress © 2016 Lu et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you http://dx.doi.org/10.2147/OTT.S91953 hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Lu et al Dovepress that have a role in RCC onset and development. In kidney sulfate polyacrylamide gel electrophoresis gel after isoelectric cancer, the expression of proteins involved in metabolism, focusing and equilibration. The gels were stained using CBB cell growth, morphology, and the heat shock response is R-250 (EMD Millipore, Billerica, MA, USA) and scanned deregulated. Therefore, we hypothesize that the defects in with a Bio-Rad GS-800 scanner (Bio-Rad Laboratories Inc.). identified pathways should serve as targets for the develop- The 2-DE analyses were independently repeated three times. ment of effective and long-lasting kidney cancer therapies The maps were analyzed by PDQuest software, Version 6.1 that will be superior to those presently in use. (Bio-Rad Laboratories Inc.). The quantity of each spot in the gel was normalized as the percentage of the total quantity of Materials and methods all spots in that gel and evaluated in terms of optical density Tissue samples (OD). The paired t-test was performed to compare the data Surgical specimens of five patients from the Navy General from three repeated experiments. Only those spots that showed Hospital, obtained after radical nephrectomy, were used to consistent and significant differences (.1.5-fold, P,0.05) prepare tissue samples of conventional RCC and the sur- were selected for further analysis with mass spectra (MS). rounding noncancerous kidney tissues. The mean age of the patients was 55.8 years. The tumor stage of the patients In-gel digestion ranged from pT1 to pT3. Macroscopic cell type of samples In-gel digestion of proteins was performed using mass (benign or cancer) was examined histologically. The tumor spectrometry grade Trypsin Gold (Promega Corporation, stage was determined according to the 1997 TNM (tumor, Madison, WI, USA). Briefly, the spots were cut out of the gel node, metastasis) criteria. The samples were not necrotic. (1–2 mm diameter) using a razor blade and destained twice Table 1 shows a summary of detailed clinicopathologic data with 100 mM NH4HCO3/50% acetonitrile (ACN) at 37°C for of patients included in the study. Institutional Ethics Com- 45 minutes in each treatment. After drying, the gels were pre- mittee of the Navy General Hospital approved this project, incubated in 10–20 μL trypsin solution for 1 hour. Following, and informed consent were obtained from all patients, or 15 μL digestion buffer was added (40 mM NH4HCO3/10% their relatives, prior to commencing the study. A patholo- ACN) to cover each gel and incubated overnight at 37°C. gist examined all specimens. The samples were immediately Tryptic digests were extracted using Milli-Q water initially, frozen in liquid nitrogen and stored at -80°C until use. followed by two 1 hour repeat extractions with 50% ACN/5% 2-DE and image analysis trifluoroacetic acid. The combined extracts were dried in a vacuum concentrator at room temperature. The samples were Two-dimensional electrophoresis (2-DE) was performed as then subjected to mass spectrometric analysis. described previously.11 Briefly, cells were lysed in the lysis buffer (8 M urea, 2 M thiourea, 4% CHAPS, 100 mM DTT, and 0.2% pH 3–10 ampholyte; Bio-Rad Laboratories Inc., MS/MS analysis and protein identification Mass spectra were acquired using a quadrupole time-of-flight Hercules, CA, USA) containing a protease inhibitor. After mass spectrometer (Micromass, Manchester, UK) fitted with sonication and centrifugation, the supernatant was retrieved, an electrospray ionization or matrix-assisted laser desorp- and protein concentrations were determined using the DC tion/ionization source (Micromass). The MS/MS analysis protein assay kit (Bio-Rad Laboratories Inc.). Protein samples was performed as described previously.12 The MS/MS data (1 mg) were applied to a immobilized pH gradient strip were acquired and processed using MassLynx V 4.1 soft- (17 cm, pH 3–10 non-linear [NL], Bio-Rad Laboratories Inc.) ware (Micromass) and converted to PKL performed using using a passive rehydration method. For the second dimension, ProteinLynx 2.2.5 software (Waters Corp, Milford, MA, a 30 mA constant current was applied to 12% sodium dodecyl USA). The pkl files were analyzed using the MASCOT Table 1 Clinicopathologic features of renal cell carcinoma samples search engine (http://www.matrixscience.com). The fol- No Sex Age Clinicopathologic features TNM lowing search parameters were used: database, Swiss-Prot, (years) stage taxonomy, Homo sapiens, enzyme, and trypsin. One missed 1 Male 52 Clear cell renal cell carcinoma T1N0M0 cleavage was allowed. Carbamidomethylation was selected 2 Male 52 Clear cell renal cell carcinoma T1N0M0 as a fixed modification, and oxidation of methionine was set 3 Male 60 Clear cell renal cell carcinoma T3N0M1 as the variable. The peptide and fragment mass tolerance 4 Female 54 Clear cell renal cell carcinoma T2N0M0 5 Male 61 Clear cell renal cell carcinoma T2N0M0 were set at 0.1 Da and 0.05 Da, respectively.
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