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Molecular Mechanism of Acute Radiation Enteritis Revealed Using Proteomics and Biological Signaling Network Analysis in Rats

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Abstract

Background and Aims

Radiation enteritis (RE) has emerged as a significant complication that can progress to severe gastrointestinal disease and the mechanisms underlying its genesis remain poorly understood. The aim of this study was to identify temporal changes in protein expression potentially associated with acute inflammation and to elucidate the mechanism underlying radiation enteritis genesis.

Methods

Male Sprague–Dawley rats were irradiated in the abdomen with a single dose of 10 Gy to establish an in vivo model of acute radiation enteritis. Two-dimensional fluorescence difference gel electrophoresis, matrix-assisted laser desorption/ionization time-of-flight spectrometer (MALDI-TOF) tandem mass spectrometry, and peptide mass fingerprinting were used to determine differentially expressed proteins between normal and inflamed intestinal mucosa. Additionally, differentially expressed proteins were evaluated by KO Based Annotation System to find the biological functions associated with acute radiation enteritis.

Results

Intensity changes of 86 spots were detected with statistical significance (ratio ≥ 1.5 or ≤ 1.5, P < 0.05). Sixty one of the 86 spots were identified by MALDI-TOF/TOF tandem mass spectrometry. These radiation-induced proteins with biological functions showed that the FAS pathway and glycolysis signaling pathways were significantly altered using the KOBAS tool.

Conclusions

Our results reveal an underlying mechanism of radiation-induced acute enteritis, which may help clarify the pathogenesis of RE and point to potential targets for therapeutic interventions.

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References

  1. Buchi K. Radiation proctitis: therapy and prognosis. JAMA. 1991;265:1180.

    Article  PubMed  CAS  Google Scholar 

  2. Ooi BS, Tjandra JJ, Green MD. Morbidities of adjuvant chemotherapy and radiotherapy for resectable rectal cancer: an overview. Dis Colon Rectum. 1999;42:403–418.

    Article  PubMed  CAS  Google Scholar 

  3. McGough C, Baldwin C, Frost G, Andreyev HJ. Role of nutritional intervention in patients treated with radiotherapy for pelvic malignancy. Br J Cancer. 2004;90:2278–2287.

    PubMed  CAS  PubMed Central  Google Scholar 

  4. Andreyev HJ. Gastrointestinal problems after pelvic radiotherapy: the past the present and the future. Clin Oncol R Coll Radiol. 2007;19:790–799.

    Article  PubMed  CAS  Google Scholar 

  5. Ghezzi F, Cromi A, Serati M, et al. Radiation-induced bowel complications: laparoscopic versus open staging of gynecologic malignancy. Ann Surg Oncol. 2011;18:782–791.

    Article  PubMed  Google Scholar 

  6. Eifel PJ, Levenback C, Wharton JT, Oswald MJ. Time course and incidence of late complications in patients treated with radiation therapy for FIGO stage IB carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys. 1995;32:1289–1300.

    Article  PubMed  CAS  Google Scholar 

  7. Potten CS, Grant HK. The relationship between ionizing radiation-induced apoptosis and stem cells in the small and large intestine. Br J Cancer. 1998;78:993–1003.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. Nguyen NP, Antoine JE, Dutta S, Karlsson U, Sallah S. Current concepts in radiation enteritis and implications for future clinical trials. Cancer. 2002;95:1151–1163.

    Article  PubMed  Google Scholar 

  9. Anderson NL, Anderson NG. Proteome and proteomics: new technologies, new concepts, and new words. Electrophoresis. 1998;19:1853–1861.

    Article  PubMed  CAS  Google Scholar 

  10. Chambers G, Lawrie L, Cash P, Murray GI. Proteomics: a new approach to the study of disease. J Pathol. 2000;192:280–288.

    Article  PubMed  CAS  Google Scholar 

  11. Hanash S. Disease proteomics. Nature. 2003;422:226–232.

    Article  PubMed  CAS  Google Scholar 

  12. Zhou G, Li H, DeCamp D, et al. 2D differential in-gel electrophoresis for the identification of esophageal scans cell cancer-specific protein markers. Mol Cell Proteomics. 2002;1:117–124.

    Article  PubMed  CAS  Google Scholar 

  13. Roxo-Rosa M, da Costa G, Luider TM, et al. Proteomic analysis of nasal cells from cystic fibrosis patients and non-cystic fibrosis control individuals: search for novel biomarkers of cystic fibrosis lung disease. Proteomics. 2006;6:2314–2325.

    Article  PubMed  CAS  Google Scholar 

  14. Zhang X, Yang J, Guo Y, et al. Functional proteomic analysis of nonalcoholic fatty liver disease in rat models: enoyl-coenzyme a hydratase down-regulation exacerbates hepatic steatosis. Hepatology. 2010;51:1190–1199.

    Article  PubMed  CAS  Google Scholar 

  15. Klimberg VS, Salloum RM, Kasper M, et al. Oral glutamine accelerates healing of the small intestine and improves outcome after whole abdominal radiation. Arch Surg. 1990;125:1040–1045.

    Article  PubMed  CAS  Google Scholar 

  16. Howarth GS, Fraser R, Frisby CL, Schirmer MB, Yeoh EK. Effects of insulin-like growth factor-I administration on radiation enteritis in rats. Scand J Gastroenterol. 1997;32:1118–1124.

    Article  PubMed  CAS  Google Scholar 

  17. Luo YX, Cui J, Wang L, et al. Identification of cancer-associated proteins by proteomics and downregulation of beta-tropomyosin expression in colorectal adenoma and cancer. Proteomics Clin Appl. 2009;3:1397–1406.

    PubMed  CAS  Google Scholar 

  18. Jin S, Shen JN, Guo QC, et al. 2-D DIGE and MALDI-TOF-MS analysis of the serum proteome in human osteosarcoma. Proteomics Clin Appl. 2007;1:272–285.

    Article  PubMed  CAS  Google Scholar 

  19. Xie C, Mao X, Huang J, et al. KOBAS 2.0: a web server for annotation and identification of enriched pathways and diseases. Nucleic Acids Res. 2011;39:W316–W322.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Wu J, Mao X, Cai T, Luo J, Wei L. KOBAS server: a web-based platform for automated annotation and pathway identification. Nucleic Acids Res. 2006;34:W720–W724.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Guicciardi ME, Gores GJ. Apoptosis: a mechanism of acute and chronic liver injury. Gut. 2005;54:1024–1033.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. Kazama H, Yonehara S. The mechanism and regulation of Fas-mediated apoptosis. Seikagaku. 2001;73:107–111.

    PubMed  CAS  Google Scholar 

  23. Shimada K, Nakamura M, Ishida E, Kishi M, Konishi N. Androgen and the blocking of radiation-induced sensitization to Fas-mediated apoptosis through c-jun induction in prostate cancer cells. Int J Radiat Biol. 2003;79:451–462.

    Article  PubMed  CAS  Google Scholar 

  24. DosReis GA, Borges VM. Role of Fas-ligand induced apoptosis in pulmonary inflammation and injury. Curr Drug Targets Inflamm Allergy. 2003;2:161–167.

    Article  PubMed  CAS  Google Scholar 

  25. Uno M, Otsuki T, Yata K, et al. Participation of Fas-mediated apoptotic pathway in KB, a human head and neck squamous cell carcinoma cell line, after irradiation. Int J Oncol. 2002;20:617–622.

    PubMed  CAS  Google Scholar 

  26. Takahashi H, Ishida-Yamamoto A, Iizuka H. Ultraviolet B irradiation induces apoptosis of keratinocytes by direct activation of Fas antigen. J Investig Dermatol Symp Proc. 2001;6:64–68.

    Article  PubMed  CAS  Google Scholar 

  27. Yang JY, Xia W, Hu MC. Ionizing radiation activates expression of FOXO3a, Fas ligand, and Bim, and induces cell apoptosis. Int J Oncol. 2006;29:643–648.

    PubMed  PubMed Central  Google Scholar 

  28. Reztsova VV. Role of glycolysis in initiation of immortality and apoptosis. Vopr Onkol. 2006;52:609–615.

    PubMed  CAS  Google Scholar 

  29. Sukhomlinov BF, Chaika Ia P, Monastyrskaia SS, Demida EN. The individual glycolysis enzymes in the enterocytes of the rat small intestine studied during exposure to ionizing radiation. Radiobiologiia. 1993;33:255–258.

    PubMed  CAS  Google Scholar 

  30. Ralser M, Wamelink MM, Kowald A, et al. Dynamic rerouting of the carbohydrate flux is key to counteracting oxidative stress. J Biol. 2007;6:10.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Grant CM. Metabolic reconfiguration is a regulated response to oxidative stress. J Biol. 2008;7:1.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Otsuki S, Morshed SR, Chowdhury SA, et al. Possible link between glycolysis and apoptosis induced by sodium fluoride. J Dent Res. 2005;84:919–923.

    Article  PubMed  CAS  Google Scholar 

  33. Robinson GL, Dinsdale D, Macfarlane M, Cain K. Switching from aerobic glycolysis to oxidative phosphorylation modulates the sensitivity of mantle cell lymphoma cells to TRAIL. Oncogene. 2012;31:4996–5006.

    Article  PubMed  CAS  Google Scholar 

  34. Zhong J, Rajaram N, Brazil DM, et al. Radiation induces aerobic glycolysis through reactive oxygen species. Radiother Oncology. 2013;1:390–396.

    Article  Google Scholar 

  35. Wajant H. The Fas signaling pathway: more than a paradigm. Science. 2002;296:1635–1636.

    Article  PubMed  CAS  Google Scholar 

  36. Brint E, O’Callaghan G, Houston A. Life in the Fas lane: differential outcomes of Fas signaling. Cell Mol Life Sci. 2013;70:4085–4099.

    Article  PubMed  CAS  Google Scholar 

  37. Fais S, De Milito A, Lozupone F. The role of FAS to ezrin association in FAS-mediated apoptosis. Apoptosis. 2005;10:941–947.

    Article  PubMed  CAS  Google Scholar 

  38. Kuwabara M, Takahashi K, Inanami O. Induction of apoptosis through the activation of SAPK/JNK followed by the expression of death receptor Fas in X-irradiated cells. J Radiat Res. 2003;44:203–209.

    Article  PubMed  CAS  Google Scholar 

  39. Dzietko M, Boos V, Sifringer M, et al. A critical role for Fas/CD-95 dependent signaling pathways in the pathogenesis of hyperoxia-induced brain injury. Ann Neurol. 2008;64:664–673.

    Article  PubMed  CAS  Google Scholar 

  40. Zhuang S, Kochevar IE. Ultraviolet A radiation induces rapid apoptosis of human leukemia cells by Fas ligand-independent activation of the Fas death pathways. Photochem Photobiol. 2003;78:61–67.

    PubMed  CAS  Google Scholar 

  41. Reap EA, Roof K, Maynor K, Borrero M, Booker J, Cohen PL. Radiation and stress-induced apoptosis: a role for Fas/Fas ligand interactions. Proc Natl Acad Sci USA. 1997;94:5750–5755.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  42. Ao X, Lubman DM, Davis MA, et al. Comparative proteomic analysis of radiation-induced changes in mouse lung: fibrosis-sensitive and -resistant strains. Radiat Res. 2008;169:417–425.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was partly supported by the Guangdong Provincial Key Scientific Research Grants (10251008901000008, L Wang), the National Natural Scientific Foundation of China Grants (81072042, L Wang; 81172040, JP Wang), and grants by ”985 project” of Sun Yat-Sen University and Guangdong Translational Medicine Public Platform (4202037) and Sun Yat-Sen Graduate Innovative Personnel Training Funded Projects (Shunxin Song and Jianping Wang). We thank Ms. Biyan Lu, Peihuang Wu, Dr. Kunhua Hu and Chuangyu Wen for their laboratory assistance.

Conflict of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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Correspondence to Jianping Wang or Lei Wang.

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Song, S., Chen, D., Ma, T. et al. Molecular Mechanism of Acute Radiation Enteritis Revealed Using Proteomics and Biological Signaling Network Analysis in Rats. Dig Dis Sci 59, 2704–2713 (2014). https://doi.org/10.1007/s10620-014-3224-1

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  • DOI: https://doi.org/10.1007/s10620-014-3224-1

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