title: Proteomic Profiling of Radiation-Induced Skin Fibrosis in Rats: Targeting the Ubiquitin-Proteasome System.
abstract: To investigate the molecular changes underlying the pathogenesis of radiation-induced skin fibrosis.
  
  
  
  Rat skin was irradiated to 30 or 45 Gy with an electron beam. Protein expression in fibrotic rat skin and adjacent normal tissues was quantified by label-free protein quantitation. Human skin cells HaCaT and WS-1 were treated by x-ray irradiation, and the proteasome activity was determined with a fluorescent probe. The effect of proteasome inhibitors on Transforming growth factor Beta (TGF-B) signaling was measured by Western blot and immunofluorescence. The efficacy of bortezomib in wound healing of rat skin was assessed by the skin injury scale.
  
  
  
  We found that irradiation induced epidermal and dermal hyperplasia in rat and human skin. One hundred ninety-six preferentially expressed and 80 unique proteins in the irradiated fibrotic skin were identified. Through bioinformatic analysis, the ubiquitin-proteasome pathway showed a significant fold change and was investigated in greater detail. In vitro experiments demonstrated that irradiation resulted in a decline in the activity of the proteasome in human skin cells. The proteasome inhibitor bortezomib suppressed profibrotic TGF-β downstream signaling but not TGF-β secretion stimulated by irradiation in HaCaT and WS-1 cells. Moreover, bortezomib ameliorated radiation-induced skin injury and attenuated epidermal hyperplasia.
  
  
  
  Our findings illustrate the molecular changes during radiation-induced skin fibrosis and suggest that targeting the ubiquitin-proteasome system would be an effective countermeasure.
authors.affiliation: School of Radiation Medicine and Protection and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, China; Cyrus Tang Hematology Center, Soochow University, Suzhou, China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Radiotherapy, Changzhou Tumor Hospital, Soochow University, Changzhou, China.
authors.forename: Judong
authors.initials: J
authors.lastname: Luo
authors.affiliation: School of Radiation Medicine and Protection and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, China.
authors.forename: Wenjiong
authors.initials: W
authors.lastname: Sheng
authors.affiliation: School of Radiation Medicine and Protection and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Xue
authors.affiliation: School of Radiation Medicine and Protection and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Dermatology, the Second Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Ji
authors.affiliation: Department of Gastroenterology, the Affiliated Jiangyin Hospital of Southeast University, Jiangyin, China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Liu
authors.affiliation: Institute of Medical Biotechnology and Jiangsu Stem Cell Key Laboratory, Medical College of Soochow University, Suzhou, China.
authors.forename: Xueguang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: School of Radiation Medicine and Protection and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Cao
authors.affiliation: School of Radiation Medicine and Protection and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, China; Cyrus Tang Hematology Center, Soochow University, Suzhou, China. Electronic address: zhang.shuyu@hotmail.com.
authors.forename: Shuyu
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000069286:Bortezomib / Q000494:pharmacology; D002478:Cells, Cultured; D005355:Fibrosis; D006801:Humans; D008297:Male; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D040901:Proteomics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000473:pathology / Q000528:radiation effects*; D016212:Transforming Growth Factor beta / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D016212:Transforming Growth Factor beta; D025801:Ubiquitin; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex