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Int J Radiat Oncol Biol Phys. 2016 Jun 1;95(2):751-60. doi: 10.1016/j.ijrobp.2016.01.021. Epub 2016 Jan 20.

Proteomic Profiling of Radiation-Induced Skin Fibrosis in Rats: Targeting the Ubiquitin-Proteasome System.

Author information

1
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.
2
Department of Radiotherapy, Changzhou Tumor Hospital, Soochow University, Changzhou, China.
3
School of Radiation Medicine and Protection and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, China.
4
Department of Dermatology, the Second Affiliated Hospital of Soochow University, Suzhou, China.
5
Department of Gastroenterology, the Affiliated Jiangyin Hospital of Southeast University, Jiangyin, China.
6
Institute of Medical Biotechnology and Jiangsu Stem Cell Key Laboratory, Medical College of Soochow University, Suzhou, China.
7
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.

Abstract

PURPOSE:

To investigate the molecular changes underlying the pathogenesis of radiation-induced skin fibrosis.

METHODS AND MATERIALS:

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.

RESULTS:

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.

CONCLUSION:

Our findings illustrate the molecular changes during radiation-induced skin fibrosis and suggest that targeting the ubiquitin-proteasome system would be an effective countermeasure.

PMID:
27045812
DOI:
10.1016/j.ijrobp.2016.01.021
[Indexed for MEDLINE]

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