Document Detail


Regulators and mediators of radiation-induced fibrosis: Gene expression profiles and a rationale for Smad3 inhibition.
MedLine Citation:
PMID:  20869563     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: Radiotherapy, an essential modality in cancer treatment, frequently induces fibrotic processes in the skin, including accumulation of extracellular matrix. Transforming growth factor-β is essential in regulating extracellular matrix gene expression and is dependent on Smad3, an intracellular mediator/transcription factor. Our study characterized the genetic expression involved in extracellular matrix accumulation during radiation-induced fibrosis. We performed Smad3 gene silencing in an attempt to abrogate the effects of radiation. STUDY DESIGN: Laboratory research. SETTING: University laboratory. SUBJECTS AND METHODS: C57 murine dermal fibroblasts were irradiated with 20 Gy RNA isolated (0, 6, 12, 24, 48, 72 hours postirradiation) and mRNA analyzed (reverse transcriptase polymerase chain reaction) for known regulators (Smad3, interleukin-13 [IL-13]), tumor necrosis factor-α [TNF-α]) and mediators of fibrosis (collagen 1A1 [Col1A1]), TGF-β, matrix metalloprotease-1 and -2 (MMP-1, MMP-2), and tissue inhibitor of metalloprotease-1 (TIMP-1). Smad3 gene expression was silenced using siRNA in an effort to restore an unirradiated gene profile. RESULTS: Following irradiation, there was a steady increase in mRNA expression of Smad3, IL-13, TGF-β, Col1A1, MMP-2, TIMP-1, with peak at 12 to 24 hours and subsequent decline by 72 hours. TNF-α expression remained elevated throughout. MMP-1 showed minimal expression initially, which decreased to negligible by 72 hours. Inhibition of Smad3 significantly decreased expression of Col1A1, TGF-β, MMP-2, and TIMP-1. IL-13 and TNF-α expression was not affected by Smad3 silencing. CONCLUSION: We have characterized the early-phase mRNA expression profiles of the major mediators of radiation-induced fibrosis. Smad3 siRNA effectively abrogated the elevation of Col1A1, TGF-β, TIMP-1, and MMP-2. IL-13 and TNF-α were unaffected by Smad3 silencing and appear to be minor regulators in fibrosis. These findings suggest a therapeutic rationale for Smad3 silencing in vivo.
Authors:
Judy W Lee; Richard A Zoumalan; Cristian D Valenzuela; Phuong D Nguyen; John P Tutela; Benjamin R Roman; Stephen M Warren; Pierre B Saadeh
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery     Volume:  143     ISSN:  1097-6817     ISO Abbreviation:  Otolaryngol Head Neck Surg     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-09-27     Completed Date:  2010-11-12     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8508176     Medline TA:  Otolaryngol Head Neck Surg     Country:  United States    
Other Details:
Languages:  eng     Pagination:  525-30     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 American Academy of Otolaryngology–Head and Neck Surgery Foundation. Published by Mosby, Inc. All rights reserved.
Affiliation:
Department of Otolaryngology-Head and Neck Surgery, New York University School of Medicine, New York, NY, USA. judy.lee@nyumc.org
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MeSH Terms
Descriptor/Qualifier:
Animals
Cells, Cultured
Collagen Type I / metabolism
Extracellular Matrix / genetics
Fibroblasts / radiation effects*
Gene Expression Profiling*
Gene Silencing
Matrix Metalloproteinase 2 / metabolism
Mice
Mice, Inbred C57BL
RNA, Small Interfering / genetics,  metabolism
Radiation Pneumonitis / genetics*,  metabolism
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Skin / pathology,  radiation effects*
Smad3 Protein / genetics*,  metabolism
Tissue Inhibitor of Metalloproteinases / metabolism
Transforming Growth Factor beta / metabolism
Up-Regulation
Chemical
Reg. No./Substance:
0/Collagen Type I; 0/RNA, Small Interfering; 0/Smad3 Protein; 0/Tissue Inhibitor of Metalloproteinases; 0/Transforming Growth Factor beta; 0/collagen type I, alpha 1 chain; EC 3.4.24.24/Matrix Metalloproteinase 2

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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