WOX1 Is Essential for UVB Irradiation–Induced Apoptosis and Down-Regulated via Translational Blockade in UVB-Induced Cutaneous Squamous Cell Carcinoma In vivo

Purpose: We investigated the role of candidate tumor suppressor and proapoptotic WOX1 (also named WWOX, FOR, or WWOXv1) in UVB-induced apoptosis and formation of cutaneous squamous cell carcinomas (SCC). Experimental Design: Expression of WOX1 and family proteins (WWOX) in human primary cutaneous SC...

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Bibliographic Details
Published in:Clinical cancer research 2005-08, Vol.11 (16), p.5769-5777
Main Authors: LAI, Feng-Jie, CHENG, Ching-Li, SHEU, Hamm-Ming, CHEN, Shur-Tzu, WU, Chin-Han, HSU, Li-Jin, YU-YUN LEE, J, CHAO, Sheau-Chiou, SHEEN, Maw-Chang, SHEN, Ching-Liang, CHANG, Nan-Shan
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Animals
Antineoplastic agents
Apoptosis - radiation effects
Biological and medical sciences
Carcinoma, Squamous Cell - etiology
Carcinoma, Squamous Cell - genetics
Carcinoma, Squamous Cell - metabolism
Cell Differentiation - genetics
Cell Line, Tumor
Down-Regulation - genetics
Female
Gene Expression Regulation, Neoplastic - radiation effects
Humans
Immunohistochemistry
In Situ Hybridization
Keratinocytes - cytology
Keratinocytes - metabolism
Male
Medical sciences
Mice
Middle Aged
Oxidoreductases - genetics
Oxidoreductases - metabolism
Pharmacology. Drug treatments
Phosphorylation - radiation effects
Protein Biosynthesis - genetics
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - genetics
RNA, Messenger - metabolism
RNA, Small Interfering - genetics
skin cancer
Skin Neoplasms - etiology
Skin Neoplasms - genetics
Skin Neoplasms - metabolism
Time Factors
Transfection
tumor suppressor gene
Tumor Suppressor Proteins
Tyrosine - metabolism
Ultraviolet Rays
UV radiation
WOX1
WW Domain-Containing Oxidoreductase
WWOX
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Summary:Purpose: We investigated the role of candidate tumor suppressor and proapoptotic WOX1 (also named WWOX, FOR, or WWOXv1) in UVB-induced apoptosis and formation of cutaneous squamous cell carcinomas (SCC). Experimental Design: Expression of WOX1 and family proteins (WWOX) in human primary cutaneous SCCs was examined by immunohistochemistry, in situ hybridization, and reverse transcription-PCR. UVB irradiation–induced WOX1 activation (Tyr 33 phosphorylation and nuclear translocation), apoptosis, and cutaneous SCC formation were examined both in vitro and in vivo . Results: Up-regulation of human WOX1, isoform WOX2, and Tyr 33 phosphorylation occurred during normal keratinocyte differentiation before cornification and death. Interestingly, significant reduction of these proteins and Tyr 33 phosphorylation was observed in nonmetastatic and metastatic cutaneous SCCs ( P < 0.001), but without down-regulation of WWOX mRNA ( P > 0.05 versus normal controls), indicating a translational blockade of WWOX mRNA to protein. During acute exposure of hairless mice to UVB, WOX1 was up-regulated and activated in epidermal cells in 24 hours. In parallel with the clinical findings in humans, chronic UVB-treated mice developed cutaneous SCCs in 3 months, with significant reduction of WOX1 and Tyr 33 phosphorylation and, again, without down-regulation of WWOX mRNA. Human SCC-25 and HaCaT cells were transfected with small interfering RNA–targeting WOX1 and shown to resist UVB-induced WOX1 expression, activation, and apoptosis. Conclusions: WOX1 is essential for UVB-induced apoptosis and likely to be involved in the terminal differentiation of normal keratinocytes. During UVB-induced cutaneous SCC, epidermal cells have apparently prevented the apoptotic pressure from overexpressed WOX1 by shutting down the translation machinery for WWOX mRNA.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-04-2274