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

Authors' Affiliations: Departments of ¹ Dermatology, ² Anatomy, ³ Microbiology and Immunology, and ⁴ Institute of Basic Medical Sciences, National Cheng Kung University; ⁵ National Tainan Institute of Nursing, Tainan, Taiwan; ⁶ Department of Surgery, Kaohsiung Medical University, Kaohsiung, Taiwan; and ⁷ Laboratory of Molecular Immunology, Guthrie Research Institute, Sayre, Pennsylvania

Requests for reprints: Feng-Jie Lai and Hamm-Ming Sheu, Department of Dermatology, National Cheng Kung University Hospital, 138 Sheng-Li Road, Tainan 70403, Taiwan. Phone: 886-6-2004326; Fax: 886-6-2004326; E-mail: laifj{at}mail.ncku.edu.tw and hmsheu{at}mail.ncku.edu.tw.

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 (Tyr³³ 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 Tyr³³ phosphorylation occurred during normal keratinocyte differentiation before cornification and death. Interestingly, significant reduction of these proteins and Tyr³³ 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 Tyr³³ 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.

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