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K. Miyazaki, S. Saika, Y. Okada, O. Yamanaka, Y. Ohnishi; Sonic Hedghog Signaling Inhibition Suppresses the Proliferation of Induced Eyelid Tumors in XPC–/– Mice . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3416.
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Purpose: To examine the expression of sonic hedgehog (Shh) in chemically induced epithelial neoplasm of the eyelid in XPC–null mice and in human squamous cell carcinoma (SCC) and to assess the effect of topical administration of cyclopamine, a steroidal alkaloid inhibitor of Shh signal, in human SCC cell lines in vitro and induced eyelid tumors in XPC–null mice. Methods: (1) Shh expression was immunohistochemically detected in human tumor specimens. (2) SCC cells were treated with 12.5 or 25.0 mg/ml recombinant Shh (rShh) and/or either 0 or 100 mg/ ml cyclopamine and cell proliferation was evaluated by using MTT assay. (3) XPC–null mice (n=4) received topical 9,10–dimethyl–1,2–benzanthracene (DMBA 0.2 mg/0.2 ml acetone) and phorbol–12–myristate 13 acetate (TPA 20 nmol/200 ml acetone) in eyelid skin twice a week and were kept in a dark room up to 6 months. Epitghelial tumors developed were treated daily with topical injection of cyclopamine (n=2, 1 mg/tumor) or phosphate–buffrered saline (n=2) for 7 days. The mice were killed after 2–hr BrdU labeling. Paraffin sections of the tumors were histologically examined. Results: (1) Human SCC was labeled for Shh. (2) The cell proliferation of SCC cell lines was stimulated by adding exogenous rShh and this effect was abolished by adding cyclopamine. In tumors chemically induced in the eyelid of XPC–null mice, topical cyclopamine suppressed BrdU incorporation and markedly increased TUNEL–positive tumor cells. Conclusions: SCC cells express Shh in vivo and exogenous Shh enhances SCC cells in vitro. Cyclopamine, a Shh signal inhibitor, suppresses SCC cell proliferation and induces apoptosis. Cyclopamine treatment may be useful in treating inoperative eyelid epithelial tumor.
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