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Snail Up-regulates Proinflammatory Mediators and Inhibits Differentiation in Oral Keratinocytes

¹ Dermatology Research Laboratories, Central Clinical School, and ² Key Centre for Microscopy, University of Sydney; ³ Sydney Head and Neck Cancer Institute, Sydney Cancer Centre, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia; and ⁴ Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland

Requests for reprints: J. Guy Lyons, Dermatology Research Laboratories, Central Clinical School, University of Sydney, Room W350, Blackburn Building, Sydney, NSW 2006, Australia. Phone: 61-2-90366314; Fax: 61-2-90365130; E-mail: glyons{at}med.usyd.edu.au.

Key Words: Snail • keratinocyte • head and neck squamous cell carcinoma • inflammation • differentiation

The transcriptional repressor Snail2 is overexpressed in head and neck squamous cell carcinomas (HNSCC) relative to nonmalignant head and neck mucosal epithelium, and in locally recurrent relative to nonrecurrent HNSCCs. We investigated the mechanisms by which Snails might contribute to the pathogenesis of HNSCCs using cell biological and molecular analyses. Oral keratinocytes that expressed Snails acquired an enhanced ability to attract monocytes and to invade a dense interstitial collagen matrix. They were also found to up-regulate production of proinflammatory cytokines and cyclooxygenase-2 (COX2), which have previously been shown to correlate with malignancy. Induction of nuclear factor-B transcriptional activity by Snails was weak and not sufficient to account for the elevated levels of COX2, interleukin (IL)-6, IL8, or CXCL1. In addition, expression of Snails in oral keratinocytes impaired desquamation in vitro and strongly repressed expression of both ELF3 and matriptase-1, which play important roles in the terminal differentiation of keratinocytes. Reexpression of matriptase-1 in Snail-expressing cells partially rescued desquamation. This implicates Snails as contributing to malignancy both at the early stages, by impeding terminal differentiation, and at later stages, when invasion and inflammation are important. [Cancer Res 2008;68(12):4525–30]

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