Snail up-regulates proinflammatory mediators and inhibits differentiation in oral keratinocytes.
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-kappaB 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.
Dermatology Research Laboratories, Central Clinical School, and Key Centre for Microscopy, University of Sydney, New South Wales, Australia. glyons@med.usyd.edu.au
J Guy
JG
Lyons
Vyomesh
V
Patel
Naomi C
NC
Roue
Sandra Y
SY
Fok
Lilian L
LL
Soon
Gary M
GM
Halliday
J Silvio
JS
Gutkind
D000818:Animals; D015820:Cadherins / Q000235:genetics; D002454:Cell Differentiation; D002460:Cell Line; D002465:Cell Movement; D054360:Chemokine CXCL1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004285:Dogs; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D009061:Mouth Mucosa / Q000166:cytology / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets; D012697:Serine Endopeptidases / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation
D015820:Cadherins; D054360:Chemokine CXCL1; D004268:DNA-Binding Proteins; C105529:ELF3 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D008156:Luciferases; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D012697:Serine Endopeptidases; C485595:matriptase