title: ERK1/2 regulation of CD44 modulates oral cancer aggressiveness.
abstract: Carcinogen-induced oral cavity squamous cell carcinoma (OSCC) incurs significant morbidity and mortality and constitutes a global health challenge. To gain further insight into this disease, we generated cell line models from 7,12-dimethylbenz(a)anthracene-induced murine primary OSCC capable of tumor formation upon transplantation into immunocompetent wild-type mice. Whereas several cell lines grew rapidly and were capable of metastasis, some grew slowly and did not metastasize. Aggressively growing cell lines displayed ERK1/2 activation, which stimulated expression of CD44, a marker associated with epithelial to mesenchymal transition and putative cancer stem cells. MEK (MAP/ERK kinase) inhibition upstream of ERK1/2 decreased CD44 expression and promoter activity and reduced cell migration and invasion. Conversely, MEK1 activation enhanced CD44 expression and promoter activity, whereas CD44 attenuation reduced in vitro migration and in vivo tumor formation. Extending these findings to freshly resected human OSCC, we confirmed a strict relationship between ERK1/2 phosphorylation and CD44 expression. In summary, our findings identify CD44 as a critical target of ERK1/2 in promoting tumor aggressiveness and offer a preclinical proof-of-concept to target this pathway as a strategy to treat head and neck cancer.
authors.affiliation: Department of Otolaryngology and John Cochran VA Medical Center, Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Nancy P
authors.initials: NP
authors.lastname: Judd
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Winkler
authors.forename: Oihana
authors.initials: O
authors.lastname: Murillo-Sauca
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Brotman
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Law
authors.forename: James S
authors.initials: JS
authors.lastname: Lewis
authors.forename: Gavin P
authors.initials: GP
authors.lastname: Dunn
authors.forename: Jack D
authors.initials: JD
authors.lastname: Bui
authors.forename: John B
authors.initials: JB
authors.lastname: Sunwoo
authors.forename: Ravindra
authors.initials: R
authors.lastname: Uppaluri
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D018960:Hyaluronan Receptors / Q000276:immunology*; D008207:Lymphatic Metastasis; D051379:Mice; D008810:Mice, Inbred C57BL; D009062:Mouth Neoplasms / Q000201:enzymology / Q000276:immunology / Q000473:pathology*
chemical_list: D018960:Hyaluronan Receptors; D048049:Extracellular Signal-Regulated MAP Kinases
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