Erk1/2 Regulation Of Cd44 Modulates Aggressiveness In A New Mouse Model Of Oral Cancer

Carcinogen-induced oral cavity squamous cell carcinoma (OSCC) causes significant morbidity and mortality and constitutes a global health challenge. To gain further insight into this disease, six unique C57BL/6 mouse OSCC cell lines were generated from 7,12-dimethylbenz(≥)anthracene (DMBA) induced murine primary OSCCs. The cell lines were designated as mouse oral cancer (MOC1, 2, 7, 10, 22 and 23) and 5/6 (excluding MOC23) formed tumors when transplanted into immunocompetent wild-type (WT) mice. Analyses of tumor growth in mice showed that MOC2, MOC7 and MOC10 grew more rapidly and metastasized to regional lymph nodes, while MOC1 and MOC22 grew much slower and did not metastasize. This aggressive growth was correlated with ERK1/2 activation, which in addition, was found to induce CD44 expression- a molecule whose expression is associated with EMT and putative cancer stem cells. Inhibiting MEK, the upstream activator of ERK1/2, led to decreased CD44 expression and promoter activity and also decreased cellular migration and invasion. Conversely, enforced activation of MEK1 led to enhanced CD44 expression and promoter activity. CD44 was required for the aggressive growth since reduction of CD44 levels significantly attenuated in vitro migration and in vivo tumor formation of MOC2 and MOC10 cell lines. These results in the mouse model were extended to freshly resected human OSCC where a strict relationship between ERK1/2 phosphorylation and CD44 expression was also identified. Thus, using a novel immunocompetent mouse model, we identify CD44 as an essential mediator of the aggressive tumor-promoting effects of ERK1/2, which highlight the potential efficacy of targeting this molecular pathway in head and neck cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2358. doi:1538-7445.AM2012-2358