Abstract
Aberrant expression of N-cadherin is associated with tumor progression in squamous cell carcinomas (SCCs). Consequently, we examined the regulation of N-cadherin by TGFbeta1, an important mediator of keratinocyte and SCC function. N-cadherin expression was increased in oral SCC (OSCC) cell lines, regulating motility and correlating with TGFbeta1 production. Moreover, in normal keratinocytes TGFbeta1 increased expression of N-cadherin to regulate motility. TGFbeta1-mediated N-cadherin expression in the oral keratinocytes was blocked using siRNA targeting Smads. Unexpectedly, we found that EGF blocked TGFbeta1-mediated N-cadherin expression in oral keratinocytes and not in OSCC cells. Mechanistically, EGF enhanced Smad phosphorylation in the linker region, and attenuated TGFbeta1-mediated phosphorylation of Smad at the C-terminus, localization of Smad to the nucleus as well as Smad-driven promoter activity exclusively in oral keratinocytes but not in OSCC cells. The effect of EGF on TGFbeta1-mediated Smad-driven promoter activity and N-cadherin expression was reversed when activation of ERK1/2 was blocked. Although EGF and TGFbeta1 independently promoted migration of both oral keratinocytes and OSCC cells, EGF decreased TGFbeta1-mediated migration of oral keratinocytes but enhanced migration of OSCC cells. Together, these data support a model wherein EGF signaling has an important negative regulatory role on TGFbeta1-mediated N-cadherin expression and motility in normal oral keratinocytes, and in which loss of this regulatory mechanism accompanies malignant transformation of the oral epithelium.
Highlights
The American Cancer Society estimates that there will be more than 20,000 new cases of squamous cell carcinoma (SCC) this year involving the oral cavity in the USA (Jemal et al, 2008), and that oral SCC (OSCC) will cause more deaths than any other oral disease (Forastiere et al, 2001; Neville and Day, 2002)
We examined E- and N-cadherin expression in two oral keratinocyte cell lines (OKF4 and OKF6) and in four malignant OSCC cell lines (SCC9, SCC25, SCC68 and UMSCC1)
transforming growth factor β1 (TGFβ1) increases the migration of oral keratinocytes by upregulating the expression of N-cadherin Since TGFβ1 can regulate N-cadherin expression (De Wever et al, 2004; Maeda et al, 2005), we examined the relative TGFβ1 production in oral keratinocytes and in OSCC cells to provide a potential explanation for the differences in the levels of N-cadherin among the six cell lines
Summary
The American Cancer Society estimates that there will be more than 20,000 new cases of squamous cell carcinoma (SCC) this year involving the oral cavity in the USA (Jemal et al, 2008), and that oral SCC (OSCC) will cause more deaths than any other oral disease (Forastiere et al, 2001; Neville and Day, 2002). Advanced OSCC is associated with high mortality, and treatment is often complicated by disruption of speech and swallowing due to surgical resection (Forastiere et al, 2001; Neville and Day, 2002). This dismal outcome is attributed to the fact that OSCC is an aggressive and a highly invasive cancer, and the cellular and biochemical factors that underlie local, regional and distant spread of the disease are poorly understood (Forastiere et al, 2001; Neville and Day, 2002). N-cadherin is being actively pursued as a therapeutic target, and inhibitors of N-cadherin are currently being evaluated in preclinical and clinical studies (Mariotti et al, 2007)
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