Differential growth factor regulation of N-cadherin expression and motility in normal and malignant oral epithelium.
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.
Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Michelle E
ME
Diamond
Limin
L
Sun
Adam J
AJ
Ottaviano
Mathew J
MJ
Joseph
Hidayatullah G
HG
Munshi
D015820:Cadherins / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D004815:Epidermal Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D004848:Epithelium / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009055:Mouth / Q000473:pathology; D009062:Mouth Neoplasms / Q000378:metabolism; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D015820:Cadherins; D053773:Transforming Growth Factor beta1; D004815:Epidermal Growth Factor; D048052:Mitogen-Activated Protein Kinase 3