Abstract
BackgroundMany cancerous cells accumulate β-catenin in the nucleus. We examined the role of epidermal growth factor receptor (EGFR) signaling in the accumulation of β-catenin in the nuclei of oral cancer cells.ResultsWe used two strains of cultured oral cancer cells, one with reduced EGFR expression (OECM1 cells) and one with elevated EGFR expression (SAS cells), and measured downstream effects, such as phosphorylation of β-catenin and GSK-3β, association of β-catenin with E-cadherin, and target gene regulation. We also studied the expression of EGFR, β-catenin, and cyclin D1 in 112 samples of oral cancer by immunostaining. Activation of EGFR signaling increased the amount of β-catenin in the nucleus and decreased the amount in the membranes. EGF treatment increased phosphorylation of β-catenin (tyrosine) and GSK-3β(Ser-(9), resulting in a loss of β-catenin association with E-cadherin. TOP-FLASH and FOP-FLASH reporter assays demonstrated that the EGFR signal regulates β-catenin transcriptional activity and mediates cyclin D1 expression. Chromatin immunoprecipitation experiments indicated that the EGFR signal affects chromatin architecture at the regulatory element of cyclin D1, and that the CBP, HDAC1, and Suv39h1 histone/chromatin remodeling complex is involved in this process. Immunostaining showed a significant association between EGFR expression and aberrant accumulation of β-catenin in oral cancer.ConclusionsEGFR signaling regulates β-catenin localization and stability, target gene expression, and tumor progression in oral cancer. Moreover, our data suggest that aberrant accumulation of β-catenin under EGFR activation is a malignancy marker of oral cancer.
Highlights
Many cancerous cells accumulate b-catenin in the nucleus
In the absence of a mitotic signal, b-catenin is sequestered in a “destruction complex” which consists of the adenomatous polyposis coli (APC) gene product, casein kinase 1 (CK1), a serine threonine glycogen synthetase kinase (GSK-3b), and axin, an adapter protein [2]
APC and b-catenin mutation in oral cancer cell lines In many cancers, activation of the Wnt/b-catenin pathway is associated with mutations of APC and b-catenin, with exon 15 of APC and exon 3 of b-catenin the most common mutation sites [10,31]
Summary
Many cancerous cells accumulate b-catenin in the nucleus. We examined the role of epidermal growth factor receptor (EGFR) signaling in the accumulation of b-catenin in the nuclei of oral cancer cells. In the absence of a mitotic signal, b-catenin is sequestered in a “destruction complex” which consists of the adenomatous polyposis coli (APC) gene product, casein kinase 1 (CK1), a serine threonine glycogen synthetase kinase (GSK-3b), and axin, an adapter protein [2]. This destruction complex is phosphorylated and degraded by the ubiquitin-proteasome system [2]. Following stimulation of mitosis signal, b-catenin accumulates in the cytoplasm, moves to the nucleus, and binds to a member of the TCF/LEF-1 family of transcription factors that modulate expression of TCF/ LEF-1 target genes [5,6,7]. The molecular mechanisms that lead to aberrant expression of b-catenin in oral cancer are unclear, and the mechanisms by which b-catenin promotes activation of target genes are not well understood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
