Downregulation of E-Cadherin enhances proliferation of head and neck cancer through transcriptional regulation of EGFR

• Type of Material: Article
• Authors: Dongsheng Wang, Emory University; Ling Su, Emory University; Donghai Huang, Emory University; Hongzheng Zhang, Emory University; Dong M Shin, Emory University; Zhuo G. Chen, Emory University
• Language: English
• Date: 2011-09-22
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2011 Wang et al; licensee BioMed Central Ltd.
• License: Creative Commons Attribution 2.0 Generic
• Final Published Version (URL): http://www.molecular-cancer.com/content/10/1/116
• Title of Journal or Parent Work: Molecular Cancer
• ISSN: 1476-4598
• Volume: 10
• Issue: 116
• Start Page: 1
• End Page: 10
• Research Categories: Health Sciences, Oncology

Abstract

Background Epidermal growth factor receptor (EGFR) has been reported to downregulate E-cadherin (E-cad); however, whether the downregulation of E-cad has any effect on EGFR expression has not been elucidated. Our previous studies have found an inverse correlation between EGFR and E-cad expression in tissue specimens of squamous cell carcinoma of the head and neck (SCCHN). To understand the biological mechanisms underlying this clinical observation, we knocked down E-cad expression utilizing E-cad siRNA in four SCCHN cell lines. Results It was observed that downregulation of E-cad upregulated EGFR expression compared with control siRNA-transfected cells after 72 hours. Cellular membrane localization of EGFR was also increased. Consequently, downstream signaling molecules of the EGFR signaling pathway, p-AKT, and p-ERK, were increased at 72 hours after the transfection with E-cad siRNA. Reverse transcriptase-polymerase chain reaction (RT-PCR) showed EGFR mRNA was upregulated by E-cad siRNA as early as 24 hours. In addition, RT-PCR revealed this upregulation was due to the increase of EGFR mRNA stability, but not protein stability. Sulforhodamine B (SRB) assay indicated growth of E-cad knocked down cells was enhanced up to 2-fold more than that of control siRNA-transfected cells at 72-hours post-transfection. The effect of E-cad reduction on cell proliferation was blocked by treating the E-cad siRNA-transfected cells with 1 μM of the EGFR-specific tyrosine kinase inhibitor erlotinib. Conclusion Our results suggest for the first time that reduction of E-cad results in upregulation of EGFR transcriptionally. It also suggests that loss of E-cad may induce proliferation of SCCHN by activating EGFR and its downstream signaling pathways.