title: Downregulation of E-Cadherin enhances proliferation of head and neck cancer through transcriptional regulation of EGFR.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Wang
authors.forename: Ling
authors.initials: L
authors.lastname: Su
authors.forename: Donghai
authors.initials: D
authors.lastname: Huang
authors.forename: Hongzheng
authors.initials: H
authors.lastname: Zhang
authors.forename: Dong M
authors.initials: DM
authors.lastname: Shin
authors.forename: Zhuo G
authors.initials: ZG
authors.lastname: Chen
mesh_terms: D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D055550:Protein Stability; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D020871:RNA Stability; D012333:RNA, Messenger; D015398:Signal Transduction; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D015820:Cadherins; D011799:Quinazolines; D012333:RNA, Messenger; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors