title: Overexpression of EGFR in head and neck squamous cell carcinoma is associated with inactivation of SH3GL2 and CDC25A genes.
abstract: The aim of this study is to understand the mechanism of EGFR overexpression in head and neck squamous cell carcinoma (HNSCC). For this reason, expression/mutation of EGFR were analyzed in 30 dysplastic head and neck lesions and 148 HNSCC samples of Indian patients along with 3 HNSCC cell lines. In addition, deletion/methylation/mutation/expression of SH3GL2 (associated with EGFR degradation) and CDC25A (associated with dephosphorylation of EGFR) were analyzed in the same set of samples. Our study revealed high frequency of EGFR overexpression (66-84%), low frequency of gene amplification (10-32.5%) and absence of functional mutation in the dysplastic lesions and HNSCC samples. No correlation was found between protein overexpression and mRNA expression/gene amplification status of EGFR. On the other hand, frequent alterations (deletion/methylation) of SH3GL2 (63-77%) and CDC25A (37-64%) were seen in the dysplastic and HNSCC samples. Two novel single nucleotide polymorphism (SNPs) were found in the promoter region of SH3GL2. Reduced expression of these genes showed concordance with their alterations. Overexpression of EGFR and p-EGFR were significantly associated with reduced expression and alterations of SH3GL2 and CDC25A respectively. In-vitro demethylation experiment by 5-aza-2'-deoxycytidine (5-aza-dC) showed upregulation of SH3GL2 and CDC25A and downregulation of EGFR expression in Hep2 cell line. Poor patient outcome was predicted in the cases with alterations of SH3GL2 and CDC25A in presence of human papilloma virus (HPV) infection. Also, low SH3GL2 and high EGFR expression was a predictor of poor patient survival. Thus, our data suggests that overexpression of EGFR due to its reduced degradation and dephosphorylation is needed for development of HNSCC.
authors.affiliation: Department of Oncogene Regulation, Chittaranjan National Cancer Institute, Kolkata, India.
authors.forename: Guru Prasad
authors.initials: GP
authors.lastname: Maiti
authors.forename: Pinaki
authors.initials: P
authors.lastname: Mondal
authors.forename: Nupur
authors.initials: N
authors.lastname: Mukherjee
authors.forename: Amlan
authors.initials: A
authors.lastname: Ghosh
authors.forename: Susmita
authors.initials: S
authors.lastname: Ghosh
authors.forename: Sanjib
authors.initials: S
authors.lastname: Dey
authors.forename: Jayanta
authors.initials: J
authors.lastname: Chakrabarty
authors.forename: Anup
authors.initials: A
authors.lastname: Roy
authors.forename: Jaydip
authors.initials: J
authors.lastname: Biswas
authors.forename: Susanta
authors.initials: S
authors.lastname: Roychoudhury
authors.forename: Chinmay Kumar
authors.initials: CK
authors.lastname: Panda
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000821:virology; D019175:DNA Methylation; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005784:Gene Amplification; D017353:Gene Deletion; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000821:virology; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D027383:Papillomaviridae; D011401:Promoter Regions, Genetic; D015203:Reproducibility of Results; D000077195:Squamous Cell Carcinoma of Head and Neck; D020687:cdc25 Phosphatases / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C107640:SH3GL2 protein, human; D066246:ErbB Receptors; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases