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.

EGFR Activation and Signaling in Cancer Cells Are Enhanced by the Membrane-Bound Metalloprotease MT4-MMP

“…EGFR is a receptor tyrosine kinase (RTK) whose activation by ligand binding (such as EGF, amphiregulin, TGFa) contributes to cancer cell proliferation, invasion, and metastasis. EGFR activation and signaling are leading causes of malignancy in many types of cancer such as breast, lung, metastatic colorectal, head and neck, ovarian, and brain cancers (2)(3)(4)(5)(6)(7). Notably, in breast cancers, EGFR is expressed by triple-negative breast cancers (TNBC) or basal-like breast cancers, which are highly aggressive cancers with a high rate of early-occurring lung and brain metastasis.…”

Annexin A1 regulates EGFR activity and alters EGFR-containing tumour-derived exosomes in head and neck cancers

“…EGFR is widely considered to be one of the central drivers of oncogenesis in HNSCC [23]. More than 80% of HNSCC cases exhibit an increased membraneous expression of EGFR, and overexpression of the receptor is linked to radiotherapy-resistance mechanisms [24,25]. Natural ligands of EGFR are growth factors, including EGF and TGF-a [26,27].…”

Expression profiles of selected genes in tumors and matched surgical margins in oral cavity cancer: Do we have to pay attention to the molecular analysis of the surgical margins?

“…12,[22][23][24][25][26][27] The majority of the research has compared tumor tissue from patients with normal tissue from healthy individuals or normal human cells obtained commercially. 12,18,[20][21][22]28,29 Simultaneous analysis of gene expression levels in the tumor and surgical margins has rarely been performed.…”