Dysregulations Of EGFR Pathway Are Early Events In Oral Carcinogenesis

A lack of understanding of how dysregulated EGFR pathway can alter key cancer phenotypes , including oral carcinogenesis, yet several large chemoprevention trials for high-risk oral premalignant lesions (OPLs) are currently targeting molecules in this pathway. Objectives: 1) To assess the alterations in EGFR and phosphorylated EGFR (p-EGFR) expressions in OPLs and 2) To assess the alterations in its major downstream cascades in OPLs and their association with EGFR expression. Methods: A unique tissue microarray composed of 138 oral tissue cores (20 oral cancers, 63 low-grade dysplasia (LGD), 30 high-grade dysplasia (HGD), and 25 normal) was created. Antibodies to EGFR, p-EGFR, Akt, p-Akt, p70S6k, p-p70S6k, p-mTOR, ERK1/2, and p-ERK1/2 were analyzed examined using immunohistochemistry. Results: There was no statistical difference of age, gender, smoking habit, and biopsy anatomical sites between LGD and HGD. There was a significant increase of EGFR and p-EGFR expression among different histology grades. While the expression level was increased from LGD to HGD; however, a down-regulation was observed in SCC, suggesting that the activation of EGFR is an early event during oral carcinogenesis. When the EGFR and its associated downstream molecules were examined, there were significant positive association between EGFR and nuclearly located p-EGFR expressions and their downstream proteins, including Akt and p-mTOR in PI3K/Akt cascade and nuclear ERK and p-ERK1/2 in the MAPK/ERK cascade, supporting the involvement of both downstream cascades in oral carcinogenesis. Conclusion: This is the first large-scaled study to examine the role of EGFR and its associated downstream molecules in oral carcinogenesis on a high throughput tissue microarray. The results supported its role in oral carcinogenesis with the involvement of both PI3K/Akt and MAPK/ERK cascades. The strong association of p-mTOR and EGFR overexpressions suggested multiple drug targets to the same pathway might be able to reduce toxicity from signal agent.