Immunohistochemical assessment of growth factor signaling molecules: MAPK, Akt, and STAT3 pathways in oral epithelial precursor lesions and squamous cell carcinoma

Several growth factors and their receptors, such as epidermal growth factor receptor, have been studied as prognostic biomarkers for many epithelial malignancies. The signal transduction cascade of those receptors includes RAS/RAF/ERK, PI3K/Akt/mTOR, and STAT3 pathways. The aim of this study was to investigate the expression levels of several key proteins of those pathways in patients with oral squamous cell carcinoma (OSCC) and oral epithelial precursor lesions (OEPLs), and to correlate the expressions of these proteins with clinicopathologic features and prognosis. Fifteen leukoplakia (LP), 15 low-grade epithelial dysplasia, 15 high-grade epithelial dysplasia (HD), and 132 OSCC specimens were immunohistochemically examined for KRAS, HRAS, NRAS, BRAF, pERK1/2, pAkt, pmTOR, and pSTAT3 expression. Immunoreactivity for these molecules predominantly occurred in regions OEPL basal to prickle layers and in most OSCC cells. KRAS and NRAS expression was significantly lower in OSCC than in OEPLs, while pAkt and pmTOR showed higher expression in OSCC than in OEPLs. pERK1/2 expression was significantly higher in HD than in LP. In OSCC, KRAS and NRAS immunoreactivity was significantly higher in advanced age and male gender. In addition, higher immunoreactivity was shown in pERK1/2 in female gender and advanced TNM stage, pAkt in advanced T classification and cases without postoperative metastasis, pmTOR in advanced mode of invasion, and pSTAT3 in invasion depth. Correlations between these markers and clinicopathological variables were also noted. MAPK, Akt, and STAT3 pathways might play diverse roles in oral carcinogenesis.