Significance of phospho-c-Met in lymph node metastasis and prognosis of oral squamous cell carcinoma

Abstract

When hepatocyte growth factor (HGF) binds, c-Met undergoes phosphorylation and initiates signal transduction cascades to trigger a variety of cellular responses. HGF/c-Met signaling in cancer has been reported to increase cell survival and stimulate proliferation, scattering, motility, and invasion of carcinoma cells. Although overexpression of HGF or c-Met in oral squamous cell carcinoma (OSCC) and its association with lymph node metastasis or poor prognosis have been reported in several studies, there is a lack of research on phospho-c-Met (p-Met) in OSCC. In the present study, using anti-p-Met (Tyr 1234/1235) antibody, c-Met activation in OSCC was examined to determine the correlations among p-Met, c-Met, and HGF expression. The expression level of p-Met, c-Met and HGF was analyzed with clinicopathological variables including lymph node metastasis and survival. High expression levels of both HGF and c-Met were significantly related with p-Met expression (P<0.001). But there were 36 cases showing p-Met positive when expression of both HGF and c-Met was low and 5 cases showing p-Met negative when expression of both HGF and c-Met was high. Positive p-Met expression was significantly related with cervical lymph node metastasis (P=0.001) and a significant predisposing factor for lymph node metastasis (adjusted odds ratio=2.859; 95% CI, 1.334-6.124; P=0.007). There was no significant difference in survival according to HGF expression level, but the survival rate of low c-Met expression and negative p-Met expression were significantly higher (c-Met, P=0.002; p-Met, P<0.001). According to multivariate Cox regression analysis, p-Met expression, not c-Met expression, was an independent prognostic factor (adjusted hazard ratio=5.884; 95% CI, 3.336-10.379; P<0.001). Our findings demonstrate that HGF or c-Met expression only is not sufficient to examine the invasive feature of carcinoma and to predict the prognosis. Activated-c-Met (phosphorylation of Tyr1234/1235) is a better biomarker to predict invasion, metastasis, and survival in OSCC patients. Therapeutic targeting of the HGF/c-Met pathway may offer new possibilities in the treatment of OSCC patients.