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Met Protein Expression Level Correlates with Survival in Patients with Late-stage Nasopharyngeal Carcinoma

Laboratories of Cancer Genetics [C-N. Q., X. G., J. C., B. T. T.], Monoclonal Antibody Production [B. C.], Analytical, Cellular, and Molecular Microscopy [E. J. K., J. H. R.], and Molecular Oncology [C-C. L., L-M. W., G. F. V. W.], Van Andel Research Institute, Grand Rapids, Michigan 49503; Department of Nasopharyngeal Carcinoma, Cancer Center, Sun Yat-sen University of Medical Sciences, Guangzhou 510060, People’s Republic of China [C-N. Q., X. G., W-Y. M., H-Q. M., M-H. H.]; and Department of Radiology/Radiation Oncology, Baylor College of Medicine, Houston, Texas 77030 [W-Y. M.]

Met tyrosine kinase, the receptor for HGF/SF, is important in various cellular functions, including proliferation, mitogenesis, formation of branching tubules, angiogenesis, and tumor cell invasion and metastasis. However, the role of Met/HGF signaling pathway in nasopharyngeal carcinoma (NPC) has not been evaluated. In this study, we determined the expression profile and clinical correlation of Met/HGF in 66 cases of advanced NPC and the activation mechanisms of Met receptor in five NPC cell lines. Immunofluorescent staining and quantitative image analysis showed that the Met protein was expressed throughout the tumors and normal nasopharyngeal epithelia. Compared with NPC, the Met expression level was higher in columnar nasopharyngeal epithelium but lower in squamous nasopharyngeal epithelium. The normal interstitial stromal tissue expressed the lowest level of Met protein. HGF was detected mainly in the normal interstitial tissue surrounding the tumor. Met protein expression level was inversely correlated with patients’ survival time; the correlation coefficient was -0.319 (P = 0.009). The mean survival time was 118 months in low Met expression group versus 52 months in high expression group (P = 0.0004). The cumulative 5-year survival rate was 77.68% in low expression group versus 38.24% in high expression group. The clinical stage was also significantly more advanced in high Met expression group. In the multivariate analysis, both clinical stage and Met protein expression level were independent prognostic indicators for patient survival. All of the five NPC cell lines tested did not express hgf mRNA but expressed met mRNA, and tyrosine phosphorylation of Met protein was mainly induced by exogenous HGF stimulation in these cells. No mutation was found in the tyrosine kinase and the juxtamembrane domains of Met receptor in the five NPC cell lines tested. These results indicate that: (a) high Met protein expression level correlates with poorer survival in late-stage NPC and serves as an independent prognostic indicator; and (b) the Met receptor in NPC is activated by its paracrine ligand HGF from the interstitial tissues rather than by an autocrine loop or its activating mutation.

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