Presence of Phosphorylated Hepatocyte Growth Factor Receptor/c-Met Is Associated with Tumor Progression and Survival in Patients with Conventional Renal Cell Carcinoma

Abstract

Hepatocyte growth factor receptor (HGFR/c-Met) signaling is associated with tumor progression in various cancers. The clinical significance and pathologic roles of phosphorylated HGFR/c-Met in renal cell carcinoma (RCC) are not fully understood; therefore, this study sought to clarify the possible role of two tyrosine residues (pY1234/pY1235 and pY1349) in HGFR/c-Met. The kinetics of tyrosine phosphorylation at these two residues was examined in a human renal carcinoma cell line, ACHN cells. In addition, phosphorylated HGFR/c-Met expression (using phosphorylation site-specific antibodies for pY1234/pY1235 and pY1349) was examined in 114 tumor sections of conventional RCC patients by immunohistochemistry. The relationships between these expressions and clinicopathologic features and survival were also investigated. Although phosphorylation of Y1349 HGFR/c-Met was observed for 120 minutes after HGF treatment of ACHN cells, maximal phosphorylation of Y1234/Y1235 was observed at 30 minutes followed by a rapid inactivation. Median rates (range) of cancer cells immunopositive for pY1234/pY1235 HGFR/c-Met and pY1349 HGFR/c-Met in the tumor sections were 0% (0-5.2%) and 14.3% (0-64.3%), respectively. Positive expression of pY1349 HGFR/c-Met was significantly associated with high pT stage, presence of metastasis, and high-grade carcinoma. Multivariate Cox analysis revealed that the positive expression of pY1349 HGFR/c-Met was a significant and an independent predictor of cause-specific survival (odds ratio, 2.94; 95% confidence interval, 1.12-7.72; P = 0.028). Phosphorylated HGFR/c-Met may be important in the tumor progression of RCC. Expression of pY1349 HGFR/c-Met is a useful predictor for metastasis and survival of conventional RCC patients.