Pathological roles of c-Met in bladder cancer: Association with cyclooxygenase-2, heme oxygenase-1, vascular endothelial growth factor-A and programmed death ligand 1

c-Met is a receptor tyrosine kinase that binds a specific ligand, namely hepatocyte growth factor (HGF). The HGF/c-Met system is important for malignant aggressiveness in various types of cancer, including bladder cancer (BC). However, although phosphorylation is the essential step required for biological activation of c-Met, pathological roles of phosphorylated c-Met at the clinical and molecular levels in patients with BC are not fully understood. In the present study, the expression levels of c-Met and the phosphorylation of two of its tyrosine residues (pY1234/pY1235 and pY1349) were immunohistochemically examined in 185 BC tissues. The associations between these expression levels and cancer cell invasion, metastasis, and cyclooxygenase-2 (COX-2), heme oxygenase-1 (HO-1), VEGF-A and programmed death ligand 1 (PD-L1) levels were investigated. c-Met was associated with muscle invasion (P=0.021), as well as the expression levels of HO-1 (P=0.028) and PD-L1 (P<0.001), whereas pY1349 c-Met was associated with muscle invasion (P=0.003), metastasis (P=0.025), and COX-2 (P=0.017), HO-1 (P=0.031) and PD-L1 (P=0.001) expression. By contrast, pY1234/1235 c-Met was associated with muscle invasion and metastasis (P=0.006 and P=0.012, respectively), but not with the panel of cancer-associated molecules. Furthermore, COX-2 and PD-L1 expression were associated with muscle invasion and metastasis, respectively (P=0.045 and P=0.036, respectively). Hence, c-Met serves important roles in muscle invasion by regulating HO-1 and PD-L1, whereas its phosphorylation at Y1349 is associated with muscle invasion and metastasis via the regulation of COX-2, HO-1 and PD-L1 in patients with BC. Furthermore, phosphorylation at Y1234/1235 may lead to muscle invasion and metastasis via alternate mechanisms associated with c-Met and pY1349 c-Met.