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

Abstract

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.

Macrophage Gal/GalNAc lectin 2 (MGL2)+ peritoneal antigen presenting cells during Fasciola hepatica infection are essential for regulatory T cell induction

“…In F. hepatica infection it induces production of IL-10 which is necessary for parasite establishment in the host 51 . Of note, hepatocyte growth factor receptor induces Ras-dependent upregulation of both HO-1 and PD-L1 in cancer 56 , 57 . In addition, myeloid cells expressing both HO-1 and PD-L1 in breast tumors suppress T cell activity 58 .…”

c-Met: A Promising Therapeutic Target in Bladder Cancer

“…47 Their subsequent studies suggested that two c-Met tyrosine residues, pY1234/pY1235 and pY1349, were related to muscular infiltration and metastasis, while c-Met itself was only significantly associated with muscular infiltration. 48 In contrast, Iyer et al found a nonsignificant association between HGF/c-Met immunoreactivity and tumour stage, grade and overall patient survival. 34 In parallel, Yeh et al found that c-Met expression did not correlate with tumour grade or lymph node involvement.…”

“…Furthermore, they demonstrated possible links between pY1349 c-Met and cancer-related substances such as cyclooxygenase-2 (COX-2), haem oxygenase-1 (HO-1) and programmed death ligand 1 (PD-L1). 48 Intriguingly, the upstream mediator of pY1349 c-Met might be SRY-box 18 (SOX18), which was proven to promote carcinogenesis and progression of BCa. In such a study, Huaqi et al observed an augmented level of phosphorylated pY1349 c-Met in SOX18-elevated BCa cells, and after applying cabozantinib, a c-Met suppressor, the migration capability of SOX18-elevated BCa cells was dramatically compromised.…”

Targeting c-Met in the treatment of urologic neoplasms: Current status and challenges

“…In addition, the correlation between c-Met and programmed death ligand 1 (PD-L1) in tumor tissues was investigated. Y. Mukae et al (38) demonstrated that the high expression of c-Met was correlated with muscle invasion and metastasis of BCa, and c-Met exerted a vital function in invasion of tumor cell by regulating PD-L1. This study shows that c-Met is indeed involved in the invasion and metastasis of BCa, which again theoretically confirms that c-Met may affect the prognosis and survival of BCa patients.…”