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

Mukae,Yuta; Miyata,Yasuyoshi; Nakamura,Yuichiro; Araki,Kyohei; Otsubo,Asato; Yuno,Tsutomu; Mitsunari,Kensuke; Matsuo,Tomohiro; Ohba,Kojiro; Sakai,Hideki

doi:10.3892/ol.2020.11540

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

Authors:
- Yuta Mukae
- Yasuyoshi Miyata
- Yuichiro Nakamura
- Kyohei Araki
- Asato Otsubo
- Tsutomu Yuno
- Kensuke Mitsunari
- Tomohiro Matsuo
- Kojiro Ohba
- Hideki Sakai
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Affiliations: Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852‑8501, Japan
Published online on: April 15, 2020 https://doi.org/10.3892/ol.2020.11540
Pages: 135-144
Copyright: © Mukae et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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