Matriptase-Induced Phosphorylation of MET is Significantly Associated with Poor Prognosis in Invasive Bladder Cancer; an Immunohistochemical Analysis

Yamasaki, Koji; Mukai, Shoichiro; Nagai, Takahiro; Nakahara, Kozue; Fujisawa, Masato; Terada, Naoki; Ohno, Akinobu; Sato, Yuichiro; Toda, Yoshinobu; Kataoka, Hiroaki

doi:10.3390/ijms19123708

Cited by 15 publications

(15 citation statements)

References 39 publications

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“…Increased phosphorylation of Tyr1234/1235 (at activation loop) and Tyr1349 (at multi-docking site) was positively correlated with pT stage, and multivariate analysis prompted the authors to conclude that phosphorylated Tyr1349 was a significant predictive factor of pT stage only. In addition, phosphorylated Tyr1349 was correlated with expression of matrix metalloprotease (MMP)-2, MMP-7, and E-cadherin [98]. Furthermore, the relationship between increased phosphorylation of Tyr 1235 in MET and worse cancer-specific survival in patients with muscle invasive bladder cancer (MIBC) was reported by Yamasaki et al In this study, increased expression of matriptase and decreased expression of HAI-1 were also correlated with poor prognosis [99].…”

Section: Significance Of Hgf-dependent Met Activation In Muscle Invassupporting

confidence: 60%

“…In addition, phosphorylated Tyr1349 was correlated with expression of matrix metalloprotease (MMP)-2, MMP-7, and E-cadherin [97]. Furthermore, the relationship between increased phosphorylation of Tyr 1235 in MET and worse cancer-specific survival in patients with muscle invasive bladder cancer (MIBC) was reported by Yamasaki et al In this study, increased expression of matriptase and decreased expression of HAI-1 were also correlated with poor prognosis [98]. Interestingly, the area of HAI expression and MET phosphorylation presented reciprocally in spite of the strong expression of both total MET and matriptase ( Figure 6b) [98].…”

Section: Significance Of Hgf-dependent Met Activation In Muscle Invassupporting

confidence: 59%

“…Pathological analysis shows that approximately 90% of bladder cancers are UC and that 5% are squamous cell carcinoma [95]. Several studies reported a positive correlation between increased expression of MET and high tumor grade, pathological staging, and survival [96][97][98][99][100]. Phosphorylation was also analyzed by immunohistochemistry [97,98].…”

Section: Significance Of Hgf-dependent Met Activation In Muscle Invasmentioning

confidence: 99%

“…Several studies reported a positive correlation between increased expression of MET and high tumor grade, pathological staging, and survival [96][97][98][99][100]. Phosphorylation was also analyzed by immunohistochemistry [97,98]. Increased phosphorylation of Tyr1234/1235 (at activation loop) and Tyr1349 (at multi-docking site) was positively correlated with pT stage, and multivariate analysis prompted the authors to conclude that phosphorylated Tyr1349 was a significant predictive factor of pT stage only.…”

Section: Significance Of Hgf-dependent Met Activation In Muscle Invasmentioning

confidence: 99%

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Dysregulation of Type II Transmembrane Serine Proteases and Ligand-Dependent Activation of MET in Urological Cancers

Mukai

Yamasaki

Fujisawa

et al. 2020

IJMS

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Unlike in normal epithelium, dysregulated overactivation of various proteases have been reported in cancers. Degradation of pericancerous extracellular matrix leading to cancer cell invasion by matrix metalloproteases is well known evidence. On the other hand, several cell-surface proteases, including type II transmembrane serine proteases (TTSPs), also induce progression through activation of growth factors, protease activating receptors and other proteases. Hepatocyte growth factor (HGF) known as a multifunctional growth factor that upregulates cancer cell motility, invasiveness, proliferative, and anti-apoptotic activities through phosphorylation of MET (a specific receptor of HGF). HGF secreted as inactive zymogen (pro-HGF) from cancer associated stromal fibroblasts, and the proteolytic activation by several TTSPs including matriptase and hepsin is required. The activation is strictly regulated by HGF activator inhibitors (HAIs) in physiological condition. However, downregulation is frequently observed in cancers. Indeed, overactivation of MET by upregulation of matriptase and hepsin accompanied by the downregulation of HAIs in urological cancers (prostate cancer, renal cell carcinoma, and bladder cancer) are also reported, a phenomenon observed in cancer cells with malignant phenotype, and correlated with poor prognosis. In this review, we summarized current reports focusing on TTSPs, HAIs, and MET signaling axis in urological cancers.

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Section: Significance Of Hgf-dependent Met Activation In Muscle Invassupporting

confidence: 60%

Section: Significance Of Hgf-dependent Met Activation In Muscle Invassupporting

confidence: 59%

Section: Significance Of Hgf-dependent Met Activation In Muscle Invasmentioning

confidence: 99%

Section: Significance Of Hgf-dependent Met Activation In Muscle Invasmentioning

confidence: 99%

See 2 more Smart Citations

Dysregulation of Type II Transmembrane Serine Proteases and Ligand-Dependent Activation of MET in Urological Cancers

Mukai

Yamasaki

Fujisawa

et al. 2020

IJMS

Self Cite

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show abstract

“…With respect to the pathological significance of c-Met phosphorylation in cancers, a previous report demonstrated that the expression of phospho-c-Met (Y1349), termed pY1349 c-Met, is positively associated with cancer growth, progression, and poor survival in patients with RCC (18). Likewise, one report indicated that high pY1235 c-Met expression is associated with an increased risk of recurrence for ovarian cancer patients (24); meanwhile, in patients with BC, several reports have shown that phosphorylated c-Met leads to highly malignant disease and poor survival (25,26). However, the precise pathological significance of phosphorylated c-Met in BC is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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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cMET promotes metastasis and epithelial‐mesenchymal transition in colorectal carcinoma by repressing RKIP

Wang

Yan

et al. 2020

Journal Cellular Physiology

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Increasing evidence indicates that c‐mesenchymal‐epithelial transition factor (cMET) plays an important role in the malignant progression of colorectal cancer (CRC). However, the underlying mechanism is not fully understood. As a metastasis suppressor, raf kinase inhibitory protein (RKIP) loss has been reported in many cancer types. In this study, the expression levels of cMET and RKIP in CRC tissues and cell lines were determined, and their crosstalk and potential biological effects were explored in vitro and in vivo. Our results showed that cMET was inversely correlated with RKIP. Both cMET upregulation and RKIP downregulation indicated poor clinical outcomes. Moreover, the MAPK/ERK signaling pathway was implicated in the regulation of cMET and RKIP. Overexpression of cMET promoted tumor cell epithelial‐mesenchymal transition, invasion, migration, and chemoresistance, whereas the effects could be efficiently inhibited by increased RKIP. Notably, small hairpin RNA‐mediated cMET knockdown dramatically suppressed cell proliferation, although no RKIP‐induced influence on cell growth was observed in CRC. Altogether, cMET overexpression may contribute to tumor progression by inhibiting the antioncogene RKIP, providing preclinical justification for targeting RKIP to treat cMET‐induced metastasis of CRC.

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Matriptase-Induced Phosphorylation of MET is Significantly Associated with Poor Prognosis in Invasive Bladder Cancer; an Immunohistochemical Analysis

Cited by 15 publications

References 39 publications

Dysregulation of Type II Transmembrane Serine Proteases and Ligand-Dependent Activation of MET in Urological Cancers

Dysregulation of Type II Transmembrane Serine Proteases and Ligand-Dependent Activation of MET in Urological Cancers

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

cMET promotes metastasis and epithelial‐mesenchymal transition in colorectal carcinoma by repressing RKIP

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