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

Hepatocyte growth factor (HGF) plays an important role in cancer progression via phosphorylation of MET (c-met proto-oncogene product, receptor of HGF). HGF-zymogen (pro-HGF) must be processed for activation by HGF activators including matriptase, which is a type II transmembrane serine protease and the most efficient activator. The enzymatic activity is tightly regulated by HGF activator inhibitors (HAIs). Dysregulated pro-HGF activation (with upregulated MET phosphorylation) is reported to promote cancer progression in various cancers. We retrospectively analyzed the expression of matriptase, phosphorylated-MET (phospho-MET) and HAI-1 in tumor specimens obtained from patients with invasive bladder cancer by immunohistochemistry. High expression of phospho-MET and increased expression of matriptase were significantly associated with poor prognosis, and high matriptase/low HAI-1 expression showed poorer prognosis. Furthermore, high expression of matriptase tended to correlate with phosphorylation of MET. Increased expression of matriptase may induce the ligand-dependent activation of MET, which leads to poor prognosis in patients with invasive bladder cancer.

• Publication year

  2018

• Venue

  International Journal of Molecular Sciences

• Publication date

  2018-11-22

• Fields of study

  Medicine

• Identifiers
  DOI 10.3390/ijms19123708PMID 30469509PMCID 6321379
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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• Matriptase and MET are prominently expressed at the site of bone metastasis in renal cell carcinoma: immunohistochemical analysis

  2014cited by this paper
• Hepatocyte growth factor activator inhibitor type‑1 in cancer: advances and perspectives (Review).

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• Expression of hepatocyte growth factor activator inhibitor-1 (HAI-1) gene in prostate cancer: clinical and biological significance.

  2014cited by this paper
• Microenvironment-derived HGF overcomes genetically determined sensitivity to anti-MET drugs.

  2014cited by this paper
• Overexpression of matriptase correlates with poor prognosis in esophageal squamous cell carcinoma

  2013cited by this paper
• Epidemiology and risk factors of urothelial bladder cancer.

  2013cited by this paper
• Acquired resistance mechanisms to tyrosine kinase inhibitors in lung cancer with activating epidermal growth factor receptor mutation—diversity, ductility, and destiny

  2012influential reference
• Strong expression association between matriptase and its substrate prostasin in breast cancer

  2012cited by this paper
• Differential Tumorigenic Potential and Matriptase Activation between PDGF B versus PDGF D in Prostate Cancer

  2012cited by this paper
• A direct role for Met endocytosis in tumorigenesis

  2011cited by this paper
• c-Met-induced epithelial carcinogenesis is initiated by the serine protease matriptase

  2010cited by this paper
• MET signalling: principles and functions in development, organ regeneration and cancer

  2010influential reference
• Expression of hepatocyte growth factor activator inhibitors (HAI-1 and HAI-2) in ovarian cancer.

  2009cited by this paper
• Phosphorylated hepatocyte growth factor receptor/c-Met is associated with tumor growth and prognosis in patients with bladder cancer: correlation with matrix metalloproteinase-2 and -7 and E-cadherin.

  2009cited by this paper
• Role of matriptase and proteinase-activated receptor-2 in nonmelanoma skin cancer.

  2009cited by this paper
• Drug development of MET inhibitors: targeting oncogene addiction and expedience

  2008cited by this paper
• Roles of Functional and Structural Domains of Hepatocyte Growth Factor Activator Inhibitor Type 1 in the Inhibition of Matriptase*

  2008cited by this paper
• The global burden of urinary bladder cancer

  2008cited by this paper
• Type II transmembrane serine proteases in development and disease.

  2008influential reference
• Clinical relevance of hepsin and hepatocyte growth factor activator inhibitor type 2 expression in renal cell carcinoma

  2007cited by this paper
• Nonurothelial cancer of the bladder.

  2007cited by this paper
• The MET receptor tyrosine kinase in invasion and metastasis

  2007influential reference
• Matriptase: Potent Proteolysis on the Cell Surface

  2006cited by this paper
• Hepatocyte growth factor activation inhibitors (HAI‐1 and HAI‐2) regulate HGF‐induced invasion of human breast cancer cells

  2006cited by this paper
• Increased expression of matriptase is associated with histopathologic grades of cervical neoplasia.

  2005cited by this paper
• Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration.

  2005cited by this paper
• Neoadjuvant Chemotherapy in Invasive Bladder Cancer: Update of a Systematic Review and Meta-Analysis of Individual Patient Data: Advanced Bladder Cancer (ABC) Meta-analysis Collaboration

  2005cited by this paper
• Deregulated activation of matriptase in breast cancer cells

  2004cited by this paper
• Roles of hepatocyte growth factor (HGF) activator and HGF activator inhibitor in the pericellular activation of HGF/scatter factor

  2003cited by this paper
• Expression of the serine protease matriptase and its inhibitor HAI-1 in epithelial ovarian cancer: correlation with clinical outcome and tumor clinicopathological parameters.

  2002cited by this paper
• Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients.

  2001cited by this paper
• Characterization of a Novel, Membrane-bound, 80-kDa Matrix-degrading Protease from Human Breast Cancer Cells

  1997cited by this paper
• Hepatocyte Growth Factor Activator Inhibitor, a Novel Kunitz-type Serine Protease Inhibitor*

  1997cited by this paper
• Hepatocyte growth factor as mitogen, motogen and morphogen, and its roles in organ regeneration.

  1994cited by this paper
• Results of contemporary radical cystectomy for invasive bladder cancer: a clinicopathological study with an emphasis on the inadequacy of the tumor, nodes and metastases classification.

  1991cited by this paper

• Membrane-Anchored Serine Protease Inhibitors: Physiological Functions, Mechanisms, and Roles in Cancer.

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• Usability Evaluation of Urinary HAI-1, STMN-1 and TN-C in the Diagnosis of Bladder Cancer

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• Phosphorylation of MET Is Upregulated in Metastatic Sites of Renal Cell Carcinoma: Possible Role of MET and Hepatocyte Growth Factor Activation-Targeted Combined Therapy

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• Engineered Expression of Hepatocyte Growth Factor Activator Inhibitor-1 (HAI-1) Reduces the Growth of Bladder Cancer Cells

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

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• c-Met: A Promising Therapeutic Target in Bladder Cancer

  2022cites this paper
• The serine protease matriptase inhibits migration and proliferation in multiple myeloma cells

  2022cites this paper
• Identification and validation of a novel signature for prediction the prognosis and immunotherapy benefit in bladder cancer

  2022cites this paper
• Novel Tyrosine Kinase Targets in Urothelial Carcinoma

  2021cites this paper
• 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

  2020cites this paper
• cMET promotes metastasis and epithelial‐mesenchymal transition in colorectal carcinoma by repressing RKIP

  2020cites this paper
• Dysregulation of Type II Transmembrane Serine Proteases and Ligand-Dependent Activation of MET in Urological Cancers

  2020influential citation
• Identifying the mRNAs associated with Bladder cancer recurrence

  2020cites this paper
• A novel cell-free single-molecule unique primer extension resequencing (cf-SUPER) technology for bladder cancer non-invasive detection in urine

  2020cites this paper
• Clinicopathological impacts of c-Met overexpression in bladder cancer: evidence from 1,336 cases

  2019cites this paper
• Clinicopathological impacts of c-Met overexpression in bladder cancer: evidence from 1,336 cases

  2019cites this paper
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  2019cites this paper