Journal
BRITISH JOURNAL OF CANCER
Volume 120, Issue 5, Pages 499-511Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41416-019-0400-2
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Funding
- Taiwan National Science Council [NSC 100-2628-B-002-004-MY4]
- Ministry of Science and Technology [MOST 104-2320-B-002-044-MY3, MOST 105-2911-I-002-521, MOST 106-2320-B-002-046-MY3]
- National Health Research Institutes Grant [NHRI-EX99-9909BC, NHRI-EX104-10401BI, NHRI-EX107-10725BI]
- National Taiwan University [NTU-CESRP-104R7602C4, NTU105R89612, NTU107L890504]
- Agricultural Biotechnology Research Center (ABRC) at Academia Sinica
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BACKGROUND: Dysregulation of pericellular proteolysis usually accounts for cancer cell invasion and metastasis. Isolation of a cell-surface protease system for lung cancer metastasis is an important issue for mechanistic studies and therapeutic target identification. METHODS: Immunohistochemistry of a tissue array (n = 64) and TCGA database (n = 255) were employed to assess the correlation between serine protease inhibitors (SPIs) and lung adenocarcinoma progression. The role of SPI in cell motility was examined using transwell assays. Pulldown and LC/MS/MS were performed to identify the SPI-modulated novel protease(s). A xenografted mouse model was harnessed to demonstrate the role of the SPI in lung cancer metastasis. RESULTS: Hepatocyte growth factor activator inhibitor-2 (HAI-2) was identified to be downregulated following lung cancer progression, which was related to poor survival and tumour invasion. We further isolated a serum-derived serine protease, plasmin, to be a novel target of HAI-2. Downregulation of HAI-2 promotes cell surface plasmin activity, EMT, and cell motility. HAI-2 can suppress plasmin-mediated activations of HGF and TGF-beta 1, EMT and cell invasion. In addition, downregulated HAI-2 increased metastasis of lung adenocarcinoma via upregulating plasmin activity. CONCLUSION: HAI-2 functions as a novel inhibitor of plasmin to suppress lung cancer cell motility, EMT and metastasis.
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