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Selenoprotein W Inhibits the c‐Met Oncogene by Regulating Receptor Ubiquitination
Author(s) -
Wilcox Christina,
Alkan Zeynep,
Hawkes Wayne
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.752.17
Subject(s) - selenoprotein p , ubiquitin , selenoprotein , chemistry , oncogene , cancer research , receptor , microbiology and biotechnology , biology , biochemistry , cell cycle , oxidative stress , apoptosis , gene , catalase , glutathione peroxidase
Background Hepatocyte Growth Factor Receptor (HGFR), or c‐Met, is the receptor for Hepatocyte Growth Factor (HGF). HGF‐bound c‐Met causes the activation of many important downstream pathways leading to cell proliferation, survival, invasion, differentiation, and migration. Selenoprotein W1 (SEPW1) is a selenium (Se) regulated, small thioredoxin‐like protein required for cell cycle entry in breast and prostate epithelial cells. Se is an essential micronutrient with an involvement in cancer, but the mechanisms of its action are unclear. Low levels of dietary Se can be a risk factor for many cancers including liver cancer. The objective of this study was to investigate the mechanisms by which SEPW1 inhibits the invasive properties of hepatocellular carcinoma in HepG2 cells. Results: Silencing SEPW1 caused an increase in total c‐Met expression, c‐Met located on the plasma membrane, and HGF‐induced c‐Met phosphorylation in HepG2 human hepatocellular carcinoma cells. Consistent with the increase in total c‐Met, HGF‐stimulated ubiquitination of c‐Met was decreased in SEPW1‐depleted HepG2 cells. HGF‐induced migration of HepG2 was assessed by both scratch assay and Boyden chamber assay. Cell migration in HepG2 cells was increased by silencing of SEPW1. Preliminary experiments suggest that SEPW1 silencing also increases invasion in HepG2 cells. These results suggest SEPW1 promotes ubiquitination of c‐Met, which increases c‐Met degradation and decreases c‐Met concentration at the cell surface. Thus, some of Se's cancer preventative effects may be exerted through SEPW1 increasing c‐Met ubiquitination. USDA CRIS Project No. 5306‐51530‐018‐00D. USDA is an equal opportunity employer.