期刊
ONCOGENE
卷 33, 期 11, 页码 1375-1384出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2013.98
关键词
LRIG1; head and neck cancers; EGFR; MAPK; SPHK1; ECM remodeling
资金
- National Science Council, Taiwan [NSC99-2320-B-400-009, NSC100-2325-B-400-014, NSC101-2320-B-039-006]
- National Health Research Institutes, Taiwan [CA-101-PP-01]
- China Medical University Hospital, Taiwan [DMR99-047]
- Department of Health, Taiwan [DOH101-TD-C-111-004, DOH101-TD-C-111-005]
EGFR overexpression and chromosome 3p deletion are two frequent events in head and neck cancers. We previously mapped the smallest region of recurrent copy-number loss at 3p12.2-p14.1. LRIG1, a negative regulator of EGFR, was found at 3p14, and its copy-number loss correlated with poor clinical outcome. Inducible expression of LRIG1 in head and neck cancer TW01 cells, a line with low LRIG1 levels, suppressed cell proliferation in vitro and tumor growth in vivo. Gene expression profiling, quantitative RT-PCR, chromatin immunoprecipitation, and western blot analysis demonstrated that LRIG1 modulated extracellular matrix (ECM) remodeling and EGFR-MAPK-SPHK1 transduction pathway by suppressing expression of EGFR ligands/activators, MMPs and SPHK1. In addition, LRIG1 induction triggered cell morphology changes and integrin inactivation, which coupled with reduced SNAI2 expression. By contrast, knockdown of endogenous LRIG1 in TW06 cells, a line with normal LRIG1 levels, significantly enhanced cell proliferation, migration and invasiveness. Such tumor-promoting effects could be abolished by specific MAPK or SPHK1 inhibitors. Our data suggest LRIG1 as a tumor suppressor for head and neck cancers; LRIG1 downregulation in cancer cells enhances EGFR-MAPK-SPHK1 signaling and ECM remodeling activity, leading to malignant phenotypes of head and neck cancers.
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