title: LRIG1 modulates aggressiveness of head and neck cancers by regulating EGFR-MAPK-SPHK1 signaling and extracellular matrix remodeling.
abstract: 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.
authors.affiliation: 1] Human Genetic Center, China Medical University Hospital, Taichung, Taiwan [2] School of Chinese Medicine, China Medical University, Taichung, Taiwan [3] Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: J J-C
authors.initials: JJ
authors.lastname: Sheu
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Zhunan Town, Taiwan.
authors.forename: C-C
authors.initials: CC
authors.lastname: Lee
authors.affiliation: Department of Otolaryngology, China Medical University Hospital, Taichung, Taiwan.
authors.forename: C-H
authors.initials: CH
authors.lastname: Hua
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Zhunan Town, Taiwan.
authors.forename: C-I
authors.initials: CI
authors.lastname: Li
authors.affiliation: 1] Department of Pathology, Chung Shan Medical University Hospital, Taichung, Taiwan [2] School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: M-T
authors.initials: MT
authors.lastname: Lai
authors.affiliation: College of Medical Science and Technology, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: S-C
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Human Genetic Center, China Medical University Hospital, Taichung, Taiwan.
authors.forename: J
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Human Genetic Center, China Medical University Hospital, Taichung, Taiwan.
authors.forename: C-M
authors.initials: CM
authors.lastname: Chen
authors.affiliation: Human Genetic Center, China Medical University Hospital, Taichung, Taiwan.
authors.forename: C
authors.initials: C
authors.lastname: Chan
authors.affiliation: Human Genetic Center, China Medical University Hospital, Taichung, Taiwan.
authors.forename: S C-C
authors.initials: SC
authors.lastname: Chao
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Zhunan Town, Taiwan.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Chen
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Zhunan Town, Taiwan.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Chang
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Zhunan Town, Taiwan.
authors.forename: C-H
authors.initials: CH
authors.lastname: Lee
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D015536:Down-Regulation; D066246:ErbB Receptors / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C484445:LRIG1 protein, human; D008562:Membrane Glycoproteins; C466999:SPHKAP protein, human; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases