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LRIG1 modulates aggressiveness of head and neck cancers by regulating EGFR-MAPK-SPHK1 signaling and extracellular matrix remodeling

Oncogene volume 33, pages 1375–1384 (2014)Cite this article

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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.

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Acknowledgements

We thank Dr Mien-Chie Hung (MD Anderson Cancer Center, TX, USA) and Dr Yosef Yarden (Weizmann Institute, Israel) for their critical comments on this study, which was supported by grants from the National Science Council, Taiwan (NSC99-2320-B-400-009, NSC100-2325-B-400-014, NSC101-2320-B-039-006 and NSC101-2320-B-039-006), the National Health Research Institutes, Taiwan (CA-101-PP-01), China Medical University Hospital, Taiwan (DMR99-047), and the Department of Health, Taiwan (DOH101-TD-C-111-004 and DOH101-TD-C-111-005).

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Authors and Affiliations

  1. Human Genetic Center, China Medical University Hospital, Taichung, Taiwan

    J J-C Sheu, J Cheng, C-M Chen, C Chan & S C-C Chao

  2. School of Chinese Medicine, China Medical University, Taichung, Taiwan

    J J-C Sheu

  3. Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan

    J J-C Sheu

  4. National Institute of Cancer Research, National Health Research Institutes, Zhunan Town, Taiwan

    C-C Lee, C-I Li, J-Y Chen, J-Y Chang & C-H Lee

  5. Department of Otolaryngology, China Medical University Hospital, Taichung, Taiwan

    C-H Hua

  6. Department of Pathology, Chung Shan Medical University Hospital, Taichung, Taiwan

    M-T Lai

  7. School of Medicine, Chung Shan Medical University, Taichung, Taiwan

    M-T Lai

  8. College of Medical Science and Technology, Chung Shan Medical University, Taichung, Taiwan

    S-C Lee

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Sheu, JC., Lee, CC., Hua, CH. et al. LRIG1 modulates aggressiveness of head and neck cancers by regulating EGFR-MAPK-SPHK1 signaling and extracellular matrix remodeling. Oncogene 33, 1375–1384 (2014). https://doi.org/10.1038/onc.2013.98

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