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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Background and Purpose-Stroke, a major health issue affecting the elderly, limits their participation in society. The aim of this study was to investigate changes in stroke survivors' handicap levels and to identify their determinants in the subacute phase from 3 months to 1 year. Methods-Data were collected from a prospective cohort of 303 Chinese stroke survivors with the use of questionnaires, including the Lawton Instrumental Activities of Daily Living-Chinese Version (IADL-CV), Barthel Index, Chinese Mini-Mental State Examination, Chinese Geriatric Depression Scale, and the Chinese version of the London Handicap Scale. Results-A total of 297 and 268 patients were successfully followed up at 6 and 12 months, respectively. Whereas IADL remained unchanged throughout, we found an improvement in Barthel Index but a deterioration in the Chinese Geriatric Depression Scale score at 12 months. Multilevel modeling revealed improvements in the mobility and social integration handicap domains and a deterioration in the orientation domain at 12 months. Overall handicap remained unchanged. At 12 months, depression was most significantly and independently associated with poststroke handicap, and advanced old age alone (Ͼ80 years) was associated with clinically significant deterioration in handicap. Conclusions-Even though IADL remained static at 1 year, mobility and social integration handicap dimensions can be improved in the early community phase after stroke. Nonphysical factors such as depression were confirmed to be significantly associated with handicap. Rehabilitation should target the high-risk group of very elderly stroke survivors who were 4 times more likely to deteriorate in handicap. (Stroke. 2008;39:148-153.)