title: CCL19-induced chemokine receptor 7 activates the phosphoinositide-3 kinase-mediated invasive pathway through Cdc42 in metastatic squamous cell carcinoma of the head and neck.
abstract: Metastatic squamous cell carcinoma of the head and neck (SCCHN) has been shown to express chemokine receptor 7 (CCR7), which activates phosphoinositide-3 kinase (PI3K) to promote invasion and survival of SCCHN cells. We hypothesized that Cdc42 might be involved in the CCR7-PI3K pathway. Adhesion assays, migration assays, immunofluorescence staining, Western blotting and immunohistochemical analysis were used to find whether Cdc42 can be activated by CCL19 (the CCR7 ligand) and its role in SCCHN. Results showed that CCL19 induced polarized localization of Cdc42 and actin polymerization in the leading edge of migrating cells. The level of activated membrane-bound Cdc42 was elevated, as measured by the GTPase activity pull-down assay. The increased membrane localization and membrane-bound activity of Cdc42 were abolished by CCR7 and PI3K inhibition, indicating the involvement of Cdc42 in the CCR7-PI3K cascade. Knockdown of Cdc42 by small interfering RNA (siRNA) led to significant reduction in the activation of Rac, filamentous actin (F-actin) accumulation as well as in the migration and invasion induced by CCL19. Taken together, our data indicate the important role played by Cdc42 in CCL19-induced migration and invasion of SCCHN cells.
authors.affiliation: Department of Orthodontics, School of Stomatology, China Medical University, No. 117. Nanjing Bei Street, Heping District, Shenyang, Liaoning 110002, PR China.
authors.forename: Zhen-Jin
authors.initials: ZJ
authors.lastname: Zhao
authors.forename: Fa-Yu
authors.initials: FY
authors.lastname: Liu
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Xue
authors.initials: X
authors.lastname: Ding
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Zong
authors.forename: Chang-Fu
authors.initials: CF
authors.lastname: Sun
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D054415:Chemokine CCL19 / Q000378:metabolism / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D018307:Neoplasms, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D054400:Receptors, CCR7 / Q000819:agonists* / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D000077195:Squamous Cell Carcinoma of Head and Neck; D014407:Tumor Cells, Cultured; D020764:cdc42 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C515370:CCR7 protein, human; D054415:Chemokine CCL19; D034741:RNA, Small Interfering; D054400:Receptors, CCR7; D019869:Phosphatidylinositol 3-Kinases; D020764:cdc42 GTP-Binding Protein