title: Tyrosine 397 phosphorylation is critical for FAK-promoted Rac1 activation and invasive properties in oral squamous cell carcinoma cells.
abstract: Oral squamous cell carcinoma (OSCC) is a common cancer worldwide. Despite advances in diagnosis and therapy, treatment options for patients with metastatic OSCC are few, due in part to the limited understanding of the molecular events involved in the invasion and metastasis of OSCC. In this study, we investigated the expression of focal adhesion kinase (FAK) and its tyrosine 397 phosphorylation (pY397) in the tissue specimens of OSCC. The roles of pY397 in regulating the activities of Rac1 and cortactin and the invasive properties of OSCC cells were further determined. Results from immunohistochemical analyses in 9 benign, 19 premalignant, and 19 malignant oral tissues showed that the immunoreactivity of FAK was observed in 5 benign (56%), 19 premalignant (100%), and 18 malignant tissues (95%), whereas the immunoreactivity of pY397 was only found in 1 of 9 (11%) benign lesions but was observed in 9 premalignant (47%) and 12 malignant (63%) lesions. Compared with the low-invading SCC4 cells, the high-invading OECM-1 cells exhibited higher levels of FAK expression and pY397, correlating with higher levels of GTP-bound Rac1 and cortactin phosphorylation. Manipulation of FAK expression or Y397 phosphorylation in SCC4, FaDu, OECM-1, or HSC-3 cells regulated their Rac1 activities and invasive properties. Furthermore, treatment of NSC23766, a Rac1-specific inhibitor, in OECM-1 and HSC-3 cells led to reduced invasive properties. Nevertheless, knockdown of FAK expression or suppression of pY397 had no effect on the cortactin activity in OECM-1 cells. The data collectively suggest that pY397 plays critical roles in the FAK-promoted Rac1 activation and invasive properties in OSCC cells. Thus, the inhibition of FAK phosphorylation at Y397 or Rac1 activity can serve as a therapeutic strategy for treating patients with metastatic OSCC.
authors.affiliation: Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, Republic of China.
authors.forename: Ya-Wen
authors.initials: YW
authors.lastname: Chiu
authors.affiliation: Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, Republic of China.
authors.forename: Li-Yin
authors.initials: LY
authors.lastname: Liou
authors.affiliation: Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, Republic of China.
authors.forename: Pin-Ting
authors.initials: PT
authors.lastname: Chen
authors.affiliation: Department of Pathology, National Dong Hwa University, Hualien, Taiwan, Republic of China.
authors.forename: Chieh-Ming
authors.initials: CM
authors.lastname: Huang
authors.affiliation: Department of Pathology, National Dong Hwa University, Hualien, Taiwan, Republic of China.
authors.forename: Fuh-Jinn
authors.initials: FJ
authors.lastname: Luo
authors.affiliation: Department of Dentistry, Mennonite Christian Hospital, Hualien, Taiwan, Republic of China.
authors.forename: Yu-Kan
authors.initials: YK
authors.lastname: Hsu
authors.affiliation: Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, Republic of China.
authors.forename: Ta-Chun
authors.identifier: http://orcid.org/0000-0003-2759-4809
authors.initials: TC
authors.lastname: Yuan
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D051356:Cortactin / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000502:physiology*; D006801:Humans; D009062:Mouth Neoplasms / Q000473:pathology*; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D011230:Precancerous Conditions / Q000473:pathology*; D014443:Tyrosine / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000502:physiology*
chemical_list: C495868:CTTN protein, human; D051356:Cortactin; C107953:RAC1 protein, human; D014443:Tyrosine; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020830:rac1 GTP-Binding Protein