Involvement of focal adhesion kinase in cellular invasion of head and neck squamous cell carcinomas via regulation of MMP-2 expression

Abstract

Focal adhesion kinase (FAK) is considered intimately involved in cancer progression. Our previous research has demonstrated that overexpression of FAK is an early and frequent event in squamous cell carcinomas of the supraglottic larynx, and it is associated with the presence of metastases in cervical lymph nodes. The purpose of this study was to examine the functional role of FAK in the progression of head and neck squamous cell carcinomas (HNSCC). To this end, expression of FAK-related nonkinase (FRNK) or small interfering RNA (siRNA) against FAK was used to disrupt the FAK-induced signal transduction pathways in the HNSCC-derived SCC40 and SCC38 cell lines. Similar phenotypic effects were observed with the two methodological approaches in both cell lines. Decreased cell attachment, motility and invasion were induced by FRNK and FAK siRNA, whereas cell proliferation was not impaired. In addition, increased cell invasion was observed upon FAK overexpression in SCC cells. FRNK expression resulted in a downregulation of MMP-2 and MMP-9 expression. Interestingly, MMP-2 overexpression in FRNK-expressing cells rescued FRNK inhibition of cell invasion. This is the first demonstration of a direct rescue of impaired cell invasion by the re-expression of MMP-2 in a tumour cell type with decreased expression of functional FAK. Collectively, these data reported here support the conclusion that FAK enhances invasion of HNSCC by promoting both increased cell motility and MMP-2 production, thus providing new insights into possible therapeutic intervention strategies. Head and neck squamous cell carcinoma (HNSCC) is one of the most common types of human cancer, comprising B50% of all malignancies in some developing nations. HNSCC is associated with severe disease-and treatment-related morbidity and has a 5-year survival rate of B50%. This survival rate has remained largely unchanged in the past three decades (Sankaranarayanan et al, 1998;Gonzalez-Botas and Vazquez Barro, 2006). A major determinant of the lethal progression of HNSCC is the spreading of the malignant cells to regional lymph nodes which represents a major prognostic indicator (Forastiere et al, 2001). Thus, attempts to identify the genes involved in metastasis are pivotal for the early prediction of HNSCC behaviour and development of novel molecular therapies. However, the identities of molecular alterations that endow cancer cells with these metastatic functions are largely unknown.The process of metastasis consists of sequential and selective steps including proliferation, motility, invasion, loss of cell -cell and cell -matrix adhesion, and remodelling of the extracellular matrix. A key factor involved in the control of cellextracellular matrix interactions is focal adhesion kinase (FAK), an intracellular tyrosine kinase protein that is localised to cellular focal contact sites (Schaller et al, 1992). Initially, phosphorylation of FAK occurs on its major autophosphorylation site, Tyr 397 . Phosphorylation of this tyrosine initiates a cascade of signal transdu...

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miR-141 Is a Key Regulator of Renal Cell Carcinoma Proliferation and Metastasis by Controlling EphA2 Expression

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