Abstract
Carcinoma cell motility and invasion are prerequisites for tumor cell metastasis, which requires regulation of the actin cytoskeleton. Cortactin is an actin-related protein 2/3 (Arp2/3) complex-activating and filamentous (F)-actin-binding protein that is implicated in tumor cell motility and metastasis, partially by its ability to become tyrosine phosphorylated. Cortactin is encoded by the CTTN gene and maps to chromosome 11q13, a region amplified in many carcinomas, including head and neck squamous cell carcinoma (HNSCC). CTTN gene amplification is associated with lymph node metastasis and poor patient outcome, and cortactin overexpression enhances motility in tumor cells lacking 11q13 amplification. However, a direct link between increased motility and invasion has not been reported in tumor cells with chromosome 11q13 amplification and cortactin overexpression. In this study, we have examined the relationship between CTTN amplification and tumor cell motility in HNSCC. In 11 of 39 (28%) HNSCC cases, cortactin overexpression determined by immunohistochemistry correlates with lymph node metastasis and CTTN gene amplification. HNSCC cells containing cortactin gene amplification and protein overexpression display increased binding and activation of Arp2/3 complex, and were more motile and invasive than HNSCC cells lacking CTTN amplification. Down-regulation of cortactin expression in CTTN-amplified HNSCC cells by small interfering RNA impairs HNSCC motility and invasion. Treatment of HNSCC cells with the epidermal growth factor receptor inhibitor gefitinib inhibits HNSCC motility and down-regulates cortactin tyrosine phosphorylation. These data suggest that cortactin may be a valid prognostic and therapeutic marker for invasive and metastatic HNSCC and other carcinomas with 11q13 amplification.
Highlights
Tumor cell motility is required for local-regional invasion and distant metastasis
Studies to date have shown that cortactin overexpression resulting from 11q13 amplification in head and neck squamous cell carcinoma (HNSCC) and other carcinomas corresponds with poor patient outcome, and that ectopic overexpression of cortactin in cancer cells lacking 11q13 amplification increases tumor cell motility, invasion, and metastasis
Our results directly show that cortactin overexpression resulting from 11q13 and corresponding CTTN amplification in carcinomas leads to increased tumor cell motility and invasion
Summary
Chemotatic receptor activation results in increased Rho GTPase and Src family kinase activity, which in turn leads to the activation of Wiskott-Aldrich syndrome proteins (WASp) that drive lamellipodia protrusion [3]. Activation of WASps by GTPase activation or tyrosine phosphorylation exposes a cryptic carboxyl-terminal domain containing an acidic region that binds and activates the actin-related protein 2/3 (Arp2/3) complex. Arp2/3 complex activity results in nascent polymerization of actin filaments at the cell periphery, providing the protrusive force responsible for lamellipodia extension at the leading edge [4]. The cortactin SH3 domain binds and activates neuronal (N)-WASp, which in turn promotes Arp2/3 actin nucleation and cell motility [10, 11]. Other functions of cortactin include stabilization of Arp2/3–F-actin networks and participation in receptor-mediated endocytosis [15, 16]
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