Amplification and Overexpression ofCTTN(EMS1) Contribute to the Metastasis of Esophageal Squamous Cell Carcinoma by Promoting Cell Migration and Anoikis Resistance

Abstract

Gain of chromosome 11q13 is a common event in esophageal squamous cell carcinoma (ESCC). The cortactin gene (CTTN, also EMS1), located at 11q13, plays a pivotal role in coupling membrane dynamics to cortical actin assembly. This gene has been implicated in the motility of several types of cells. In the present study, we found that the amplification and overexpression of the CTTN gene was associated with lymph node metastasis in ESCC. Functional analysis by small interfering RNA-mediated silencing of CTTN revealed that in addition to the effect on cell migration, CTTN influenced cell invasiveness by anoikis resistance. In vivo assay showed that inhibition of CTTN expression also decreased tumor growth and lung metastasis of ESCC cells. At the molecular level, we showed for the first time that the protective role of CTTN in anoikis resistance was correlated with the activation of the phosphatidylinositol 3-kinase/Akt pathway. Overall, the data suggest that CTTN is an oncogene in the 11q13 amplicon and exerts functions on tumor metastasis in ESCC.

Cortactin expression predicts poor survival in laryngeal carcinoma

“…Downregulation of cortactin in cancer cell lines decreases the cellular motility and ability to migrate (Rothschild et al, 2006;van Rossum et al, 2006) whereas overexpression resulted in an increased invasive potential (van Rossum et al, 2003;Rothschild et al, 2006). In addition to the effect on cell migration by mediating actin polymerization and cell adhesion (van Rossum et al, 2006), cortactin might also influence cell migration and metastasis by anoikis resistance and PI3K/Akt signalling (Luo et al, 2006;Luo and Wang, 2007). Because of these biological functions and its overexpression due to DNA amplification, cortactin is the most likely gene within the 11q13.3 amplicon to mediate the worse clinical behaviour of late stage LSCC with 11q13 amplification.…”

“…Gene by gene functional analyses have revealed that cyclin D1 (Opitz et al, 2001;Nelsen et al, 2005), FADD (Alappat et al, 2003;Chen et al, 2005) and cortactin (van Rossum et al, 2003;Luo et al, 2006) are potentially able to enhance cancer development. However, these studies do not account for the effect of multiple genes located within the 11q13.3 amplicon.…”

“…Cortactin amplification was related to increased lymph node stage, advanced disease stage and reduced survival (Rodrigo et al, 2000). Cortactin mRNA expression (Luo et al, 2006) and protein expression (Rothschild et al, 2006) have been correlated to increased lymph node metastasis.In summary, FADD, cyclin D1 and cortactin expression may each be involved in processes resulting in increased lymph node metastasis and in poor prognosis. Because the prognostic value of these genes has not been evaluated within the same group of patients simultaneously, we have performed immunohistochemistry (IHC) on 167 patients with late stage LSCC.…”

“…Cortactin amplification was related to increased lymph node stage, advanced disease stage and reduced survival (Rodrigo et al, 2000). Cortactin mRNA expression (Luo et al, 2006) and protein expression (Rothschild et al, 2006) have been correlated to increased lymph node metastasis.…”

Prognostic significance of cortactin levels in head and neck squamous cell carcinoma: comparison with epidermal growth factor receptor status

“…Thus, the functional properties of cortactin, together with amplification of chromosome locus 11q13, suggest a link between its overexpression and tumour invasion and/or metastasis. Accordingly, in several animal models ectopic overexpression of cortactin has been shown to accelerate tumour dissemination, and decreased expression of cortactin, by RNA interference, leads to impaired tumour cell migration and metastasis (Li et al, 2001;Chuma et al, 2004;Hill et al, 2006;Luo et al, 2006).…”