Cortactin overexpression regulates actin-related protein 2/3 complex activity, motility, and invasion in carcinomas with chromosome 11q13 amplification.
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.
Rothschild
Brian L
BL
Department of Craniofacial Biology, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado, USA.
Shim
Ann H
AH
Ammer
Amanda Gatesman
AG
Kelley
Laura C
LC
Irby
Kimberly B
KB
Head
Julie A
JA
Chen
Lin
L
Varella-Garcia
Marileila
M
Sacks
Peter G
PG
Frederick
Barbara
B
Raben
David
D
Weed
Scott A
SA
D051376:Actin-Related Protein 2-3 Complex / Q000502:physiology*; D000199:Actins / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D051356:Cortactin / Q000235:genetics*; D005784:Gene Amplification; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009361:Neoplasm Invasiveness / Q000235:genetics*; D014162:Transfection
D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; C495868:CTTN protein, human; D051356:Cortactin