Overexpression of CRKII increases migration and invasive potential in oral squamous cell carcinoma

Abstract

CT10 regulator of kinase (CRK) was originally identified as an oncogene product of v-CRK in a CT10 chicken retrovirus system. Overexpression of CRKII has been reported in several human cancers. CRKII regulates cell migration, morphogenesis, invasion, phagocytosis, and survival; however, the underlying mechanisms are not well understood. In the present study, we evaluated the possibility of CRKII as an appropriate molecular target for cancer gene therapy. The expression of CRKII in 71 primary oral squamous cell carcinomas and 10 normal oral mucosal specimens was determined immunohistochemically, and the correlation of CRKII overexpression with clinicopathological factors was evaluated.Overexpression of CRKII was detected in 41 of 70 oral squamous cell carcinomas, the frequency being more significant than in normal oral mucosa. In addition, CRKII overexpression was more frequent in higher-grade cancers according to the T classification, N classification, and invasive pattern. Moreover, RNAi-mediated suppression of CRKII expression reduced the migration and invasion potential of an oral squamous cell carcinoma cell line, OSC20. Downregulation of CRKII expression also reduced the expression of Dock180, p130Cas, and Rac1, and the actin-associated scaffolding protein cortactin. These results indicate that the overexpression of CRKII is tightly associated with an aggressive phenotype of oral squamous cell carcinoma. Therefore, we propose that CRKII could be a potential molecular target of gene therapy by RNAi-targeting in oral squamous cell carcinoma. 4

CRKL plays a pivotal role in tumorigenesis of head and neck squamous cell carcinoma through the regulation of cell adhesion

“…Since the gene loci of CRKL and CRK are completely distinct [3,27], the functional priority for CRKL is likely to be important for HNSCC-carcinogenesis at a genetic level. Here we also explored similar expression profiles of both CRKL and CRK in HNSCC by immunohistochemistry, although Yamada et al [13] indicated the prominent expression and function of CRKII in HNSCC. They employed the CRKII-specific antibody which does not recognize CRKI and revealed the clinicopathological significance of CRKII in HNSCC, including clinical stage and patient's survival.…”

“…CRK was shown to play an essential role in the malignant potential of various human tumors including ovarian cancer, synovial sarcoma, glioblastoma, and head and neck squamous cell carcinoma (HNSCC) [10][11][12][13].…”

SH3 domains: modules of protein–protein interactions

“…Overexpression of the CT10 regulator of kinase (CRKII), which has been found in several human cancers, is associated with an aggressive phenotype of oral squamous cell carcinoma. CRKII regulates cell migration, morphogenesis, invasion, phagocytosis and survival (Yamada et al 2011). Two isoforms, CrkI (SH2-SH3) and CrkII (SH2-SH3-SH3), differ in their transforming activity, which is high for CrkI and low for CrkII.…”

“…Such vital processes as migration and invasiveness (Yamada et al 2011), actin reorganization induced by extracellular signals (Antoku and Mayer 2009), shaping spines (Sheng and Kim 2000;Ehlers 2002), among others take a central role when new treatments rely on an understanding of cellular control mechanisms.…”

Fibroblast Growth Requires CT10 Regulator of Kinase (Crk) and Crk-like (CrkL)

“…CrkI is a more potent transforming gene than CrkII and CrkL in part because, like v-Crk, it lacks a C-terminal regulatory phosphorylation site (3). Overexpression of Crk and CrkL has been reported in several human cancers, including oral squamous cell carcinoma (5), ovarian carcinoma (6), colon cancer (7), lung cancer (8,9), breast cancer (10,11), gastric cancer (12), and glioblastoma (13,14). Reduced expression of either Crk or CrkL by RNA interference-mediated knockdown lowered the in vivo tumor formation of human ovarian (15), synovial sarcoma (16), glioblastoma (14), breast cancer (10), head and neck squamous cell carcinoma (17), and rhabdomyosarcoma (18) cell lines.…”