17p13.3

CRKII,p38

Various diseases

Crk is overexpressed in various human cancers especially in lung adenocarcinoma and in brain tumor. Crk knockdown study demonstrates the essential roles for Crk in malignant potentials of various human cancers including ovarian cancer, sarcoma, and brain tumor. Recently, microRNA-126 was shown to suppress lung cancer growth by the suppression of Crk expression. Crk has been reported to bind to NS1 protein of influenza virus type H5N1, CagA protein of Helicobacter pylori, and also known to regulate the infection of Pseudomonas aeruginosa and Shigella flexneri. Therefore, Crk can be a therapeutic target molecule for cancer and infectious diseases.

Lung cancer

96 cases of lung adenocarcinoma were analyzed by using Gene chip and in the cases of stage III, mRNA levels of Crk were increased comparing to those of in stage I (Beer et al., 2002).
Affymetrix oligonucleotide arrays were used to analyze 86 lung adenocarcinomas and 10 uninvolved lung tissues, and Crk mRNA expression was increased in more advanced (stage III versus stage I), larger (T2-4 versus T1), and poorly differentiated tumors and in tumors from patients demonstrating poor survival (Miller et al., 2003).
Immunohistochemical analysis of Crk-II demonstrated that the levels of Crk-II were significantly elevated in most of the tumors, particularly in the colon and lung cancers. Furthermore, immunoblot analysis using human lung cancer cell lines revealed that the expression levels of Crk-II were correlated to growth rates of cells (Nishihara et al., 2002).

Expression of Crk mRNA was increased in patients with poor prognosis (P=0.00034) (Miller et al., 2003).

Brain tumor

CrkII mRNA was detected both in normal brain and glioblastoma tissues, whereas crkI mRNA levels were quite low in normal brain and up-regulated in glioblastoma tissues. Expression of CrkI but not CrkII in glioblastoma U87MG cells induced transformation that stimulated cell migration and invasion concomitant with tyrosine phosphorylation of p130 Cas (Takino et al., 2003).
Crk-knockdown cell lines of glioblastoma KMG4 was established by siRNA, and early phase of cell adhesion to laminin was found to be suppressed. Wound healing assay revealed the decreased cell motility in Crk knockdown cells, and suppression of both anchorage-dependent and -independent growth were demonstrated in these cells. Furthermore, in vivo tumor forming potential was also markedly suppressed (Wang et al., 2007).

Ovarian cancer

Crk expression was targeted in the human ovarian cancer cell line MCAS through RNA interference, resulting in disorganized actin fibers, reduced number of focal adhesions, and decreased Rac activity in association with suppression of cell motility and invasion, and anchorage-dependent growth in soft agar. Tumor forming potential in nude mice was attenuated and intraperitoneal dissemination was not observed when Crk knockdown cells were injected into the peritoneal cavity (Linghu et al., 2006).

Breast cancer

CrkI/II knockdown resulted in a significant decrease in migration and invasion of multiple malignant breast and other human cancer cell lines (MDA-231, MDA-435s, H1299, KB, and HeLa). Moreover, CrkI/II knockdown decreased cell spreading on extracellular matrix and led to a decrease in actin stress fibers and the formation of mature focal adhesions. Using immunohistochemistry, we show elevated CrkI/II protein levels in patients with breast adenocarcinoma (Rodrigues et al., 2005).

Crk adaptor protein is required for the sustained phosphorylation of Gab1 in response to HGF, leading to the enhanced cell motility of human synovial sarcoma cell lines SYO-1, HS-SY-II, and Fuji. Crk knockdown by RNA interference disturbed this HGF-induced tyrosine phosphorylation of Gab1. The elimination of Crk in these cells induced the disorganization of actin cytoskeleton and complete abolishment of HGF-mediated Rac1 activation and cell motility. Furthermore, the depletion of Crk remarkably inhibited the tumor formation and its invasive growth in vivo (Watanabe et al., 2006).

Oral cancer

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 (Yamada et al., 2011).

Endometriosis

The expression levels of miR-126 and and its putative target Crk mRNA were quantified using real time PCR in ectopic endometrium and eutopic endometrium in patients with endometriosis. The expression level of miR-126 was significantly downregulated in ectopic endometrium whereas the protein levels of Crk was increased. Thus, miR-126 may play an initial role in the development and progression of endometriosis (Liu et al., 2012).