Overexpression And Cell Proliferation-Regulating Function Of Crkl Protein In Gastric Cancer

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Genomic DNA amplification is a genetic factor involved in cancer, and some oncogenes, such as ERBB2, are highly amplified in gastric cancer. To identify previously undiscovered amplified genes in gastric cancer, a genome-wide single nucleotide polymorphism microarray analysis was performed using three cell lines of differentiated gastric cancers. Twenty-two genes (including ERBB2) in five highly amplified chromosome regions (with a copy number of more than 6) were identified. Particular attention was paid to the CRKL gene, which has not been previously characterized in gastric cancer and the product of which is an adaptor protein containing Src homology 2 and 3 (SH2/SH3) domains. A relatively high CRKL copy number was confirmed in the MKN74 gastric cancer cell line using fluorescence in situ hybridization, and a high level of CRKL expression was also observed in the cells. The RNA-interference-mediated knockdown of CRKL in MKN74 disclosed the ability of CRKL to upregulate gastric cell proliferation. An immunohistochemical analysis revealed that CRKL protein was overexpressed in 24.4% (88/360) of the primary gastric cancers that were analyzed. Finally, we showed that MKN74 cells with CRKL amplification were responsive to the dual Src/BCR-ABL kinase inhibitor BMS354825, likely via the inhibition of CRKL phosphorylation, and that the proliferation of MKN74 cells was suppressed by treatment with a CRKL-targeting peptide. These results suggested that CRKL protein is overexpressed in a subset of gastric cancers, that it regulates gastric cell proliferation, and that it has the potential to be a molecular therapy target for gastric cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3682. doi:1538-7445.AM2012-3682