The CRKL gene encoding an adaptor protein is amplified, overexpressed, and a possible therapeutic target in gastric cancer

Journal of Translational Medicine

Haruhiko Sugimura¹  Satoki Nakamura²  Hiroyuki Konno⁴  Matsuyoshi Maeda³  Hidetaka Yamada¹  Masanori Goto¹  Kiyoko Nagura¹  Masaya Suzuki¹  Hisaki Igarashi¹  Hong Tao¹  Kazuya Shinmura¹  Hiroko Natsume¹ 

[1] Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka, 431-3192, Japan;Third Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka, 431-3192, Japan;Department of Pathology, Toyohashi Municipal Hospital, 50 Hachiken Nishi, Aotake-cho, Toyohashi, Aichi, 441-8570, Japan;Second Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka, 431-3192, Japan

关键词: Copy number amplification;    Overexpression;    Cell proliferation;    Gastric cancer;    CRKL;   

Others  :  1205984
DOI  :  10.1186/1479-5876-10-97

 received in 2011-12-22, accepted in 2012-05-16,  发布年份 2012

【 摘 要 】

Background

Genomic DNA amplification is a genetic factor involved in cancer, and some oncogenes, such as ERBB2, are highly amplified in gastric cancer. We searched for the possible amplification of other genes in gastric cancer.

Methods and Results

A genome-wide single nucleotide polymorphism microarray analysis was performed using three cell lines of differentiated gastric cancers, and 22 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, the product of which is an adaptor protein containing Src homology 2 and 3 (SH2/SH3) domains. An extremely high CRKL copy number was confirmed in the MKN74 gastric cancer cell line using fluorescence in situ hybridization (FISH), 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. The CRKL copy number was also examined in 360 primary gastric cancers using a FISH analysis, and CRKL amplification was found to be associated with CRKL overexpression. 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.

Conclusion

These results suggested that CRKL protein is overexpressed in a subset of gastric cancers and is associated with CRKL amplification in gastric cancer. Furthermore, our results suggested that CRKL protein has the ability to regulate gastric cell proliferation and has the potential to serve as a molecular therapy target for gastric cancer.

【 授权许可】

   
2012 Natsume et al.; licensee BioMed Central Ltd.

【 图 表 】

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