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Natsume et al. Journal of Translational Medicine 2012, 10:97 http://www.translational-medicine.com/content/10/1/RESEARCHOpen AccessThe CRKL gene encoding an adaptor protein is amplified, overexpressed, and a possible therapeutic target in gastric cancerHiroko Natsume1, Kazuya Avermectin B1a side effects Shinmura1, Hong Tao1, Hisaki Igarashi1, Masaya Suzuki1, Kiyoko Nagura1, Masanori Goto1, Hidetaka Yamada1, Matsuyoshi Maeda2, Hiroyuki Konno3, Satoki Nakamura4 and Haruhiko Sugimura1*AbstractBackground: 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-interferencemediated 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 PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/27597769 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. Keywords: CRKL, Gastric cancer, Cell proliferation, Overexpression, Copy number amplificationBackground Although the overall incidence of gastric cancer is decreasing in many countries, the high incidence of gastric cancer remains a serious health problem, and gastric cancer continues to be the second-leading cause of cancerrelated death worldwide [1,2]. Gastric carcinogenesis is a multi-step process in which environmental and genetic* Correspondence: [email protected] 1 Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka 431-3192, Japan Full list of author information is available at the end of the articlefactors interact [1?]. Among the genetic changes observed in cancerous cells, genomic DNA amplification is a wellknown alteration that is involved in gastric cance.
