BCL2L2 is a probable target for novel 14q11.2 amplification detected in a non-small cell lung cancer cell line

Amplification of chromosomal DNA is thought to be one of the mechanisms that activates cancer-related genes in tumors. In a previous genome-wide screening of DNA copy number aberrations in a panel of non-small cell lung cancer (NSCLC) cell lines using an in-house bacterial artificial chromosome-based array, we identified a novel amplification at 14q11.2 in HUT29 cells derived from human lung adenocarcinoma. To identify the most likely target for the 14q11.2 amplification, we determined the extent of the amplicon by fluorescence in.situ hybridization and then analyzed NSCLC cell lines for the expression levels of 28 genes present within the 1-Mb amplified region. Significant overexpression in the HUT29 cell line with amplification, relatively frequent overexpression in additional NSCLC cell lines compared with an immortalized normal lung epithelial cell line, and reported information about the function of each candidate gene prompted us to characterize the BCL2-like2 (BCL2L2) gene, a prosurvival member of the BCL2 family, as the most likely target for the 14q11.2 amplicon. Immunohistochemical analysis of 61 primary cases of lung adenocarcinoma demonstrated that BCL2L2 overexpression was significantly associated with tumor stage and differentiation status, and tended to be associated with a poorer prognosis. Downregulation of BCL2L2 expression using small interfering RNA dramatically inhibited the growth of HUT29 cells, but showed no effect on anticancer reagent-induced cell death of the same cell line. These findings demonstrate that overexpressed BCL2L2, through amplification or other mechanisms, promotes the growth of NSCLC, especially the adenocarcinoma subtype, and might be a therapeutic target.