BCL2L2 is a probable target for novel 14q11.2 amplification detected in a non-small cell lung cancer cell line
BCL2L2 is a probable target for novel 14q11.2 amplification detected in a non-small cell lung cancer cell line
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DOI：
10.1111/j.1349-7006.2007.00491.x
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发表时间：
2007-07-01
期刊：
影响因子：
5.7
通讯作者：
Inazawa, Johji
中科院分区：
文献类型：
--
作者：
Kawasaki, Tsutomu;Yokoi, Sana;Inazawa, Johji
染色体DNA的扩增被认为是激活肿瘤中癌症相关基因的机制之一。在之前使用内部细菌人工染色体阵列对一组非小细胞肺癌 (NSCLC) 细胞系中 DNA 拷贝数畸变进行全基因组筛查时，我们在源自人肺腺癌的 HUT29 细胞中发现了 14q11.2 处的新扩增。为了确定 14q11.2 扩增最可能的目标，我们通过荧光原位杂交确定了扩增子的范围，然后分析了 NSCLC 细胞系中 1 Mb 扩增区域中存在的 28 个基因的表达水平。 HUT29 细胞系中的显着过度表达和扩增、与永生化正常肺上皮细胞系相比在其他 NSCLC 细胞系中相对频繁的过度表达以及有关每个候选基因功能的报告信息促使我们将 BCL2-like2 (BCL2L2) 基因（BCL2 家族的促存活成员）描述为 14q11.2 扩增子最有可能的目标。对 61 例原发性肺腺癌的免疫组织化学分析表明，BCL2L2 过表达与肿瘤分期和分化状态显着相关，并且往往与较差的预后相关。使用小干扰RNA下调BCL2L2表达可显着抑制HUT29细胞的生长，但对抗癌试剂诱导的同一细胞系的细胞死亡没有影响。这些发现表明，过表达的 BCL2L2 通过扩增或其他机制促进 NSCLC，特别是腺癌亚型的生长，并可能成为治疗靶点。
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.