Comparison of Gene Expression Profiles in Chromate Transformed BEAS-2B Cells

BackgroundHexavalent chromium [Cr(VI)] is a potent human carcinogen. Occupational exposure has been associated with increased risk of respiratory cancer. Multiple mechanisms have been shown to contribute to Cr(VI) induced carcinogenesis, including DNA damage, genomic instability, and epigenetic modulation, however, the molecular mechanism and downstream genes mediating chromium's carcinogenicity remain to be elucidated. Methods/ResultsWe established chromate transformed cell lines by chronic exposure of normal human bronchial epithelial BEAS-2B cells to low doses of Cr(VI) followed by anchorage-independent growth. These transformed cell lines not only exhibited consistent morphological changes but also acquired altered and distinct gene expression patterns compared with normal BEAS-2B cells and control cell lines (untreated) that arose spontaneously in soft agar. Interestingly, the gene expression profiles of six Cr(VI) transformed cell lines were remarkably similar to each other yet differed significantly from that of either control cell lines or normal BEAS-2B cells. A total of 409 differentially expressed genes were identified in Cr(VI) transformed cells compared to control cells. Genes related to cell-to-cell junction were upregulated in all Cr(VI) transformed cells, while genes associated with the interaction between cells and their extracellular matrices were down-regulated. Additionally, expression of genes involved in cell proliferation and apoptosis were also changed. ConclusionThis study is the first to report gene expression profiling of Cr(VI) transformed cells. The gene expression changes across individual chromate exposed clones were remarkably similar to each other but differed significantly from the gene expression found in anchorage-independent clones that arose spontaneously. Our analysis identified many novel gene expression changes that may contribute to chromate induced cell transformation, and collectively this type of information will provide a better understanding of the mechanism underlying chromate carcinogenicity.背景 六价铬（hexavalent chromium, Cr(VI)）是强效人类致癌物，职业暴露与呼吸系统癌症风险升高密切相关。已有研究表明，DNA损伤、基因组不稳定性及表观遗传调控等多种机制参与Cr(VI)诱导的致癌过程，但介导六价铬致癌性的分子机制及下游靶点基因仍有待阐明。 方法与结果 我们通过将正常人支气管上皮BEAS-2B细胞长期暴露于低剂量六价铬，随后进行非锚定依赖性生长筛选，成功建立了铬酸盐转化细胞系。与正常BEAS-2B细胞及软琼脂中自发形成的未处理对照细胞系相比，这些转化细胞系不仅呈现出一致的形态学改变，还获得了显著改变且独特的基因表达谱。值得注意的是，6株Cr(VI)转化细胞系的基因表达谱彼此高度相似，但与对照细胞系或正常BEAS-2B细胞的表达谱存在显著差异。与对照细胞相比，Cr(VI)转化细胞中共鉴定出409个差异表达基因：所有Cr(VI)转化细胞中，细胞间连接相关基因均呈上调表达，而细胞与其细胞外基质相互作用相关基因则呈下调表达；此外，参与细胞增殖与凋亡的基因表达也发生了改变。 结论 本研究首次报道了Cr(VI)转化细胞的基因表达谱。各铬酸盐暴露克隆的基因表达变化彼此高度相似，但与自发形成的非锚定依赖性克隆的基因表达存在显著差异。本研究分析鉴定出多种可能参与铬酸盐诱导细胞转化的新型基因表达变化，此类信息将有助于更深入地阐明铬酸盐致癌作用的潜在机制。