Altered gene expression pattern in cultured human breast cancer cells treated with hepatocyte growth factor/scatter factor in the setting of DNA damage.
Altered gene expression pattern in cultured human breast cancer cells treated with hepatocyte growth factor/scatter factor in the setting of DNA damage.
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发表时间：
2001-11
期刊：
影响因子：
11.2
通讯作者：
R. Yuan;S. Fan;M. Achary;D. Stewart;I. Goldberg;E. Rosen
中科院分区：
文献类型：
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作者：
R. Yuan;S. Fan;M. Achary;D. Stewart;I. Goldberg;E. Rosen
细胞因子肝细胞生长因子/分散因子（HGF/SF）通过涉及c-Met->磷脂酰肌醇-3-激酶-> c-Akt信号传导的途径保护上皮细胞和癌细胞免受DNA损伤剂的侵害。然而，由该途径引起的基因表达的下游改变尚未建立。在cDNA微阵列和半定量RT-PCR分析的基础上，我们发现，MDA-MB-453人乳腺癌细胞与HGF/SF预孵育，然后暴露于阿霉素（ADR），DNA拓扑异构酶II抑制剂，表现出基因表达模式的改变，与ADR单独处理的细胞相比。[HGF/SF + ADR]处理的细胞表现出参与DNA损伤反应、细胞周期调节、信号转导、代谢和发育的基因表达改变。其中一些改变提示HGF/SF可能发挥其保护活性的机制，例如，多囊性肾病-1（钙粘蛋白-连环蛋白复合物的存活促进组分）的上调、51C（肌醇多磷酸-5-磷酸酶）的下调和TOPBP1（拓扑异构酶IIB结合蛋白）的下调。我们发现，cdc42相互作用蛋白质CIP4（一种在[HGF/SF + ADR]处理的细胞中表达减少的细胞因子相关蛋白质）的强制表达抑制了HGF/SF介导的对ADR的保护作用。cDNA微阵列的方法可能开辟了新的途径，调查的DNA损伤反应和HGF/SF的调控。
The cytokine hepatocyte growth factor/scatter factor (HGF/SF) protects epithelial and cancer cells against DNA-damaging agents via a pathway involving signaling from c-Met --> phosphatidylinositol-3- kinase --> c-Akt. However, the downstream alterations in gene expression resulting from this pathway have not been established. On the basis of cDNA microarray and semiquantitative RT-PCR assays, we found that MDA-MB-453 human breast cancer cells preincubated with HGF/SF and then exposed to Adriamycin (ADR), a DNA topoisomerase II inhibitor, exhibit an altered pattern of gene expression, as compared with cells treated with ADR only. [HGF/SF+ADR]-treated cells showed altered expression of genes involved in the DNA damage response, cell cycle regulation, signal transduction, metabolism, and development. Some of these alterations suggest mechanisms by which HGF/SF may exert its protective activity, e.g., up-regulation of polycystic kidney disease-1 (a survival-promoting component of cadherin-catenin complexes), down-regulation of 51C (an inositol polyphosphate-5-phosphatase), and down-regulation of TOPBP1 (a topoisomerase IIB binding protein). We showed that enforced expression of the cdc42-interacting protein CIP4, a cytoskeleton-associated protein for which expression was decreased in [HGF/SF+ADR]-treated cells, inhibited HGF/SF-mediated protection against ADR. The cDNA microarray approach may open up new avenues for investigation of the DNA damage response and its regulation by HGF/SF.