YB-1、E2F 通路与肿瘤细胞生长的调控。
YB-1, the E2F pathway, and regulation of tumor cell growth.
机构信息
Department of Molecular Medicine and Pathology, School of Medical Sciences, University of Auckland, Auckland, New Zealand.
出版信息
J Natl Cancer Inst. 2012 Jan 18;104(2):133-46. doi: 10.1093/jnci/djr512. Epub 2011 Dec 28.
BACKGROUND
Y-box binding factor 1 (YB-1) has been associated with prognosis in many tumor types. Reduced YB-1 expression inhibits tumor cell growth, but the mechanism is unclear.
METHODS
YB-1 mRNA levels were compared with tumor grade and histology using microarray data from 771 breast cancer patients and with disease-free survival and distant metastasis-free survival using data from 375 of those patients who did not receive adjuvant therapy. Microarrays were further searched for genes that had correlated expression with YB-1 mRNA. Small interfering RNA (siRNA) was used to study the effects of reduced YB-1 expression on growth of three tumor cell lines (MCF-7 breast, HCT116 colon, and A549 lung cancer cells), on tumorigenesis by A549 cells in nude mice, and on global transcription in the three cancer cell lines. Reporter gene assays were used to determine whether YB-1 siRNAs affected the expression of E2F1, and chromatin immunoprecipitation was used to determine whether YB-1 bound to various E2F promoters as well as E2F1-regulated promoters. All P values were from two-sided tests.
RESULTS
YB-1 levels were elevated in more aggressive tumors and were strongly associated with poor disease-free survival and distant metastasis-free survival. YB-1 expression was often associated with the expression of genes with E2F sites in their promoters. Cells expressing YB-1 siRNA grew substantially more slowly than control cells and formed tumors less readily in nude mice. Transcripts that were altered in cancer cell lines with YB-1 siRNA included 32 genes that are components of prognostic gene expression signatures. YB-1 regulated expression of an E2F1 promoter-reporter construct in A549 cells (eg, relative E2F1 promoter activity with control siRNA = 4.04; with YB-1 siRNA = 1.40, difference= -2.64, 95% confidence interval = -3.57 to -1.71, P < .001) and bound to the promoters of several well-defined E2F1 target genes.
CONCLUSION
YB-1 expression is associated with the activity of E2F transcription factors and may control tumor cell growth by this mechanism.
背景
Y 盒结合因子 1（YB-1）与许多肿瘤类型的预后有关。YB-1 表达减少会抑制肿瘤细胞生长，但机制尚不清楚。
方法
使用来自 771 例乳腺癌患者的微阵列数据比较 YB-1mRNA 水平与肿瘤分级和组织学，并使用未接受辅助治疗的 375 例患者的无病生存和无远处转移生存数据进行比较。进一步对微阵列进行搜索，寻找与 YB-1mRNA 表达相关的基因。使用小干扰 RNA（siRNA）研究减少 YB-1 表达对三种肿瘤细胞系（MCF-7 乳腺癌、HCT116 结肠癌和 A549 肺癌细胞）生长、A549 细胞在裸鼠中的致瘤性以及三种癌细胞系的全局转录的影响。报告基因检测用于确定 YB-1siRNA 是否影响 E2F1 的表达，染色质免疫沉淀用于确定 YB-1 是否与各种 E2F 启动子以及 E2F1 调节的启动子结合。所有 P 值均来自双侧检验。
结果
在侵袭性更强的肿瘤中，YB-1 水平升高，与无病生存和无远处转移生存不良密切相关。YB-1 表达通常与启动子中含有 E2F 位点的基因表达相关。表达 YB-1siRNA 的细胞比对照细胞生长明显缓慢，在裸鼠中形成肿瘤的能力也较低。在具有 YB-1siRNA 的癌细胞系中改变的转录本包括 32 个基因，它们是预后基因表达特征的组成部分。YB-1 调节 A549 细胞中 E2F1 启动子报告基因构建体的表达（例如，对照 siRNA 时的相对 E2F1 启动子活性=4.04；YB-1siRNA 时=1.40，差异=-2.64，95%置信区间=-3.57 至-1.71，P<0.001），并与几个明确的 E2F1 靶基因的启动子结合。
结论
YB-1 表达与 E2F 转录因子的活性有关，可能通过这种机制控制肿瘤细胞生长。
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