MiR-34a expression has an effect for lower risk of metastasis and associates with expression patterns predicting clinical outcome in breast cancer.
MiR-34a expression has an effect for lower risk of metastasis and associates with expression patterns predicting clinical outcome in breast cancer.
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DOI：
10.1371/journal.pone.0026122
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Nevanlinna H
中科院分区：
文献类型：
--
作者：
Peurala H;Greco D;Heikkinen T;Kaur S;Bartkova J;Jamshidi M;Aittomäki K;Heikkilä P;Bartek J;Blomqvist C;Bützow R;Nevanlinna H
miR-34 a作为一种候选肿瘤抑制基因，其表达在几种癌症类型中减少。我们的目的是研究miR-34 a在乳腺癌中的表达及其与肿瘤特征和临床结果的相关性，以及与其他基因的调控联系。我们分析了1，172例乳腺肿瘤中的miR-34 a表达。25%的肿瘤显示miR-34 a高表达，43%中等表达和32%低表达。高miR-34 a表达与乳腺癌的不良预后因素相关：阳性淋巴结状态（p = 0.006）、高肿瘤分级（p<0.0001）、ER阴性（p = 0.0002）、HER 2阳性（p = 0.0002）、高增殖率（p<0.0001）、p53阳性（p<0.0001）、高细胞周期蛋白E（p<0.0001）和γ H2 AX（p<0.0001）。 然而，调整常规预后因素的多变量分析表明，高miR-34 a表达实际上与乳腺癌复发或死亡风险较低相关（HR = 0.63，95%CI = 0.41-0.96，p = 0.031）。 通过差异miR-34 a表达的基因表达分析揭示了对患者的5年和10年生存率都有影响的表达特征（p<0.001）。功能基因组分析强调了转录因子MAZ对miR-34 a和许多miR-34 a靶点表达的新的调节作用，除了已知的p53控制之外。我们的研究结果表明，虽然miR-34 a表达激活是侵袭性乳腺肿瘤表型的标志物，但它对降低乳腺癌复发或死亡风险发挥着独立作用。我们还提供了与miR-34 a表达相关的190个基因的表达特征。我们对调控环的分析表明，MAZ和p53转录因子在调节miR-34 a以及参与几种细胞途径的miR-34 a靶点方面合作。综上所述，这些结果表明，与miR-34 a共调控并被miR-34 a靶向的基因网络形成了一组下游效应子，这些效应子可能用于预测临床结果，并突出了乳腺癌中的新调控机制。
MiR-34a acts as a candidate tumour suppressor gene, and its expression is reduced in several cancer types. We aimed to study miR-34a expression in breast cancer and its correlation with tumour characteristics and clinical outcome, and regulatory links with other genes. We analysed miR-34a expression in 1,172 breast tumours on TMAs. 25% of the tumours showed high, 43% medium and 32% low expression of miR-34a. High miR-34a expression associated with poor prognostic factors for breast cancer: positive nodal status (p = 0.006), high tumour grade (p<0.0001), ER-negativity (p = 0.0002), HER2-positivity (p = 0.0002), high proliferation rate (p<0.0001), p53-positivity (p<0.0001), high cyclin E (p<0.0001) and γH2AX (p<0.0001). However, multivariate analysis adjusting for conventional prognostic factors indicated that high miR-34a expression in fact associated with a lower risk of recurrence or death from breast cancer (HR = 0.63, 95% CI = 0.41–0.96, p = 0.031). Gene expression analysis by differential miR-34a expression revealed an expression signature with an effect on both the 5-year and 10-year survival of the patients (p<0.001). Functional genomic analysis highlighted a novel regulatory role of the transcription factor MAZ, apart from the known control by p53, on the expression of miR-34a and a number of miR-34a targets. Our findings suggest that while miR-34a expression activation is a marker of aggressive breast tumour phenotype it exerts an independent effect for a lower risk of recurrence or death from breast cancer. We also present an expression signature of 190 genes associated with miR-34a expression. Our analysis for regulatory loops suggest that MAZ and p53 transcription factors co-operate in modulating miR-34a, as well as miR-34a targets involved in several cellular pathways. Taken together, these results suggest that the network of genes co-regulated with and targeted by miR-34a form a group of down-stream effectors that maybe of use in predicting clinical outcome, and that highlight novel regulatory mechanisms in breast cancer.
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影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
64.8
作者：
He, Lin;He, Xingyue;Hannon, Gregory J.
通讯作者：
Hannon, Gregory J.
影响因子：
5.8
作者：
Cartharius, K;Frech, K;Werner, T
通讯作者：
Werner, T
影响因子：
9.7
作者：
Li, Na;Fu, Hanjiang;Zheng, Xiaofei
通讯作者：
Zheng, Xiaofei