Cyclin D1-mediated microRNA expression signature predicts breast cancer outcome.
Cyclin D1-mediated microRNA expression signature predicts breast cancer outcome.
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Cyclin D1 介导的 microRNA 表达特征控制乳腺癌结果
DOI：
10.7150/thno.23877
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发表时间：
2018
期刊：
影响因子：
12.4
通讯作者：
Pestell RG
中科院分区：
文献类型：
--
作者：
Wang G;Gormley M;Qiao J;Zhao Q;Wang M;Di Sante G;Deng S;Dong L;Pestell T;Ju X;Casimiro MC;Addya S;Ertel A;Tozeren A;Li Q;Yu Z;Pestell RG
背景：基于编码信使核糖核酸的乳腺癌基因分类暗示了不同亚型的进化。非编码基因组是否与编码基因组一致改变，以及细胞周期直接控制非编码基因组的机制尚不清楚。方法：在此，定义了内源性细胞周期蛋白D1维持的人乳腺癌细胞的miRNA特征。为了确定细胞周期蛋白D1介导的miRNA信号的临床意义，我们从459例乳腺癌样本中定义了miRNA表达超集。我们比较了乳腺癌亚型的编码基因组和非编码基因组。结果：通过Kaplan-Meier分析，人类乳腺癌的等级聚类定义了四个不同的miRNA簇(G1-G4)，它们与可区分的无复发生存率相关。Cyclin D1调控的miRNA信号包括多个癌基因，在多个乳腺癌细胞系中保守，与G2肿瘤miRNA簇、ERα+状态、更好的预后和Wnt通路的激活有关。在乳腺癌亚型中，编码和非编码基因组是不一致的。在包括DKK在内的63个Wnt信号通路基因中发现了细胞周期蛋白D1调节miRNA的种子元件。细胞周期蛋白D1通过3‘非编码区抑制Dkk1的表达。利用可诱导转基因技术进行的体内研究证实，细胞周期蛋白D1可诱导依赖于Wnt的基因表达。结论：非编码基因组定义的乳腺癌亚型与其编码基因组亚型不一致，提示肿瘤内存在不同的进化驱动因素。细胞周期蛋白D1miRNA信号的表达可诱导Wnt/β-连环蛋白信号的表达，因此细胞周期蛋白D1在WnT/β-连环蛋白信号的上游和下游都起作用。
Background: Genetic classification of breast cancer based on the coding mRNA suggests the evolution of distinct subtypes. Whether the non-coding genome is altered concordantly with the coding genome and the mechanism by which the cell cycle directly controls the non-coding genome is poorly understood. Methods: Herein, the miRNA signature maintained by endogenous cyclin D1 in human breast cancer cells was defined. In order to determine the clinical significance of the cyclin D1-mediated miRNA signature, we defined a miRNA expression superset from 459 breast cancer samples. We compared the coding and non-coding genome of breast cancer subtypes. Results: Hierarchical clustering of human breast cancers defined four distinct miRNA clusters (G1-G4) associated with distinguishable relapse-free survival by Kaplan-Meier analysis. The cyclin D1-regulated miRNA signature included several oncomirs, was conserved in multiple breast cancer cell lines, was associated with the G2 tumor miRNA cluster, ERα+ status, better outcome and activation of the Wnt pathway. The coding and non-coding genome were discordant within breast cancer subtypes. Seed elements for cyclin D1-regulated miRNA were identified in 63 genes of the Wnt signaling pathway including DKK. Cyclin D1 restrained DKK1 via the 3'UTR. In vivo studies using inducible transgenics confirmed cyclin D1 induces Wnt-dependent gene expression. Conclusion: The non-coding genome defines breast cancer subtypes that are discordant with their coding genome subtype suggesting distinct evolutionary drivers within the tumors. Cyclin D1 orchestrates expression of a miRNA signature that induces Wnt/β-catenin signaling, therefore cyclin D1 serves both upstream and downstream of Wnt/β-catenin signaling.
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影响因子：
3.7
作者：
Enerly E;Steinfeld I;Kleivi K;Leivonen SK;Aure MR;Russnes HG;Rønneberg JA;Johnsen H;Navon R;Rødland E;Mäkelä R;Naume B;Perälä M;Kallioniemi O;Kristensen VN;Yakhini Z;Børresen-Dale AL
通讯作者：
Børresen-Dale AL
影响因子：
3.8
作者：
Barnes, DM;Gillett, CE
通讯作者：
Gillett, CE
影响因子：
64.8
作者：
Bhanot, P;Brink, M;Nusse, R
通讯作者：
Nusse, R
影响因子：
4
作者：
Casimiro, Sandra;Luis, Ines;Costa, Luis
通讯作者：
Costa, Luis
影响因子：
30.8
作者：
Bentwich, I;Avniel, A;Bentwich, Z
通讯作者：
Bentwich, Z