CDK4/RB/E2Fs axis as potential therapeutic target of endometrial cancer
CDK4/RB/E2Fs axis as potential therapeutic target of endometrial cancer
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DOI：
10.1016/j.biopha.2020.109870
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发表时间：
2020-05-01
影响因子：
7.5
通讯作者：
Sun, Jing
中科院分区：
文献类型：
--
作者：
Hu, Jing;Shen, Junwei;Sun, Jing
近几十年来，子宫内膜癌（EC）的发病率不断上升，患者5年生存率不断下降，这表明有必要进一步研究与癌症发生和进展有关的分子特征。本研究通过分析the Cancer Genome Atlas （TCGA）的RNA-seq数据发现，与正常子宫内膜样品相比，原代EC样品中与有丝分裂细胞周期相关的通路丰富。三种激活因子E2Fs （E2F1、E2F2和E2F3）及其靶基因的mRNA表达量在EC样品中显著升高。此外，激活因子E2Fs的高转录活性与生存率低、临床分期晚期、高组织学分级和侵袭性组织学类型相关。我们进一步证明E2Fs的过度激活与DNA低甲基化和高周期蛋白依赖性激酶4 （CDK4）表达相关。此外，选择性CDK4抑制剂abemaciclib在体外显著抑制人EC细胞株的增殖率。abemaciclib对裸鼠模型EC细胞的生长也有明显的抑制作用。总的来说，我们的数据表明CDK4/RB/E2Fs轴的失调与EC的肿瘤发生有关，而abemaciclib是EC的潜在靶向药物。
The increasing incidence rate and decreasing patients' five-year survival rate for endometrial cancer (EC) in recent decades highlight the necessity for further investigation of the molecular characteristics involved in cancer initiation and progression. In this study, we found that the pathways associated with mitotic cell cycle were enriched in primary EC samples versus normal endometrial samples through analyzing RNA-seq data of The Cancer Genome Atlas (TCGA). The messenger RNA (mRNA) expression of three activator E2Fs (E2F1, E2F2, and E2F3) and their target genes increased significantly in EC samples. Additionally, the high transcriptional activity of activator E2Fs was associated with poor survival, advanced clinical stage, high histologic grade, and aggressive histological type. We further demonstrated that E2Fs hyperactivation correlated with DNA hypomethylation and high cyclin-dependent kinase 4 (CDK4) expression. Moreover, abemaciclib, a selective CDK4 inhibitor, significantly inhibited the proliferation rates of human EC cell lines in vitro. And, abemaciclib also obviously inhibited EC cell growth in nude mice model. Collectively, our data suggest that the misregulation of CDK4/RB/E2Fs axis is associated with EC oncogenesis, and abemaciclib is a potential targeted drug for EC.