Cheng Frank H C, Aguda Baltazar D, Tsai Je-Chiang, Kochańczyk Marek, Lin Jora M J, Chen Gary C W, Lai Hung-Cheng, Nephew Kenneth P, Hwang Tzy-Wei, Chan Michael W Y
Department of Life Science, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan, Republic of China; Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan, Republic of China.
DiseasePathways LLC, Bethesda, Maryland, United States of America.
PLoS One. 2014 Dec 29;9(12):e116050. doi: 10.1371/journal.pone.0116050. eCollection 2014.
Accumulating data indicate that cancer stem cells contribute to tumor chemoresistance and their persistence alters clinical outcome. Our previous study has shown that ovarian cancer may be initiated by ovarian cancer initiating cells (OCIC) characterized by surface antigen CD44 and c-KIT (CD117). It has been experimentally demonstrated that a microRNA, namely miR-193a, targets c-KIT mRNA for degradation and could play a crucial role in ovarian cancer development. How miR-193a is regulated is poorly understood and the emerging picture is complex. To unravel this complexity, we propose a mathematical model to explore how estrogen-mediated up-regulation of another target of miR-193a, namely E2F6, can attenuate the function of miR-193a in two ways, one through a competition of E2F6 and c-KIT transcripts for miR-193a, and second by binding of E2F6 protein, in association with a polycomb complex, to the promoter of miR-193a to down-regulate its transcription. Our model predicts that this bimodal control increases the expression of c-KIT and that the second mode of epigenetic regulation is required to generate a switching behavior in c-KIT and E2F6 expressions. Additional analysis of the TCGA ovarian cancer dataset demonstrates that ovarian cancer patients with low expression of EZH2, a polycomb-group family protein, show positive correlation between E2F6 and c-KIT. We conjecture that a simultaneous EZH2 inhibition and anti-estrogen therapy can constitute an effective combined therapeutic strategy against ovarian cancer.
越来越多的数据表明，癌症干细胞会导致肿瘤产生化学抗性，其持续存在会改变临床结果。我们之前的研究表明，卵巢癌可能由以表面抗原CD44和c-KIT（CD117）为特征的卵巢癌起始细胞（OCIC）引发。实验证明，一种名为miR-193a的微小RNA可靶向c-KIT mRNA进行降解，并可能在卵巢癌发展中发挥关键作用。目前对miR-193a的调控机制了解甚少，而且情况复杂。为了揭示这种复杂性，我们提出了一个数学模型，以探讨雌激素介导的miR-193a的另一个靶标E2F6的上调如何通过两种方式减弱miR-193a的功能，一种是通过E2F6和c-KIT转录本竞争miR-193a，另一种是E2F6蛋白与多梳蛋白复合体结合，作用于miR-193a的启动子以下调其转录。我们的模型预测，这种双峰控制会增加c-KIT的表达，并且表观遗传调控的第二种模式是在c-KIT和E2F6表达中产生开关行为所必需的。对TCGA卵巢癌数据集的进一步分析表明，多梳蛋白家族蛋白EZH2低表达的卵巢癌患者中，E2F6和c-KIT之间呈正相关。我们推测，同时抑制EZH2和进行抗雌激素治疗可能构成一种有效的联合治疗卵巢癌的策略。
