A mathematical model of bimodal epigenetic control of MIR-193a in ovarian cancer stem cells

Frank H.C. Cheng, Baltazar D. Aguda, Je Chiang Tsai, Marek Kochańczyk, Jora M.J. Lin, Gary C.W. Chen, Hung Cheng Lai, Kenneth P. Nephew, Tzy Wei Hwang, Michael W.Y. Chan

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8 引文 斯高帕斯(Scopus)

摘要

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 downregulate its transcription. Our model predicts that this bimodal control increases the expression of c-KITand 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.

原文英語
文章編號e116050
期刊PloS one
9
發行號12
DOIs
出版狀態已發佈 - 2014 十二月 29

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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