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

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)e116050
JournalPLoS One
Volume9
Issue number12
DOIs
Publication statusPublished - 2014

Fingerprint

ovarian neoplasms
Neoplastic Stem Cells
Stem cells
Epigenomics
epigenetics
Ovarian Neoplasms
stem cells
Estrogens
Theoretical Models
mathematical models
Mathematical models
Transcription
Surface Antigens
MicroRNAs
Tumors
Proteins
Association reactions
Degradation
Messenger RNA
estrogens

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Cheng, F. H. C., Aguda, B. D., Tsai, J. C., Kochańczyk, M., Lin, J. M. J., Chen, G. C. W., ... Chan, M. W. Y. (2014). A mathematical model of bimodal epigenetic control of miR-193a in ovarian cancer stem cells. PLoS One, 9(12), e116050. https://doi.org/10.1371/journal.pone.0116050

A mathematical model of bimodal epigenetic control of miR-193a in ovarian cancer stem cells. / 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.

In: PLoS One, Vol. 9, No. 12, 2014, p. e116050.

Research output: Contribution to journalArticle

Cheng, FHC, Aguda, BD, Tsai, JC, Kochańczyk, M, Lin, JMJ, Chen, GCW, Lai, HC, Nephew, KP, Hwang, TW & Chan, MWY 2014, 'A mathematical model of bimodal epigenetic control of miR-193a in ovarian cancer stem cells', PLoS One, vol. 9, no. 12, pp. e116050. https://doi.org/10.1371/journal.pone.0116050
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. / A mathematical model of bimodal epigenetic control of miR-193a in ovarian cancer stem cells. In: PLoS One. 2014 ; Vol. 9, No. 12. pp. e116050.
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