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.
Highlights
Ovarian cancer is the most lethal gynecological malignancy and the 5th leading cause of cancer death among women [1]
Expression of miR-193a resulted in a significant down-regulation of c-KIT mRNA and E2F6 mRNA, suggesting that c-KIT mRNA and E2F6 mRNA are targets of miR-193a in ovarian cancer cells (Fig. 1B)
Our mathematical model postulates the existence of a bimodal epigenetic control of miR-193a in ovarian carcinogenesis
Summary
Ovarian cancer is the most lethal gynecological malignancy and the 5th leading cause of cancer death among women [1]. An emerging hypothesis states that cancer arises from a small population of self-renewing cancer initiating cells (CIC) [4]. These CICs are thought to possess tumorigenic potential and enhanced drug resistance within a tumor, and are able to repopulate tumor colonies in vivo. We have previously isolated ovarian CICs (OCICs) from ovarian cancer patients [5]. These OCICs exhibit increased drug resistance towards cisplatin and taxol, and are characterized by the expression of several cell surface markers, including c-KIT (CD117, or stem cell factor receptor). The mechanism of how OCICs arise and how these cell surface markers are transcriptionally controlled are not fully understood
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