Article Text

Download PDFPDF

PR058/#188  Microrna-dependent inhibition of wee1 controls cancer stem-like characteristics and malignant behavior in ovarian cancer
  1. Woo Yeon Hwang,
  2. So Young Kim,
  3. Sun Woo Choi,
  4. Moon Yeon Hwang,
  5. Da Young Kang,
  6. Ji Eun Jung,
  7. Min Hyung Jung and
  8. Byung Su Kwon
  1. Kyung Hee University Hospital, Obstetrics and Gynecology, Seoul, Korea, Republic of


Introduction Cancer stem-like cells (CSCs) are recognized to be responsible for chemoresistance and tumor recurrence owing to their self-renewal capacity and differentiation potential. Although WEE1 is a promising target for anticancer therapies, its function in ovarian CSCs remains unknown. We present evidence that WEE1 regulates CSC properties and tumor resistance to carboplatin through a microRNA-dependent mechanism.

Methods Plasmid DNA constructs were transfected into human ovarian cancer cell lines. RNA and protein were extracted from pathologically confirmed tumor tissues. The SKOV3 spheroid tumor model were developed. Immunofluorescence analyses were performed on the xenograft tumors. miR-424 and miR-503 were detected by quantitative real-time PCR and western blot analysis. Spheroid formation assay was performed to investigate the presence and self-renewal ability of CSCs.

Results We found that WEE1 expression is upregulated in ovarian cancer spheroids because of the decreased expression of miR-424 and miR-503, which directly target WEE1. The overexpression of miR-424/503 suppressed CSC activity by inhibiting WEE1 expression, but restoring WEE1 expression reversed this effect. Furthermore, we demonstrated that NANOG modulates the miR-424/503-WEE1 axis that regulates the properties of CSCs. We also demonstrated the pharmacological restoration of the NANOG-miR-424/503-WEE1 axis and attenuation of ovarian CSC characteristics in response to atorvastatin treatment. Lastly, miR-424/503- mediated WEE1 inhibition re-sensitized chemoresistant ovarian cancer cells to carboplatin. Additionally, combined treatment with atorvastatin and carboplatin synergistically reduced tumor growth, chemoresistance, and peritoneal seeding in the intraperitoneal mouse models of ovarian cancer.

Conclusion/Implications We identified a novel NANOG-miR-424/503-WEE1 pathway for regulating ovarian CSCs, which has potential therapeutic utility in ovarian cancer treatment.

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.