Dual inhibition of EGFR and IL-6-STAT3 signalling by miR-146b: a potential targeted therapy for epithelial ovarian cancer

J Enzyme Inhib Med Chem. 2021 Dec;36(1):1905-1915. doi: 10.1080/14756366.2021.1963240.

Abstract

Epidermal growth factor receptor (EGFR) signalling and the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) are aberrantly activated in ovarian cancer. However, inhibition of EGFR signalling in ovarian cancer patients resulted in a disappointing clinical benefit. In this study, we found that EGFR could activate IL-6-STAT3 pathway in ovarian cancer cells. However, we also demonstrated that EGFR knockdown could increase STAT3 phosphorylation in HO8910 and OVCAR-3 ovarian cancer cells. Interestingly, we further demonstrated that the non-coding RNA miR-146b could simultaneously block both the EGFR and IL-6-STAT3 pathways. Finally, our data demonstrated that miR-146b overexpression resulted in a greater suppression of cell migration than STAT3 pathway inhibition alone.These results suggest a complex and heterogeneous role of EGFR in ovarian cancer. Combined blockade of EGFR and IL-6-STAT3 pathways by miR-146b might be a strategy for improving the clinical benefit of targeting the EGFR pathway in ovarian cancer patients in the future.

Keywords: EGFR; MiR-146b; STAT3; epithelial ovarian cancer.

MeSH terms

  • Carcinoma, Ovarian Epithelial / metabolism*
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Female
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Humans
  • Interleukin-6 / metabolism*
  • MicroRNAs / metabolism*
  • Ovarian Neoplasms / metabolism*
  • Phosphorylation
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction

Substances

  • Interleukin-6
  • MIRN146 microRNA, human
  • MicroRNAs
  • STAT3 Transcription Factor
  • ErbB Receptors

Grants and funding

Our research was supported by Jiangsu Provincial Commission of Health and Family Planning [H2019064], and Suzhou "Science, Education and Health" Youth Science and Technology Project [KJXW2019039], and National Natural Science Foundation of China [81273202].