Transforming growth factor‑β/miR‑143‑3p/cystatin B axis is a therapeutic target in human ovarian cancer

Int J Oncol. 2019 Jul;55(1):267-276. doi: 10.3892/ijo.2019.4815. Epub 2019 May 28.


We previously reported that cystatin B (CSTB) is a progression marker of human ovarian cancer (OC); however, the regulatory mechanism of CSTB and its function in OC remain unclear. The present study aimed to explore the mechanism underlying transforming growth factor-β (TGF‑β) 1‑mediated CSTB regulation, and to examine the function of CSTB on OC cell proliferation and apoptosis. Using the online program, miRWalk, a microRNA (miR)‑143‑3p was detected, which contains a homologous sequence of the potential binding site to the 3'‑untranslated region (3'‑UTR) of CSTB. A dual‑luciferase reporter assay confirmed the interaction between miR‑143‑3p and CSTB 3'‑UTR. Treating OC cells with miR‑143‑3p mimics or inhibitors resulted in a decrease or an increase of CSTB expression at mRNA and protein levels, respectively. Additionally, CSTB was significantly overexpressed, whereas miR‑143‑3p was downregulated in human OC tissues compared with normal ovarian tissues. A negative correlation between miR‑143‑3p and CSTB mRNA expression was observed in ovarian malignant tumors. The levels of primary and mature miR‑143‑3p expression were upregulated in OC cells after TGF‑β1 treatment; the action of TGF‑β1 was abolished in the presence of an inhibitor of TGF‑β type I receptor. These results indicated an axis between TGF‑β, miR‑143‑3p and CSTB in OC cells. Furthermore, high levels of CSTB expression were associated with the poor overall survival of patients with OC. Knockdown of CSTB resulted in a decrease in OC cell proliferation and arrested cells in G2/M phase. In addition, suppression of CSTB induced cell apoptosis. In conclusion, CSTB was overexpressed and miR‑143‑3p was downregulated in ovarian malignant tumors. Mature miR‑143‑3p directly bound CSTB 3'‑UTR, leading to a decrease in CSTB expression in OC cells, which was regulated by TGF‑β1. Our findings suggest the potential therapeutic application of targeting the TGF‑β/miR‑143‑3p/CSTB axis for treating patients with OC.

MeSH terms

  • 3' Untranslated Regions
  • Adult
  • Aged
  • Aged, 80 and over
  • Apoptosis / physiology
  • Carcinoma, Ovarian Epithelial / genetics
  • Carcinoma, Ovarian Epithelial / metabolism*
  • Carcinoma, Ovarian Epithelial / pathology
  • Cell Line, Tumor
  • Cell Proliferation / physiology
  • Cystatin B / biosynthesis
  • Cystatin B / genetics
  • Cystatin B / metabolism*
  • Female
  • Gene Knockdown Techniques
  • Humans
  • MicroRNAs / biosynthesis
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Middle Aged
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism*
  • Up-Regulation
  • Young Adult


  • 3' Untranslated Regions
  • CSTB protein, human
  • MIRN143 microRNA, human
  • MicroRNAs
  • RNA, Messenger
  • TGFB1 protein, human
  • Transforming Growth Factor beta1
  • Cystatin B