Cancer-associated fibroblast exosomes promote chemoresistance to cisplatin in hepatocellular carcinoma through circZFR targeting signal transducers and activators of transcription (STAT3)/ nuclear factor -kappa B (NF-κB) pathway

Bioengineered. 2022 Mar;13(3):4786-4797. doi: 10.1080/21655979.2022.2032972.

Abstract

Chemoresistance in hepatocellular carcinoma (HCC) has been found to be influenced by exosomal transport of circRNAs. However, the role of circZFR in HCC chemoresistance still remains unclear. In the present study, circZFR was highly expressed in cisplatin (DDP)-resistant HCC cell lines and could regulate DDP resistance of the HCC cells. Also, circZFR was highly expressed in cancer-associated fibroblast (CAFs) and the exosome of CAFs. In addition, supplementation of CAFs in culture medium could promote DDP resistance of HCC cells. In vivo tumor xenograft experiments showed that knockdown of circZFR inhibited tumor growth and weakened DDP resistance, while CAFs-derived exosomes incubation increased the expression of circZFR, inhibited the STAT3/NF-κB pathway, promoted tumor growth, and enhanced DDP resistance. In general, CAFs-derived exosomes deliver circZFR to HCC cells, inhibit the STAT3/NF-κB pathway, and promote HCC development and chemoresistance. The results provided a new sight for the prevention and treatment of chemoresistance in HCC.

Keywords: Cancer-associated fibroblast exosomes; circZFR; cisplatin resistance; hepatocellular carcinoma.

MeSH terms

  • Cancer-Associated Fibroblasts* / metabolism
  • Cancer-Associated Fibroblasts* / pathology
  • Carcinoma, Hepatocellular* / drug therapy
  • Carcinoma, Hepatocellular* / genetics
  • Carcinoma, Hepatocellular* / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Cisplatin / pharmacology
  • Cisplatin / therapeutic use
  • Drug Resistance, Neoplasm / genetics
  • Exosomes* / metabolism
  • Humans
  • Liver Neoplasms* / drug therapy
  • Liver Neoplasms* / genetics
  • Liver Neoplasms* / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • RNA, Circular* / genetics
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Transducers

Substances

  • NF-kappa B
  • RNA, Circular
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Cisplatin

Grants and funding

The author(s) reported there is no funding associated with the work featured in this article.