CAFs-secreted exosomal cricN4BP2L2 promoted colorectal cancer stemness and chemoresistance by interacting with EIF4A3

Exp Cell Res. 2022 Sep 15;418(2):113266. doi: 10.1016/j.yexcr.2022.113266. Epub 2022 Jun 22.

Abstract

Cancer-associated fibroblasts secreted exosomes (CAFs-exo) are important for tumor carcinogenesis and chemoresistance, but its underlying mechanism in colorectal cancer (CRC) has not yet been clarified. In this study, we investigated the regulatory mechanism of CAFs-exo cricN4BP2L2 on the proliferation, apoptosis, stemness and chemoresistance of LoVo cells. We found that CAFs-exo promoted the oxaliplatin resistance and stemness of LoVo cells, while inhibited the LoVo cell apoptosis. Moreover, knockdown of cricN4BP2L2 in CAFs-exo inhibited the oxaliplatin resistance and stemness characteristics of LoVo cells. Mechanistically, cricN4BP2L2 regulated PI3K/AKT/mTOR axis by binding to EIF4A3. Rescue experiments proved that CAFs-derived exosomal cricN4BP2L2 promoted CRC cells stemness and oxaliplatin resistance by upregulating EIF4A3. Moreover, in vivo experiments showed that depletion of cricN4BP2L2 suppressed CRC tumorigenesis growth. In conclusion, CAFs-exo cricN4BP2L2 promoted the CRC cells stemness and oxaliplatin resistance through EIF4A3/PI3K/AKT/mTOR pathway.

Keywords: Cancer-associated fibroblasts; Colorectal cancer; Exosome; Oxaliplatin; circN4BP2L2.

MeSH terms

  • Cancer-Associated Fibroblasts* / pathology
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Colorectal Neoplasms* / drug therapy
  • Colorectal Neoplasms* / genetics
  • Colorectal Neoplasms* / metabolism
  • DEAD-box RNA Helicases / metabolism
  • Drug Resistance, Neoplasm
  • Eukaryotic Initiation Factor-4A / metabolism
  • Exosomes* / metabolism
  • Humans
  • MicroRNAs* / metabolism
  • Oxaliplatin
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • MicroRNAs
  • Oxaliplatin
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Eukaryotic Initiation Factor-4A
  • EIF4A3 protein, human
  • DEAD-box RNA Helicases