Cancer-associated fibroblast-released extracellular vesicles carrying miR-199a-5p induces the progression of​ gastric cancer through regulation of FKBP5-mediated AKT1/mTORC1 signaling pathway

Cell Cycle. 2022 Dec;21(24):2590-2601. doi: 10.1080/15384101.2022.2105092. Epub 2022 Aug 25.

Abstract

Accumulating evidence has unfolded the significance of extracellular vesicles (EVs) in diseases and cancers. Here, we attempted to discuss the role of cancer-associated fibroblasts (CAFs)-derived EVs containing miR-199a-5p in gastric tumorigenesis. Upregulated miR-199a-5p was first identified in cancer cells. Then, we selected CAFs for isolation of EVs which were co-cultured with AGS cells. We observed successful delivery of miR-199a-5p via CAF-derived EVs. Besides, miR-199a-5p promoted malignant properties of AGS cells. Moreover, miR-199a-5p downregulated FKBP5, leading to upregulated phosphorylation level of AKT1, which promoted the malignant phenotypes of AGS cells by activating mammalian target of rapamycin complex 1(mTORC1). Exosomal miR-199a-5p from CAFs promoted gastric tumorigenesis in vivo. Our findings point toward the critical role of CAFs-derived EVs carrying miR-199a-5p in gastric cancer progression.

Keywords: AKT1; Cancer-associated fibroblasts; FKBP5; extracellular vesicles; gastric cancer; mTORC1; microRNA-199a-5p.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cancer-Associated Fibroblasts* / metabolism
  • Carcinogenesis / pathology
  • Extracellular Vesicles* / metabolism
  • Extracellular Vesicles* / pathology
  • Humans
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • Stomach Neoplasms* / pathology

Substances

  • MicroRNAs
  • Mechanistic Target of Rapamycin Complex 1
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt

Grants and funding

This study was supported by Nantong Municipal Science and Technology Planning Project [grant no. JCZ20208, MS12020046], Youth Science and Research Foundation of Nantong Municipal Health Commission [grant no. QA2021032], and Natural Science Foundation of Jiangsu Higher Education Institutions of China [grant no. 19KJA24000 to Z. W].