MSC-regulated lncRNA MACC1-AS1 promotes stemness and chemoresistance through fatty acid oxidation in gastric cancer

Oncogene. 2019 Jun;38(23):4637-4654. doi: 10.1038/s41388-019-0747-0. Epub 2019 Feb 11.


Chemotherapy is the preferred treatment for advanced stage gastric cancer (GC) patients and chemotherapy resistance is the major obstacle to effective cancer therapy. Increasing evidence suggests that mesenchymal stem cells (MSCs) make important contributions to development of drug resistance. However, the underlying mechanism remains elusive. In this study, we discovered that abundant MSCs in tumor tissues predicted a poor prognosis in GC patients. MSCs promoted stemness and chemoresistance in GC cells through fatty acid oxidation (FAO) in vitro and in vivo. Mechanically, transforming growth factor β1 (TGF-β1) secretion by MSCs activated SMAD2/3 through TGF-β receptors and induced long non-coding RNA (lncRNA) MACC1-AS1 expression in GC cells, which promoted FAO-dependent stemness and chemoresistance through antagonizing miR-145-5p. Moreover, pharmacologic inhibition of FAO with etomoxir (ETX) attenuated MSC-induced FOLFOX regiment resistance in vivo. These results suggest that FAO plays an important role in MSC-mediated stemness and chemotherapy resistance in GC and FAO inhibitors in combination with chemotherapeutic drugs present as a promising strategy to overcome chemoresistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Cells, Cultured
  • Drug Resistance, Neoplasm / genetics*
  • Fatty Acids / metabolism*
  • Female
  • Fluorouracil / administration & dosage
  • Fluorouracil / therapeutic use
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Leucovorin / therapeutic use
  • Lipid Metabolism / drug effects
  • Lipid Metabolism / physiology
  • Mesenchymal Stem Cells / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Organoplatinum Compounds / therapeutic use
  • Oxidation-Reduction
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism
  • RNA, Long Noncoding / physiology*
  • Stomach Neoplasms* / drug therapy
  • Stomach Neoplasms* / genetics
  • Stomach Neoplasms* / metabolism
  • Stomach Neoplasms* / pathology
  • Trans-Activators
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics


  • Fatty Acids
  • MACC1 protein, human
  • Organoplatinum Compounds
  • RNA, Long Noncoding
  • Trans-Activators
  • Transcription Factors
  • Leucovorin
  • Fluorouracil

Supplementary concepts

  • Folfox protocol