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

Wanming He,Jia Liu,Yi Xiang,Min Shi,Yajing Liu,Zhiqi Yao,Qiong Huang,Wangjun Liao,Zexian Liu,Shaowei Li,Chunlin Wang,Yang Zhao,Qijing Wu,Shuyi Zhang,Bishan Liang

doi:10.1038/s41388-019-0747-0

Abstract

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.

Highlights

Gastric cancer (GC) is a critical health burden and the second common cause of cancer-related death globally [1]
Colonyformation assay showed that growth inhibition effects of 1 μg/mL 5-FU and 3 μg/mL oxaliplatin on GC cells were remarkably decreased in the presence of mesenchymal stem cells (MSCs) (Fig. 1c)
Our findings demonstrated that MSCs promoted GC cell self-renewal and chemoresistance through fatty acid oxidation (FAO)

Summary

Introduction

Gastric cancer (GC) is a critical health burden and the second common cause of cancer-related death globally [1]. Chemotherapy is the preferred treatment for advanced stage GC patients. 5-Florouracil (5-FU)-based chemotherapy regimens, such as 5-FU in combination with cisplatin (DDP) or oxaliplatin, are generally accepted as the first-line treatments in advanced GC [2,3,4]. These authors contributed : Wanming He, Bishan Liang, Chunlin Wang

Methods

Results

Conclusion