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.

中文翻译：

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MSC调控的lncRNA MACC1-AS1通过脂肪酸氧化促进胃癌的干性和化学抗性。

化学疗法是晚期胃癌（GC）患者的首选疗法，而化学疗法的耐药性是有效癌症疗法的主要障碍。越来越多的证据表明，间充质干细胞（MSCs）对耐药性的发展做出了重要贡献。但是，基本机制仍然难以捉摸。在这项研究中，我们发现肿瘤组织中大量MSCs预示了GC患者的预后不良。MSC通过体外和体内的脂肪酸氧化（FAO）促进了GC细胞的干性和化学抗性。在机械上，MSC分泌的转化生长因子β1（TGF-β1）通过TGF-β受体激活SMAD2 / 3，并诱导GC细胞中长非编码RNA（lncRNA）MACC1-AS1表达，从而促进了FAO依赖的干性和化学抗性拮抗miR-145-5p。而且，依托莫司（ETX）对FAO的药理抑制作用减弱了MSC诱导的FOLFOX方案在体内的耐药性。这些结果表明，FAO在MSC介导的干性和GC中的化学抗性中起着重要作用，FAO抑制剂与化学疗法药物联合使用可作为克服化学耐药性的一种有前途的策略。