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

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.

Retracted: Long noncoding RNA MALAT1 promotes the stemness of esophageal squamous cell carcinoma by enhancing YAP transcriptional activity

“…For example, lncRNA CASC11 promotes the stemness of small cell lung cancer cells and predicts postoperative survival probably by promoting transforming growth factor b1 expression [6]. Mesenchymal stem cells could induce lncRNA MACC1-AS1 expression, which promotes the fatty acid oxidationdependent stemness of gastric cancer cells [8]. Mesenchymal stem cells could induce lncRNA MACC1-AS1 expression, which promotes the fatty acid oxidationdependent stemness of gastric cancer cells [8].…”

MSC-induced lncRNA HCP5 drove fatty acid oxidation through miR-3619-5p/AMPK/PGC1α/CEBPB axis to promote stemness and chemo-resistance of gastric cancer

“…However, only HCP5 was induced by MSC coculture in GC cells, indicating that MSC might regulate HCP5 to affect GC cells. Previous studies have revealed that MSCs released TGF-β-containing exosomes to transcriptionally induce lncRNA MACC1-AS1 in GC cells 32 . Therefore, it is also possible that HCP5 could be induced by certain exosome-derived factors from MSCs.…”

“…uncovered to play a role in chemo-resistance, stemness, and tumorigenesis in cancer cells [27][28][29][30] . Also, it has been proved that the facilitated FAO can induce metastasis, confer chemo-resistance and improve stemness of GC cells 31,32 . Thus, we hypothesized that MSC-activated HCP5/miR-3619-5p regulated FAO in GC cells.…”

“…In GC, the facilitated FAO is supported to aggravate the omental metastasis 31 . Interestingly, a recent study points out that MSC co-culture activates FAO in GC cells, leading to enhanced chemo-resistance 32 . However, mechanism of MSC-regulated FAO in GC remains to be further explored.…”

“…MACC1-AS1 enhances glycolysis to contribute to GC progression 40 . Moreover, MACC-AS1 is induced by MSC co-culture and promotes fatty acid oxidation in GC 32 . LncRNA HCP5 has been verified to elicit tumorpromoting function in lung adenocarcinoma 41 , colorectal cancer 42 , and thyroid carcinoma 43 .…”