MALAT1 Induces Fibroblast Activation to Promote Cancer Progression via Blunting Autophagic Flux and Instigating IL-6 Secretion in Gastric Cancer Cells

Abstract

BackgroundAutophagy defection contributes to inflammation dysregulation, which plays an important role in gastric cancer (GC) progression. Various studies have demonstrated that long noncoding RNA could function as novel regulators of autophagy. However, the epigenetic regulatory mechanisms by which blockage of autophagy caused by long noncoding RNAs develops cancer progression remain unclear. This study aimed to investigate the role of the long noncoding RNA MALAT1 in the autophagy related inflammation dysregulation of GC progression and elucidate the underlying molecular mechanisms.MethodsThe effect of MALAT1 on autophagy in GC cells was analysed by immunoblotting, immunofluorescence and transmission electron microscopy. The role of MALAT1 in regulating inflammation dysregulation was evaluated by ELISA, qPCR and immunoblotting. Bioinformatic prediction, RNA immunoprecipitation-qRCP and immunofluorescence were performed to identify the competitive binding relationship among MALAT1, ELAVL1 and PTEN 3'-UTRs.The chromatin immunoprecipitation assay was performed to examine STAT3 interaction in the MALAT1 promoter region. Immunoblotting was performed to identify the PTEN/AKT/mTOR and SQSTM1/NF-kb mediated pathways altered by MALAT1. The influence of MALAT1 on fibroblasts activation were determined both in in vitro and in vivo.ResultsWe found that the long noncoding RNA MALAT1 could promote interleukin-6 (IL-6) secretion in GC cells by blocking autophagic flux. Moreover, IL-6 induced by MALAT1 could activate normal to cancer-associated fibroblast conversion. The interaction between GC cells and cancer-associated fibroblasts in the tumour microenvironment could facilitate cancer progression. Mechanistically, MALAT1 overexpression destabilized the PTEN mRNA in GC cells by competitively interacting with the RNA-binding protein ELAVL1 to activate the AKT/mTOR pathway for impairing autophagic flux. As the consequence of autophagy inhibition, SQSTM1 accumulation promotes NF-κB translocation to elevate IL-6 expression. Furthermore, STAT3 induced by IL-6 is responsible for upregulation of MALAT1 in GC.ConclusionsOverall, these results demonstrated that intercellular interaction between GC cells and fibroblasts was mediated by autophagy inhibition caused by increased MALAT1 that promote GC progression, providing novel prevention and therapeutic strategies for GC.