Overexpressed LncRNA ADAMTS9-AS2 inhibited gastric cancer (GC) development and sensitized chemoresistant GC cells to cisplatin by regulating miR-223-3p/NLRP3 axis

Abstract Background The role of LncRNA ADAMTS9-AS2 in the regulation of pathogenesis and chemoresistance of gastric cancer (GC) is largely unkonwn, and this study aimed to solve this problem. Methods Real-Time qPCR was used to examine LncRNA ADAMTS9-AS2 and miR-223-3p expressions, and pearson correlation analysis was conducted to analyse their correlations. Kaplan-Meier survival analysis was performed to evaluate prognosis of GC patients. Dual-luciferase reporter gene system and pull-down assay were employed to validate the target sites of LncRNA ADAMTS9-AS2, miR-223-3p and NLRP3 mRNA. Cell viability was evaluated by CCK-8 assay, trypan blue staining and colony formation assay. Cell apoptosis ratio was detected by FCM and TUNEL assay. Transwell assay for cell migration and Western Blot for protein expressions. ELISA was used to measure cytokines secretion. FISH was conducted to examine LncRNA ADAMTS9-AS2 expressions and localization in mice cancer tissues. Results LncRNA ADAMTS9-AS2 was low-expressed in GC tissues and cells compared to their normal counterparts. Besides, LncRNA ADAMTS9-AS2 inhibited miR-223-3p expressions in GC cells by acting as competing endogenous RNA, and the levels of LncRNA ADAMTS9-AS2 and miR-223-3p showed negative correlations in GC tissues. Of note, overexpression of LncRNA ADAMTS9-AS2 inhibited GC cell viability and motility by sponging miR-223-3p. In addition, the levels of LncRNA ADAMTS9-AS2 were lower, and miR-223-3p was higher in cisplatin-resistant GC (CR-GC) cells than their parental cisplatin-sensitive GC (CS-GC) cells. LncRNA ADAMTS9-AS2 overexpression enhanced the cytotoxic effects of cisplatin on CR-GC cells, which were reversed by overexpressing miR-223-3p. Furthermore, LncRNA ADAMTS9-AS2 increased NLRP3 expressions by targeting miR-223-3p, and upregulation of LncRNA ADAMTS9-AS2 triggered pyroptotic cell death in cisplatin treated CR-GC cells by activating NLRP3 inflammasome through downregulating miR-223-3p. Finally, the promoting effects of LncRNA ADAMTS9-AS2 overexpression on CR-GC cell death were abrogated by pyroptosis inhibitor NSA.Conclusions LncRNA ADAMTS9-AS2 acted as a tumor suppressor and enhanced cisplatin sensitivity in GC cells by regulating miR-223-3p/NLRP3 axis mediated pyroptosis.