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

Yanwei Xing,Chengbo Wang,Niansheng Ren,Tao Jiang,Tiemin Zhang,Daxun Piao,Shilin Xie,Yuekun Zhu

doi:10.18632/aging.103314

Yanwei Xing, Chengbo Wang + Show 6 more

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https://doi.org/10.18632/aging.103314

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Abstract

The role of LncRNA ADAMTS9-AS2 in the regulation of chemoresistance of gastric cancer (GC) is largely unknown. Here we found that LncRNA ADAMTS9-AS2 was low-expressed in GC tissues and cells compared to their normal counterparts. In addition, 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 Necrosulfonamide (NSA). Collectively, LncRNA ADAMTS9-AS2 acted as a tumor suppressor and enhanced cisplatin sensitivity in GC cells by activating NLRP3 mediated pyroptotic cell death through sponging miR-223-3p.

Highlights

Gastric cancer (GC) is a common malignancy in the digestive system [1, 2], the number of inpatient admissions for GC have decreased over the past decades, the healthcare burden and cost related to it has increased significantly [3]
The results showed that Long non-coding RNAs (LncRNAs) ADAMTS9-AS2 was lowexpressed (Figure 1A), while miR-223-3p was highexpressed (Figure 1B) in GC tissues compared to their corresponding normal tissues
The expression levels of LncRNA ADAMTS9-AS2 and miR-223-3p were negatively correlated in GC tissues (Figure 1C), which were validated by the online Pan-cancer correlation analysis for 372 specimens from the patients with stomach adenocarcinoma (STAD) (Figure 1D)

Summary

Introduction

Gastric cancer (GC) is a common malignancy in the digestive system [1, 2], the number of inpatient admissions for GC have decreased over the past decades, the healthcare burden and cost related to it has increased significantly [3]. Surgical resection [4], radiotherapy [5], chemotherapy [6] and combined therapy [7] remain the primary therapies for GC treatment in clinic. Cisplatin is the first-line chemotherapeutic drug for GC treatment [8, 9], and cisplatin induces GC cell death by triggering DNA damage response (DDR) [10, 11]. Cell pyroptosis is a type of programmed cell death characterized by NLRP3 inflammasome activation and inflammatory cytokines secretion [15, 16]. Recent study found that cisplatin induced pyroptotic cell death in lung cancer cells by www.aging-us.com targeting Caspase-3/Gasdermin E (GSDME) signaling cascade [17], it is still unclear whether cisplatin induced GC cell pyroptosis

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