Functional Role of the SLC7A11-AS1/xCT Axis in the Development of Gastric Cancer Cisplatin-resistance by a GSH-dependent Mechanism
Abstract Background: Resistance to platinum-based chemotherapy is a major obstacle in gastric cancer (GC) treatment. Abundant long noncoding RNAs (lncRNAs) are reported to play important roles in tumorigenesis and drug resistance biology. We aimed to investigate the roles and mechanisms of SLC7A11-AS1 in GC cisplatin resistance.Methods: Quantitative real-time PCR (qRT-PCR), RNA fluorescence in situ hybridization (RNA-FISH), immunofluorescence staining and immunohistochemistry were performed on GC tissues or cells to assess expression of SLC7A11-AS1/xCT axis. Cell migration, invasion and apoptosis ability were evaluated by wound healing, transwell and flow cytometry assays. The functional roles of SLC7A11-AS1/xCT axis in GC cisplatin resistance were demonstrated by a series of in-vitro and in-vivo experiments.Results: We report that the SLC7A11-AS1 and xCT are involved in cisplatin resistance in GC. SLC7A11-AS1 was downregulated and xCT was upregulated in cisplatin-resistant GC tissues and cell lines. GC patients with low expression of SLC7A11-AS1 and high expression of xCT had a poor prognosis and relatively poor response to chemotherapy. Overexpression of SLC7A11-AS1 weakened GC growth, reduced intracellular GSH biosynthesis, enhanced intracellular reactive oxygen species (ROS) and conferred sensitivity to cisplatin to resistant GC cells in vitro and in vivo. Mechanistically, SLC7A11-AS1 directly suppressed xCT expression, while miR-33a-5p remarkably reduced SLC7A11-AS1 and xCT expression by directly targeting the SLC7A11-AS1 and xCT 3’UTRs. In addition, we found that low SLC7A11-AS1 expression activated the p38MAPK-JNK signaling pathway, and increased the expression of cisplatin export gene ATP7A and the GSH biosynthesis gene GCLM in GC. Conclusions: These findings suggest that the SLC7A11-AS1/xCT axis is a crucial therapeutic target to overcome platinum-related resistance for GC treatment.