Functional role of the SLC7A11-AS1/xCT axis in the development of gastric cancer cisplatin-resistance by a GSH-dependent mechanism

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. Herein, 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.