Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 184, Issue -, Pages 53-65Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2022.03.026
Keywords
Long non-coding RNA; Gastric cancer; SLC7A11-AS1; xCT; Cisplatin resistance
Funding
- National Natural Science Foundation of China [81270561]
- Key Project of Sichuan Provincial Department of Science and Technology Applied Basic Research Program, China [22YYJC1850]
- Sichuan Provincial Outstanding Youth Fund Project, China [2015JQ0060]
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This study reveals the involvement of SLC7A11-AS1 and xCT in cisplatin resistance in gastric cancer. Downregulation of SLC7A11-AS1 and upregulation of xCT are associated with poor prognosis and chemotherapy response. Overexpression of SLC7A11-AS1 suppresses gastric cancer cell growth and enhances sensitivity to cisplatin.
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.
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