Mechanism of gastric cancer cell-derived exosomal circPDSS1 promoting ferroptosis of natural killer cells by regulating miR-1278/GOT1 molecular axis

Abstract

Abstract Background: Gastric cancer (GC) is one of the malignant tumors, with complex molecular mechanisms. Ferroptosis plays an important regulatory role in the development of GC. But no studies have investigated the specific mechanism of ferroptosis in natural killer (NK) cells in GC. This study aims to elucidate the molecular mechanism of GC cells regulating ferroptosis in NK cells. Methods: qRT-qPCR was used to test the expression of circular RNA decaprenyl diphosphate synthase subunit 1 (circPDSS1) and microRNA-1278 (miR-1278). The protein expressions of glutathione peroxidase 4 (GPX4) and aspartate aminotransferase 1 (GOT1) were tested by Western blot, used fluorescence in situ hybridization to analyse location of circPDSS1 expressions, and the level of reactive oxygen species (ROS) was detected by immunofluorescence. Malondialdehyde (MDA) levels were detected by MDA kit, dual luciferase reporter gene to analyze targeting relationship, CCK-8 analyze the cell proliferation, transwell analyze the cell migration, and cell apoptosis was detected by flow cytometry. Results: circPDSS1 expression is elevated in GC tissues and peripheral blood, and that GC cells secrete circPDSS1 by exosomes. Exosomes of knockdown circPDSS1 significantly reduced ROS and MDA levels and elevated GPX4 expression in NK cells. More importantly, circPDSS1 can act as a sponge for miR-1278 in NK cells, inhibiting its up-regulation and promoting the expression of GOT1, thereby impaired NK cell function and ultimately induced GC progression. Conclusion: The GC cells-derived exosomal circPDSS1 promotes ferroptosis of NK cells by regulating the miR-1278/GOT1 molecular axis, thereby inducing GC progression.