RBM15-mediated m6A modification of XPR1 promotes the malignant progression of lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is a leading cause of cancer-related deaths worldwide. The poor prognosis of LUAD is attributed to its aggressive biological behavior and resistance to conventional therapies. Xenotropic and polytropic retrovirus receptor 1 (XPR1), a member of the XPR family, has been implicated in the pathogenesis of various malignancies, including LUAD. However, the regulatory mechanism of XPR1 in LUAD remains elusive. The study employed immunohistochemistry (IHC) and western blotting to analyze the protein expression of XPR1, RNA binding motif protein 15 (RBM15) and nuclear proliferation marker (ki-67) in LUAD tissues and cells. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression of XPR1, glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), and RBM15. Cell proliferation was assessed using a CCK-8 assay, colony-formation assay, and 5-Ethynyl-2'-deoxyuridine assay. Cell invasion and apoptosis were evaluated through transwell assay and flow cytometry, respectively. Caspase 3 activity and Fe levels were determined using colorimetric assays. Reactive oxygen species (ROS) levels were analyzed by flow cytometry. The dual-luciferase reporter assay and m6A RNA immunoprecipitation assay were performed to investigate the association between RBM15 and XPR1. An actinomycin D assay was conducted to analyze the effect of RBM15 silencing on XPR1 mRNA stability. A subcutaneous xenograft mouse model was established to validate the role of RBM15 and XPR1 in regulating the malignant behaviors of LUAD cells. Both XPR1 and RBM15 expression levels were upregulated in LUAD tissues and cells. Knockdown of XPR1 inhibited the proliferation and invasion of LUAD cells, while promoting cell apoptosis, oxidative stress, and ferroptosis. RBM15 was identified to stabilize XPR1 mRNA through m6A modification in LUAD cells. Overexpression of XPR1 attenuated the effects of RBM15 silencing on both A549 and PC-9 cells. Moreover, RBM15 silencing delayed tumor growth by regulating XPR1 in vivo. RBM15-mediated m6A modification of XPR1 promoted the malignant progression of lung adenocarcinoma. These findings provide new insights into the molecular mechanism underlying the pathogenesis of LUAD and suggest potential therapeutic strategies for the treatment of this devastating disease.