Pakistan Journal of Pharmaceutical Sciences

Abstract: Background: Immunotherapy has significantly improved the treatment of lung cancer, but some patients experience aggressive disease, the mechanisms of which remain unclear. In particular, the interaction between lncRNA and the MDM2/MDM4 pathway warrants in-depth exploration. Objectives: This study aimed to investigate the role of LINC00511 in promoting aggressive disease during immunotherapy for lung carcinoma by modulating MDM2/MDM4 expression. Methods: This study collected tissues from 30 lung cancer patients undergoing immunotherapy and used A549 cell lines. RT-PCR detected expression of LINC00511, while immunohistochemistry and immunofluorescence detected MDM2/MDM4 expression. Bioinformatics analysis and luciferase reporter assays were performed to confirm their relationship. Cell migration, invasion, proliferation and response to PD-1 inhibitors were assessed. Results: using A549 cells and female BALB/c nude mice (n=6 per group). LINC00511 was significantly upregulated in aggressive disease tissues and positively correlated with tumor stage. MDM2/MDM4 expression was also elevated (P < 0.01). LINC00511 directly targeted MDM2/MDM4. Silencing LINC00511 effectively inhibited tumor cell proliferation, migration, invasion and Ki-67 expression in vitro and in vivo . In the xenograft model, BALB/c nude mice treated with Nivolumab (0.1 mg/kg i.p. every 3 days) showed reduced tumor volume (mean ± SD: 445.6 ± 45.3 mm3 vs. 720.4 ± 80.2 mm3 in controls; P < 0.01).Conclusion: LINC00511 promotes hyperprogressive disease in lung cancer during immunotherapy by upregulating MDM2/MDM4. Inhibition of LINC00511 effectively reverses tumor progression, suggesting a potential therapeutic target.