IGF2BP2 Facilitates DDP Resistance in NSCLC Through Stabilizing SEZ6L2 Expression

Area of Science:

• Molecular Oncology
• Cancer Biology
• Drug Resistance Mechanisms

Background:

• Non-small cell lung cancer (NSCLC) patients exhibit poor survival, particularly those resistant to cisplatin (DDP).
• The role of Insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) in DDP-resistant NSCLC remains unelucidated.

Purpose of the Study:

• To investigate the mechanism of IGF2BP2 in DDP-resistant NSCLC.
• To identify the downstream target of IGF2BP2 and its role in tumor progression.

Main Methods:

• Quantitative real-time PCR (qRT-PCR) and Western blot for gene and protein expression analysis.
• In vitro assays (CCK-8, colony formation, wound healing, Transwell, flow cytometry, tube formation) to assess cell behavior.
• RNA immunoprecipitation (RIP), dual luciferase reporter, and RNA decay assays to confirm molecular interactions.
• In vivo xenograft mouse models to evaluate tumor growth.

Main Results:

• IGF2BP2 was upregulated in DDP-resistant NSCLC, correlating with poor prognosis.
• IGF2BP2 knockdown inhibited proliferation, migration, invasion, angiogenesis, and M2 macrophage polarization, while promoting apoptosis.
• Seizure related 6 homolog like 2 (SEZ6L2) was identified as a direct target, regulated by IGF2BP2 via m6A methylation, and associated with poor prognosis.
• SEZ6L2 overexpression partially reversed the inhibitory effects of IGF2BP2 knockdown.

Conclusions:

• IGF2BP2 promotes DDP-resistant NSCLC progression by mediating m6A methylation of SEZ6L2 mRNA.
• IGF2BP2 and SEZ6L2 represent potential therapeutic targets for DDP-resistant NSCLC.