IGF2BP2 Facilitates DDP Resistance in NSCLC Through Stabilizing SEZ6L2 Expression

Abstract

Non-small cell lung cancer (NSCLC) is a type of lung cancer, patients with which harbor poor overall survival. Insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) is an RNA-binding protein, and its mechanism of action in DDP-resistant NSCLC has not been reported. Quantitative real-time PCR (qRT-PCR) and western blot were used to detect gene and protein expression. DDP-resistant NSCLC cells were established to study the function of IGF2BP2 in vitro by Cell Counting Kit-8 (CCK-8), colony formation, wound healing, transwell, flow cytometry, and tube formation assays. Seizure related 6 homolog like 2 (SEZ6L2) was identified as the target, and the interaction between IGF2BP2 and SEZ6L2 were predicted by online websites, which was confirmed by RNA immunoprecipitation (RIP), and dual luciferase reporter assay, and RNA decay assay. In vivo, DDP-resistant cell-derived xenograft mice models were used to verify the effects of IGF2BP2 on tumor growth. IGF2BP2 was upregulated in DDP-resistant NSCLC patients and cells, which represented a poor prognosis. The silence of IGF2BP2 blocked proliferation, migration, and invasion of DDP-resistant NSCLC cells and accelerated apoptosis. Meanwhile, IGF2BP2 knockdown retarded the angiogenesis and macrophage M2 polarization. Furthermore, SEZ6L2 was highly expressed in DDP-resistant NSCLC patients and cells, and the patients with SEZ6L2 high expression had poor prognosis. Mechanistically, IGF2BP2 mediated the N6-methyladenosine (m6A) methylation and expression of SEZ6L2. Moreover, the inhibitory effects of IGF2BP2 silence on DDP-resistant NSCLC cell malignant behaviors were weakened by SEZ6L2 overexpression. The knockdown of IGF2BP2 also confined the tumor growth in vivo. In the present study, IGF2BP2 promotes the progression of DDP-resistant NSCLC by mediating m6A methylation on SEZ6L2 mRNA, providing a certain reference for the treatment of DDP-resistant NSCLC.

Keywords: DDP resistance; Insulin like growth factor 2 mRNA binding protein 2; N6‐methyladenosine; non‐small cell lung cancer; seizure related 6 homolog like 2.