The m6A reader IGF2BP3 promotes gastric cancer progression via increasing the expression of FBXO32 protein

Abstract

AbstractN6-methyladenosine (m6A) is the most common chemical modification of eukaryotic mRNAs, and there is increasing evidence that it plays a vital role in human cancer. However, the relationship between the m6A reader, IGF2BP3, and gastric cancer (GC) has not been fully elucidated. Compared with adjacent normal tissues, the expression level of IGF2BP3 in GC tissues was significantly elevated, which was associated with lymph node metastasis and advanced TNM stage. After the expression level of IGF2BP3 was knocked down in GC cells, the proliferation, migration and invasion ability of the cells were significantly inhibited, the apoptosis level increased, and the levels of glucose, lactic acid and ATP in the cells significantly decreased. When IGF2BP3 was overexpressed, the cell showed the opposite effect. Knocking down IGF2BP3 can inhibit the growth of GC xenograftsin vivo. Through RNA-seq, MeRIP-seq, RIP-seq and bioinformatics analysis, it was determined that the downstream target gene of IGF2BP3 in GC was FBXO32, which was highly expressed in GC. The interaction between IGF2BP3 and FBXO32 was confirmed by RIP-qPCR, Co-IP and Co-IF. Subsequently, qRT-PCR, WB and rescue studies confirmed that IGF2BP3 could regulate the expression of FBXO32 protein, and the effect of IGF2BP3 on GC cell function was influenced by FBXO32. In summary, our research reveals that IGF2BP3 regulates the expression of FBXO32 protein in an m6A-dependent manner, thereby promoting the progression of GC. The IGF2BP3-FBXO32 axis is crucial for GC occurrence and development and is expected to serve as a potential novel target for the development of GC therapeutics.