IGF2BP2 promotes gastric cancer progression by regulating the IGF1R-RhoA-ROCK signaling pathway

Our study aimed to probe the intrinsic and concrete molecular mechanism of IGF2 mRNA-binding protein 2 (IGF2BP2) in gastric cancer (GC). The mRNA and protein expressions were assessed using qRT-PCR and western blot, respectively. CCK-8 assay was employed to determine cell proliferation. Levels of TNFα and IL-1β were analyzed using ELISA. Furthermore, cell apoptosis was evaluated using flow cytometry analysis. Cell migration and invasion were evaluated using Transwell assay. The experiment of tumor formation in nude mice was employed to analyze the effect of IGF2BP2 in regulating GC tumor growth and lung metastasis in vivo. Finally, the binding relationship between IGF1R and IGF2BP2 was verified using RIP and RNA pull down assays. IGF2BP2 was significantly elevated in both GC tissues and cells. Silencing of IGF2BP2 dramatically suppressed the inflammation, proliferation, migration and invasion, yet promoted cell apoptosis in vitro and in vivo. Furthermore, IGF2BP2, as a m6A reader, was proved to increase the expression of IGF1R by identifying m6A methylation modification sites in IGF1R mRNA, thus activating RhoA-ROCK pathway. Importantly, the anti-carcinogenic impacts of IGFBP2 silence were restrained by IGF1R overexpression, which was eliminated by the inactivation of RhoA-ROCK. We emphasized the oncogenic role of IGF2BP2 in gastric carcinogenesis and confirmed its activation is partly due to the activation of IGF1R-RhoA-ROCK signaling pathway. Our findings identified that IGF2BP2 might be a promising prognostic biomarker and provided clinical translational potential.