IGF2BP2-meidated m 6 A modification of CSF2 reprograms MSC to promote gastric cancer progression

Abstract

Abstract Background The interaction between tumor cells and stromal cells in tumor microenvironment is critical for cancer progression. MSCs represent a dominant source of tumor stromal cells and exert pro-oncogenic activities when reprogrammed by tumor. The precise mechanism for MSC reprogramming in gastric cancer has not been fully understood. Methods The gene and protein expression levels were examined by qRT-PCR, western blot, and immunohistochemistry. The biological functions of gastric cancer cells were detected by in vitro and in vivo experiments. RNA‐sequencing, RNA immunoprecipitation (RIP), and meRIP assays were conducted to explore the potential regulatory mechanisms. Results We identified that the expression and N6-methyladenosine (m6A) modification levels of colony stimulating factor 2 (CSF2) were significantly increased in gastric cancer MSCs. CSF2 upregulation and stimulation induced the reprogramming of normal MSCs to cancer-promoting MSCs, which promoted the proliferation, migration, and drug resistance of gastric cancer cells through the secretion of various pro-inflammatory factors. We further demonstrated that CSF2 mRNA was recognized and stabilized by m6A reader IGF2BP2, whose overexpression mimicked the effect of CSF2 on MSCs to promote gastric cancer progression. Finally, we found that CSF2 exerted the reprograming effect of MSCs by inducing the ubiquitination of Notch1. Conclusions The increased m6A modification of CSF2 by IGF2BP2 reprogrammed MSCs into a cancer-promoting phenotype. The IGF2BP2/CSF2/Notch1 axis represents a new mechanism for MSC programming in gastric cancer and offers a novel target for gastric cancer therapy.