Ras guanine nucleotide exchange factor RasGRP1 promotes acute inflammatory response and restricts inflammation-contributed cancer cell growth

Abstract

Acute inflammatory response needs to be tightly regulated for promoting the elimination of pathogens and preveting the risk of tumorigenesis, but the mechanism has not been fully elucidated. Here, we report that Ras guanine nucleotide releasing protein 1 (RasGRP1) plays a bifunctional regulator that promotes acute inflammation and inhibits inflammation-associated cancer. At the mRNA level, RasGRP1 strengthens the inflammatory response by functioning as a competing endogenous RNA to specifically promote IL-6 expression by sponging let-7a. In vivo overexpression of the RasGRP1 3' untranslated region significantly aggravated lipopolysaccharide-induced systemic inflammation and dextran sulphate sodium-induced colitis in IL-6+/+ mice but not in IL-6-/- mice. At the protein level, RasGRP1 restricts the growth of inflammation-contributed cancer cells by impairing EGFR-SOS1-Ras-AKT signalling. Tumour patients with high RasGRP1 expression showed a better clinical outcome than those with low expression. Considering acute inflammation rarely leads to tumorigenesis, this work reveals that RasGRP1 is an essential bifunctional regulator for acute inflammatory response.