RasGRP1 promotes the acute inflammatory response and restricts inflammation-associated cancer cell growth
Open Access
- 16 November 2022
- journal article
- research article
- Published by Springer Nature in Nature Communications
- Vol. 13 (1) , 1-17
Abstract
An acute inflammatory response needs to be properly regulated to promote the elimination of pathogens and prevent the risk of tumorigenesis, but the relevant regulatory mechanism has not been fully elucidated. Here, we report that Ras guanine nucleotide-releasing protein 1 (RasGRP1) is a bifunctional regulator that promotes acute inflammation and inhibits inflammation-associated cancer. At the mRNA level, Rasgrp1 activates 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 enhances lipopolysaccharide-induced systemic inflammation and dextran sulphate sodium-induced colitis in Il6+/+ mice but not in Il6-/- mice. At the protein level, RasGRP1 overexpression significantly inhibits the tumour-promoting effect of IL-6 in hepatocellular carcinoma progenitor cell-like spheroids. Examination of the EGFR signalling pathway shows that RasGRP1 inhibits inflammation-associated cancer cell growth by disrupting the EGFR-SOS1-Ras-AKT signalling pathway. Tumour patients with high RasGRP1 expression have better clinical outcomes than those with low RasGRP1 expression. Considering that acute inflammation rarely leads to tumorigenesis, this study suggests that RasGRP1 may be an important bifunctional regulator of the acute inflammatory response and tumour growth.Keywords
This publication has 58 references indexed in Scilit:
- In Vivo Identification of Tumor- Suppressive PTEN ceRNAs in an Oncogenic BRAF-Induced Mouse Model of MelanomaCell, 2011
- Coding-Independent Regulation of the Tumor Suppressor PTEN by Competing Endogenous mRNAsCell, 2011
- A Long Noncoding RNA Controls Muscle Differentiation by Functioning as a Competing Endogenous RNACell, 2011
- A ceRNA Hypothesis: The Rosetta Stone of a Hidden RNA Language?Cell, 2011
- Analysis of the host microRNA response to Salmonella uncovers the control of major cytokines by the let‐7 familyThe EMBO Journal, 2011
- Mutant nucleophosmin and cooperating pathways drive leukemia initiation and progression in miceNature Genetics, 2011
- STIM1, PKC-δ and RasGRP set a threshold for proapoptotic Erk signaling during B cell developmentNature Immunology, 2011
- An Epigenetic Switch Involving NF-κB, Lin28, Let-7 MicroRNA, and IL6 Links Inflammation to Cell TransformationCell, 2009
- Response and resistance to MEK inhibition in leukaemias initiated by hyperactive RasNature, 2009
- Thymic selection threshold defined by compartmentalization of Ras/MAPK signallingNature, 2006