RasGRP1 promotes the acute inflammatory response and restricts inflammation-associated cancer cell growth

Cong Wang, Xue Li, Binbin Xue, Changping Yu, Luoling Wang, Rilin Deng, Hui Liu, Zihao Chen, Yingdan Zhang, Suping Fan, Chaohui Zuo, Hungyu Sun, Haizhen Zhu (), Jianli Wang () and Songqing Tang ()
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Cong Wang: Hunan University
Xue Li: Hunan University
Binbin Xue: Hunan University
Changping Yu: Hunan University
Luoling Wang: Hunan University
Rilin Deng: Hunan University
Hui Liu: Hunan University
Zihao Chen: Hunan University
Yingdan Zhang: Hunan University
Suping Fan: Zhejiang University School of Medicine
Chaohui Zuo: Translational Medicine Research Center of Liver Cancer, Hunan Cancer Hospital
Hungyu Sun: Hunan University
Haizhen Zhu: Hunan University
Jianli Wang: Zhejiang University School of Medicine
Songqing Tang: Hunan University

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34659-x

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