Colitis-induced IL11 promotes colon carcinogenesis.

Abstract

Colitis increases the risk of colorectal cancer; however, the mechanism of the association between colitis and cancer remains largely unknown. To identify colitis-associated cancer promoting factors, we investigated gene expression changes caused by dextran sulfate sodium (DSS)-induced colitis in mice. By analyzing gene expression profiles, we found that IL11 was upregulated in DSS-induced colitis tissue and 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP)/DSS-induced colon tumours in mice as well as in human colorectal cancer. By characterizing the activation/phosphorylation of STAT3 (pSTAT3), we found that pSTAT3 was induced transiently in colitis, but maintained at higher levels from hyper-proliferative dysplastic lesions to tumours. Using the IL11 receptor (IL11Rα1) knockout mice, we found that pSTAT3 in the newly regenerated crypt epithelial cells in colitis is abolished in IL11Rα1+/- and -/- mice, suggesting that colitis-induced IL11 activates STAT3 in colon crypt epithelial cells. Moreover, colitis-promoted colon carcinogenesis was significantly reduced in IL11Rα1+/- and -/- mice. To determine the roles of the IL11 in colitis, we found that the inhibition of IL11 signalling by recombinant IL11 antagonist mutein during colitis was sufficient to attenuate colitis-promoted carcinogenesis. Together, our results demonstrated that colitis-induced IL11 plays critical roles in creating cancer promoting microenvironment to facilitate the development of colon cancer from dormant premalignant cells.

• Authors: Hong Wang, David H Wang, Xu Yang, Yuhai Sun, Chung S Yang
• Journal: Carcinogenesis (Carcinogenesis) Vol. 42 Issue 4 Pg. 557-569 (04 30 2021) ISSN: 1460-2180 [Electronic] England
• PMID: 33196831 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• IL11 protein, human
• Il11ra1 protein, mouse
• Interleukin-11
• Interleukin-11 Receptor alpha Subunit
• STAT3 Transcription Factor
• Dextran Sulfate

Topics

• Animals
• Carcinogenesis (genetics)
• Colitis (chemically induced, complications, genetics)
• Colitis-Associated Neoplasms (genetics, pathology)
• Colonic Neoplasms (complications, genetics, pathology)
• Dextran Sulfate (toxicity)
• Gene Expression Regulation, Neoplastic (genetics)
• Humans
• Interleukin-11 (genetics)
• Interleukin-11 Receptor alpha Subunit (genetics)
• Intestinal Mucosa
• Mice
• Mice, Knockout
• STAT3 Transcription Factor (genetics)
• Signal Transduction
• Tumor Microenvironment (genetics)