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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2020

01-12-2020 | Chronic Inflammatory Bowel Disease | Rapid communication

HMGB1 released from GSDME-mediated pyroptotic epithelial cells participates in the tumorigenesis of colitis-associated colorectal cancer through the ERK1/2 pathway

Authors: Gao Tan, Chongyang Huang, Jiaye Chen, Fachao Zhi

Published in: Journal of Hematology & Oncology | Issue 1/2020

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Abstract

Background

Pyroptosis is a form of proinflammatory gasdermin-mediated programmed cell death. Abnormal mucosal inflammation in the intestine is a critical risk factor for colitis-associated colorectal cancer (CAC). However, it is unknown whether pyroptosis participates in the development of CAC.

Methods

To investigate the role of gasdermin E (GSDME)-mediated pyroptosis in the development of CAC, Gsdme−/− mice and their wild-type (WT) littermate controls were challenged with azoxymethane (AOM) and dextran sodium sulfate (DSS) to induce a CAC model. Neutralizing antibodies against high-mobility group box protein 1 (HMGB1) were used to determine the role of HMGB1 in CAC. To identify the role of ERK1/2 in HMGB1-induced colon cancer cell proliferation, we performed western blotting and CCK8 assays using the ERK1/2-specific inhibitor U0126 in CT26 colon cancer cells.

Results

In the CAC model, Gsdme−/− mice exhibited reduced weight loss and colon shortening, attenuated rectal prolapse, and reduced tumor numbers and sizes compared to WT littermates. Furthermore, treatment with neutralizing anti-HMGB1 antibodies decreased the numbers and sizes of tumors, ERK1/2 activation and proliferating cell nuclear antigen (PCNA) expression in AOM/DSS-challenged WT mice. In addition, our in vitro experiments demonstrated that HMGB1 induced proliferation and PCNA expression in CT26 colon cancer cells through the ERK1/2 pathway.

Conclusion

GSDME-mediated pyroptosis promotes the development of CAC by releasing HMGB1, which induces tumor cell proliferation and PCNA expression through the ERK1/2 pathway. This finding reveals a previously unrecognized link between pyroptosis and CAC tumorigenesis and offers new insight into CAC pathogenesis.
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Metadata
Title
HMGB1 released from GSDME-mediated pyroptotic epithelial cells participates in the tumorigenesis of colitis-associated colorectal cancer through the ERK1/2 pathway
Authors
Gao Tan
Chongyang Huang
Jiaye Chen
Fachao Zhi
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2020
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-020-00985-0

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