Dataset Information

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

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.

SUBMITTER: Tan G

PROVIDER: S-EPMC7648939 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Tan Gao G Huang Chongyang C Chen Jiaye J Zhi Fachao F

Journal of hematology & oncology 20201107 1

<h4>Background</h4>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.<h4>Methods</h4>To investigate the role of gasdermin E (GSDME)-mediated pyroptosis in the development of CAC, Gsdme<sup>-/-</sup> mice and their wild-type (WT) littermate controls were challenged w ...[more]

PMID: 33160389

Similar Datasets

Project description:Lung adenocarcinoma (LUAD) is a prevalent type of thoracic cancer with a poor prognosis and high mortality rate. However, the exact pathogenesis of this cancer is still not fully understood. One potential factor that can contribute to the development of lung adenocarcinoma is DNA methylation, which can cause changes in chromosome structure and potentially lead to the formation of tumors. The baculoviral IAP repeat containing the 5 (BIRC5) gene encodes the Survivin protein, which is a multifunctional gene involved in cell proliferation, migration, and invasion of tumor cells. This gene is elevated in various solid tumors, but its specific role and mechanism in lung adenocarcinoma are not well-known. To identify the potential biomarkers associated with lung adenocarcinoma, we screened the methylation-regulated differentially expressed genes (MeDEGs) of LUAD via bioinformatics analysis. Gene ontology (GO) process and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were applied to investigate the biological function and pathway of MeDEGs. A protein-protein interaction (PPI) network was employed to explore the key module and screen hub genes. We screened out eight hub genes whose products are aberrantly expressed, and whose DNA methylation modification level is significantly changed in lung adenocarcinoma. BIRC5 is a bona fide marker which was remarkably up-regulated in tumor tissues. Flow cytometry analysis, lactate dehydrogenase release (LDH) assay and Micro-PET imaging were performed in A549 cells and a mouse xenograft tumor to explore the function of BIRC5 in cell death of lung adenocarcinoma. We found that BIRC5 was up-regulated and related to a high mortality rate in lung adenocarcinoma patients. Mechanically, the knockdown of BIRC5 inhibited the proliferation of A549 cells and induced pyroptosis via caspase3/GSDME signaling. Our findings have unraveled that BIRC5 holds promise as a novel biomarker and therapeutic target for lung adenocarcinoma. Additionally, we have discovered a novel pathway in which BIRC5 inhibition can induce pyroptosis through the caspase3-GSDME pathway in lung adenocarcinoma cells.

Dataset Information

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

Background

Methods

Results

Conclusion

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets