Abstract
BackgroundPyroptosis 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.MethodsTo 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.ResultsIn 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.ConclusionGSDME-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.
Highlights
Colorectal cancer (CRC) is one of the most common types of fatal malignant tumors worldwide [1]
To investigate the involvement of pyroptosis in mucosal inflammation in inflammatory bowel diseases (IBD), we measured the expression levels of gasdermins in the mucosa of IBD patients and found that the protein levels of gasdermin E (GSDME) were significantly increased in the colonic mucosa of IBD patients compared to healthy controls (Fig. 1a, d)
We found that GSDME was mainly located in the epithelial cells of the mucosa (Fig. 1d), which was consistent with previous findings showing that gasdermins are mainly expressed in the epithelium of the gastrointestinal tract and skin
Summary
Colorectal cancer (CRC) is one of the most common types of fatal malignant tumors worldwide [1]. Recent studies have shown that gasdermin D (GSDMD) and GSDME are cleaved by active caspase-1/4/5/11 and caspase-3, respectively, via the middle linker, releasing their gasdermin-N fragments to induce pyroptosis by perforating the cell membrane [10–12]. This pore-forming activity causes cytoplasmic swelling and releases intracellular contents, such as immunogenic damage-associated molecular patterns (DAMPs) [13, 14]. Abnormal mucosal inflammation in the intestine is a critical risk factor for colitis-associated colorectal cancer (CAC). It is unknown whether pyroptosis participates in the development of CAC
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