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.

ERK/Drp1‐dependent mitochondrial fission contributes to HMGB1‐induced autophagy in pulmonary arterial hypertension

“…These results are in agreement with previous reports demonstrated in cancer cells. 17,46 Moreover, it has been shown that TLR4 and RAGE receptors are implicated in HMGB1-induced vascular remodelling, 6,[47][48][49] and we found that TLR4 was the predominant receptor that mediated HMGB1-induced ERK1/2 and Drp1 activation. Taken together, our study suggests that ERK/Drp1 pathway plays an important role in HMGB1-induced PASMCs proliferation/ migration and pulmonary vascular remodelling.…”

Induction of Pyroptosis: A Promising Strategy for Cancer Treatment

“…The chronic inflammation caused by inflammatory mediators released from pyroptotic tissues increases the risk of tumorigenesis. HMGB1 released from pyroptotic epithelial cells promotes tumorigenesis of colitis-associated colorectal cancer by activating ERK 1/2 pathway (52). A recent study showed that pyroptosis triggered in the central hypoxic region of tumor provoked tumor progression and correlated with reduced survival (37).…”

Colonic epithelial adaptation to EGFR-independent growth induces chromosomal instability and is accelerated by prior injury

“…Our RNA-sequencing analysis revealed that genes related to pyroptosis were significantly upregulated in iEGFR lines (Figure 2C-D). Pyroptosis, a caspase-dependent form of proinflammatory programmed cell death, has emerging roles in the tumor microenvironment and has been recently implicated in promoting colitis-associated cancer 54,55 . Recent investigation of somatic evolution in IBD colonic epithelium revealed clonal expansions of mutations in the IL-17 pathway which render epithelium resistant to the IL-17A-induced pro-apoptotic response 56,57 .…”