HMGB1 downregulates DDX3 to activate the MAPK pathway, promoting the progression of colorectal cancer.

High mobility group box 1 (HMGB1) has been implicated in the development of various cancers, but its role in colorectal cancer (CRC) remains poorly understood. This study investigated the role of HMGB1 in CRC progression, particularly through its interaction with DEAD-box helicase 3 (DDX3), which, as demonstrated by our previous research, regulates CRC via the MAPK pathway. We analysed HMGB1 expression in CRC using public databases and tissue microarrays and detected significantly higher expression in CRC tissues than in normal tissues, which was associated with poor prognosis. HMGB1 expression was knocked down in the SW480 and HCT116 cell lines using siRNA and lentiviral vectors, and this knockdown inhibited CRC cell proliferation, migration, invasion, and adhesion, as confirmed by both in vitro and in vivo experiments. Molecular analyses revealed reduced phosphorylation of Erk1/2, c-Jun, and Elk1, along with decreased β-catenin and Snail expression and increased E-cadherin expression. Coimmunoprecipitation assay results further confirmed the interaction between HMGB1 and DDX3. These findings suggest that HMGB1 is an oncogene in CRC that promotes tumour progression through the MAPK pathway by downregulating DDX3. These findings highlight HMGB1 as a potential therapeutic target in CRC.