High-mobility group Box 1: A novel inducer of the epithelial–mesenchymal transition in colorectal carcinoma

Abstract

Proinflammatory cytokine high-mobility group box 1 (HMGB1) mediates critical processes of tumour metastasis. Because the epithelial-to-mesenchymal transition (EMT) is a key player in metastasis, the aim of this study was to determine whether and through which mechanism HMGB1 induces EMT in colorectal carcinoma. The direct treatment of cells with recombinant human HMGB1 induced alterations in the epithelial morphology consistent with the EMT and enhanced cell migration through a process mediated by the receptor for advanced glycation end-products (RAGE). The levels of Snail and phospho-NF-κB were upregulated during the HMGB1-induced EMT, and these effects were reversed by inhibiting Snail and NF-κB. In addition, HMGB1 increased the expression of MMP-7 but not that of MMP-9, and this effect was also regulated by Snail/NF-κB signalling. Collectively, these findings indicate that HMGB1 acts as a potent driver of cancer EMT through the RAGE/Snail/NF-κB signalling pathways accompanied by the activation of MMP-7, thereby suggest the feasibility of targeting HMGB1 for the treatment of tumour metastasis.