High Mobility Group Box 1 in Human Cancer

Abstract

High mobility group box 1 (HMGB1) is an extremely versatile protein that is located predominantly in the nucleus of quiescent eukaryotic cells, where it is critically involved in maintaining genomic structure and function. During cellular stress, however, this multifaceted, cytokine-like protein undergoes posttranslational modifications that promote its translocation to the cytosol, from where it is released extracellularly, either actively or passively, according to cell type and stressor. In the extracellular milieu, HMGB1 triggers innate inflammatory responses that may be beneficial or harmful, depending on the magnitude and duration of release of this pro-inflammatory protein at sites of tissue injury. Heightened awareness of the potentially harmful activities of HMGB1, together with a considerable body of innovative, recent research, have revealed that excessive production of HMGB1, resulting from misdirected, chronic inflammatory responses, appears to contribute to all the stages of tumorigenesis. In the setting of established cancers, the production of HMGB1 by tumor cells per se may also exacerbate inflammation-related immunosuppression. These pro-inflammatory mechanisms of HMGB1-orchestrated tumorigenesis, as well as the prognostic potential of detection of elevated expression of this protein in the tumor microenvironment, represent the major thrusts of this review.

Keywords: T regulatory cells; Toll-like receptors; cytokines; immunosuppression; myeloid-derived suppressor cells; prognostic factor; receptor for advanced glycation end-products; redox isoforms; tumor microenvironment; tumorigenesis.

Figure 1

The structure of High mobility group box protein 1 (HMGB1). The A- and B-box binding moieties are shown. The three cysteines determine whether HMGB1 acts as a proinflammatory mediator when outside the cell or binds to DNA when inside the nucleus. In addition, protein stability and DNA bending in vitro is determined by the C-terminal acidic tail [15]. Adapted and reproduced from Festoff, B.W.; Citron, B.A. Thrombin and the Coag-Inflammatory Nexus in neurotrauma, ALS, and other neurodegenerative disorders. Front. Neurol. 2019. doi: 10.3389/fneur.2019.00059 under the Creative Commons Attribution 4.0 license: 4.0 license: http://creativecommons.org/license/by/4.0/.

Figure 2

The redox state of HMGB1 determines the activity of the protein. Chemokine production and leukocyte recruitment are mediated by all-thiol-HMGB1. In turn, disulfide-HMGB1 facilitates the release of proinflammatory cytokines. During resolution of inflammation, reactive oxygen species inactivate HMGB1 by inducing the terminal oxidation of the protein [16]. Reprinted by permission from RightsLink Copyright Clearance Center: Springer Nature; Molecular Medicine. Tang, D.; Billiar, T.A.; Lotze, M.T. A Janus tale of two active HMGB1 redox states. 2012. doi:10.2119/molmed.2012.00314. License number: 4832451166310.

Figure 3

Summary of events by which HMGB1 derived from endothelial cells, tissue macrophages and parenchymal cells at sites of chronic tissue injury may drive a chronic inflammatory response that potentially leads to the development of epithelial cell injury, oxidative/inflammatory damage to DNA and tumor promotion.

Figure 4

Summary of the cellular sources of HMGB1 and mechanisms of HMGB1-mediated enhancement of tumor cell proliferation. DC = Dendritic cell; IL = Interleukin; MDSC = Myeloid-derived suppressor cell; PD-L1 = Programmed death ligand 1; RAGE = Receptor for advanced glycation end products; TAM = Tumor-associated macrophage; TAN = Tumor-associated neutrophil; TIM-3 = T cell immunoglobulin mucin-3; TLR = Toll-like receptor; Treg = Regulatory T cell; TSLP = Thymic stromal cell lymphopoietin; UVR = Ultraviolet radiation.