Role of HMGB1 in Cutaneous Melanoma: State of the Art - PubMed (original) (raw)

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Role of HMGB1 in Cutaneous Melanoma: State of the Art

Federica Li Pomi et al. Int J Mol Sci. 2022.

Abstract

High-mobility Group Box 1 (HMGB1) is a nuclear protein that plays a key role in acute and chronic inflammation. It has already been studied in several diseases, among them melanoma. Indeed, HMGB1 is closely associated with cell survival and proliferation and may be directly involved in tumor cell metastasis development thanks to its ability to promote cell migration. This research aims to assess the role of this molecule in the pathogenesis of human melanoma and its potential therapeutic role. The research has been conducted on the PubMed database, and the resulting articles are sorted by year of publication, showing an increasing interest in the last five years. The results showed that HMGB1 plays a crucial role in the pathogenesis of skin cancer, prognosis, and therapeutical response to therapy. Traditional therapies target this molecule indirectly, but future perspectives could include the development of new target therapy against HMGB1, thus adding a new approach to the therapy, which has often shown primary and secondary resistance. This could add a new therapy arm which has to be prolonged and specific for each patient.

Keywords: DAMPs; HMGB1; RAGE; alarmins; biomarkers; cancer; immunogenic cell death; melanoma; metastasis; targeted therapy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Figure 1

Tumor microenvironment and hypoxia, caused by cancer cells’ metabolic and oxygen demands, enhance HMGB1 release. HMGB1 binds to RAGE and actives several pathways: γδ-T cells, pro-inflammatory cytokines release, M2-macrophages, VEGF activation, and endothelial cell activation. All these lead to melanoma growth through the maintenance of an inflammatory microenvironment. Created with BioRender.com.

Figure 2

Figure 2

HMGB1 is released into the extracellular environment through a passive mechanism by melanoma cells. HMGB1 binds to RAGE, TLR2, and TLR4 and transduces cellular signals through a common pathway that induces the NF-κB pathway. The activated NF-κB translocates to the nucleus. HMGB1 also interacts with CXCR4 to activate the NF-κB pathway and induce chemotaxis and recruitment of inflammatory cells. The interaction of HMGB1 and TIM-3 induces the secretion of VEGF to promote tumor angiogenesis. All these pathways promote cell survival, cell proliferation and, finally, melanoma progression. Created with BioRender.com.

Figure 3

Figure 3

T-VEC is subcutaneously injected directly into the site of cancer. T-VEc attacks the melanoma cells locally, but also triggers the release of GM-CSF which recruits and actives dendritic cells. Dendritic cells activate CD8+ and CD4+ cells which, in turn, attack melanoma causing cell apoptosis and tumor reduction. Created with BioRender.com.

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