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01 April 2019 : Clinical Research  

High-Mobility Group Box 1 (HMGB1) Promotes Angiogenesis and Tumor Migration by Regulating Hypoxia-Inducible Factor 1 (HIF-1α) Expression via the Phosphatidylinositol 3-Kinase (PI3K)/AKT Signaling Pathway in Breast Cancer Cells

Honger He1AC, Xingmu Wang2BCF, Jianjun Chen2EFG, Liping Sun3AG, Honggang Sun2DE, Kejie Xie2BCD*

DOI: 10.12659/MSM.915690

Med Sci Monit 2019; 25:2352-2360


BACKGROUND: High-mobility group box 1 (HMGB1) is an essential contributor towards initiation and progression of many kinds of cancers. Nevertheless, our understanding of the molecular etiology of HMGB1-modulated vasculogenesis, as well as invasion, of breast cancer is poor. This study explored HMGB1 expression in breast cancer and its role in the development and spread of malignancy.

MATERIAL AND METHODS: We enrolled 15 patients with breast cancer who received primary surgery at the Department of Thyroid and Breast Surgery in our hospital. HMGB1 was recorded and analyzed.

RESULTS: Our investigation successfully proves that HMGB1 is upregulated in breast cancer tissues in comparison to the surrounding non-malignant tissues. HMGB1 enhanced vessel formation in breast cancer tissues by regulating hypoxia-inducible factor 1 (HIF-1α), which in turn upregulates the expression of VEGF. Furthermore, HMGB1-mediated upregulation of HIF-1α relies on its ability to stimulate the phosphatidylinositol 3-kinase (PI3K) pathway to reinforce AKT subunit phosphorylation. HMGB1 overexpression reinforces the vasculogenesis in malignancies not only in vivo but also in vitro. Additionally, shRNA knockdown of HMGB1 prohibited the vessel-forming and invasive capabilities, downregulated VEGF and HIF-1α, and suppressed AKT phosphorylation in breast cancer cells. Most importantly, PI3K/AKT axis suppression eliminated the effect of HMGB1-modulated vascularization and invasion in breast cancer cells.

CONCLUSIONS: Our research indicates that HMGB1 serves as a crucial regulator of malignant cell-modulated vessel formation and is involved in the development of malignancy. Our findings indicate that HMGB1 is a promising target for breast cancer treatment.

Keywords: Angiogenesis Inducing Agents, Angiogenesis Inhibitors, HMGB1 Protein, Breast Neoplasms, Hypoxia-Inducible Factor 1, alpha Subunit, Neovascularization, Pathologic, phosphatidylinositol 3-kinase, Phosphorylation, Proto-Oncogene Proteins c-akt, transcriptional activation, Vascular Endothelial Growth Factor A

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Med Sci Monit 2024; 30:e944600


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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750