• Journal of Life Science
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• v.29 no.11
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• pp.1179-1191
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• 2019

Cancer cells undergo the epithelial-mesenchymal transition (EMT) and show unique oncogenic metabolic phenotypes such as the glycolytic switch (Warburg effect) which are important for tumor development and progression. The EMT is a critical process for tumor invasion and metastasis. High-mobility group box 1 (HMGB1) is a chromatin-associated nuclear protein, but it acts as a damage-associated molecular pattern molecule when released from dying cells and immune cells. HMGB1 induces the EMT, as well as invasion and metastasis, thereby contributing to tumor progression. Here, we show that HMGB1 induced the EMT by activating Snail. In addition, the HMGB1/Snail cascade was found induce a glycolytic switch. HMGB1 also suppressed mitochondrial respiration and cytochrome c oxidase (COX) activity by a Snail-dependent reduction in the expression of the COX subunits COXVIIa and COXVIIc. HMGB1 also upregulated the expression of several key glycolytic enzymes, including hexokinase 2 (HK2), phosphofructokinase-2/fructose-2,6-bisphosphatase 2 (PFKFB2), and phosphoglycerate mutase 1 (PGAM1), in a Snail-dependent manner. However, HMGB1 was found to regulate some other glycolytic enzymes including lactate dehydrogenases A and B (LDHA and LDHB), glucose transporter 1 (GLUT1), and monocarboxylate transporters 1 and 4 (MCT1 and 4) in a Snail-independent manner. Transfection with short hairpin RNAs against HK2, PFKFB2, and PGAM1 prevented the HMGB1-induced EMT, indicating that glycolysis is associated with HMGB1-induced EMT. These findings demonstrate that HMGB1 signaling induces the EMT, glycolytic switch, and mitochondrial repression via Snail activation.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.11
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• pp.5569-5571
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• 2012

Objectives: To evaluate the clinical significance of HMGB1 expression in T-cell lymphoma. Methods: Immunohistochemical staining for HMGB1 and survivin was performed with specimens from 120 cases of T-cell lymphoma and 40 cases of reactive lymphoid hyperplasia with antibodies against human HMGB1 and survivin. Results: The expression of HMGB1 and survivin was significantly higher in tissues of T-cell lymphoma than in reactive lymphoid hyperplasia. Positive expression of HMGB1 and survivin was observed in 63.7% (65/102) and 61.8% (63/102) of T-cell lymphoma cases, respectively. While was associated with gender, age, and tumor location, significant correlations with malignancy and clinical stage were observed. Spearman rank correlation analysis revealed that the expression of HMGB1 and survivin was positively correlated in T-cell lymphomas (P<0.01). Conclusions: Expression of HMGB1 and survivin in T-cell lymphomas is significantly associated with malignancy and clinical stage, but not with gender, age and tumor location. Elevated expression of HMGB1 may be an important biomarker for the development and progression of T-cell lymphoma.

• Molecules and Cells
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• v.41 no.4
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• pp.362-372
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• 2018

High mobility group box 2 (HMGB2) is an abundant, chromatin-associated, non-histone protein involved in transcription, chromatin remodeling, and recombination. Recently, the HMGB2 gene was found to be significantly downregulated during senescence and shown to regulate the expression of senescent-associated secretory proteins. Here, we demonstrate that HMGB2 transcription is repressed by p21 during radiation-induced senescence through the ATM-p53-p21 DNA damage signaling cascade. The loss of p21 abolished the downregulation of HMGB2 caused by ionizing radiation, and the conditional induction of p21 was sufficient to repress the transcription of HMGB2. We also showed that the p21 protein binds to the HMGB2 promoter region, leading to sequestration of RNA polymerase and transcription factors E2F1, Sp1, and p300. In contrast, NF-Y, a CCAAT box-binding protein complex, is required for the expression of HMGB2, but NF-Y binding to the HMGB2 promoter was unaffected by either radiation or p21 induction. A proximity ligation assay results confirmed that the chromosome binding of E2F1 and Sp1 was inhibited by p21 induction. As HMGB2 have been shown to regulate premature senescence by IR, targeting the p21-mediated repression of HMGB2 could be a strategy to overcome the detrimental effects of radiation-induced senescence.

• BMB Reports
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• v.49 no.4
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• pp.214-219
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• 2016

A nucleosomal protein, high mobility group box 1 (HMGB1) is known to be a late mediator of sepsis. Dabrafenib is a B-Raf inhibitor and initially used for the treatment of metastatic melanoma therapy. Inhibition of HMGB1 and renewal of vascular integrity is appearing as an engaging therapeutic strategy in the administration of severe sepsis or septic shock. Here, we examined the effects of dabrafenib (DAB) on the modulation of HMGB1-mediated septic responses. DAB inhibited the release of HMGB1 and downregulated HMGB1-dependent inflammatory responses by enhancing the expressions of cell adhesion molecules (CAMs) in human endothelial cells. In addition, treatment with DAB inhibited the HMGB1 secretion by CLP and sepsis-related mortality and pulmonary injury. This study demonstrated that DAB could be alternative therapeutic options for sepsis or septic shock via the inhibition of the HMGB1 signaling pathway.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.1
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• pp.359-365
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• 2013

The high mobility group box 1 (HMGB1) protein is a multifunctional cytokine-like molecule that plays an important role in the pathogenesis of tumors. In this study, real-time polymerase chain reactions and Western blot assays indicated that HMGB1 transcriptional activity and protein level are increased in $Tax^+$-T cells (TaxP). To clarify the mechanisms, a series of HMGB1 deletion reporter plasmids (pHLuc1 to pHLuc6) were transfected into $Tax^-$-T cells (TaxN, Jurkat) and $Tax^+$-T cells (TaxP). We found that promoter activity in $Tax^+$-T cells to be higher than that in $Tax^-$-T cells, indicating a significant increase in pHLuc6. Bay11-7082 (NF-${\kappa}B$ inhibitor) treatment did not block the enhancing effect. Chromatin immunoprecipitation assays revealed that Tax was retained on a HMGB1 promoter fragment encompassing -1163 to -975. Bioinformatics analysis showed six characteristic cis-elements for CdxA, AP-1, AML-1a, USF, v-Myb, and C/EBP in the fragment in question. Mutation of cis-elements for C/EBP reduced significant HMGB1 promoter activity induced by Tax. These findings indicate that Tax enhances the expression of HMGB1 gene at the transcriptional level, possibly by interacting with C/EBP.

• Tuberculosis and Respiratory Diseases
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• v.80 no.2
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• pp.153-158
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• 2017

Background: Recently, increased levels of high-mobility group box 1 protein (HMGB1) have been identified in various inflammatory conditions and infections. However, no studies have evaluated the HMGB1 level in nontuberculous mycobacterial (NTM) lung disease, and compared it to mycobacterial lung disease. Methods: A total of 60 patients newly diagnosed with NTM lung disease, 44 culture-positive pulmonary tuberculosis (TB) patients, and 34 healthy controls, were included in this study. The serum HMGB1 concentrations were quantified using HMGB1 enzyme-linked immunosorbent assay kits. Results: Serum HMGB1 level in patients with pulmonary TB or NTM lung disease, was significantly lower than that of the healthy controls. In addition, the serum HMGB1 level in TB patients was significantly lower than patients with NTM lung disease. However, the levels in NTM patient subgroups did not differ according to the causative species, disease progression, and disease phenotype. Conclusion: Although low levels of serum HMGB1 has the potential to be a marker of mycobacterial lung disease, these levels were unable to differentiate disease progression and disease phenotype in NTM lung diseases.

• BMB Reports
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• v.44 no.9
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• pp.601-606
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• 2011

HMGB1 is associated with human cancers and is an activator of autophagy which mediates chemotherapy resistance. We here show that the mRNA levels of HMGB1 are high in leukemia cells and it is involved in the progression of childhood chronic myeloid leukemia (CML). HMGB1 decreases the sensitivity of human myeloid leukemia cells K562 to anti-cancer drug induced death through up-regulating the autophagy pathway, which is confirmed by the observation with an increase in fusion of autophagosomes and autophagolysosomes. When overexpressing HMGB1, both mRNA levels of Beclin-1, VSP34 and UVRAG which are key genes involved in mammalian autophagy and protein levels of p-Bcl-2 and LC3-II are increased. Luciferase assays document that over-expression of HMGB1 increases the transcriptional activity of JNK and ERK, which may be silenced by siRNA. The results suggest that HMGB1 regulates JNK and ERK required for autophagy, which provides a potential drug target for therapeutic interventions in childhood CML.

• IMMUNE NETWORK
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• v.23 no.3
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• pp.25.1-25.17
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• 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces excessive pro-inflammatory cytokine release and cell death, leading to organ damage and mortality. High-mobility group box 1 (HMGB1) is one of the damage-associated molecular patterns that can be secreted by pro-inflammatory stimuli, including viral infections, and its excessive secretion levels are related to a variety of inflammatory diseases. Here, the aim of the study was to show that SARS-CoV-2 infection induced HMGB1 secretion via active and passive release. Active HMGB1 secretion was mediated by post-translational modifications, such as acetylation, phosphorylation, and oxidation in HEK293E/ACE2-C-GFP and Calu-3 cells during SARS-CoV-2 infection. Passive release of HMGB1 has been linked to various types of cell death; however, we demonstrated for the first time that PANoptosis, which integrates other cell death pathways, including pyroptosis, apoptosis, and necroptosis, is related to passive HMGB1 release during SARS-CoV-2 infection. In addition, cytoplasmic translocation and extracellular secretion or release of HMGB1 were confirmed via immunohistochemistry and immunofluorescence in the lung tissues of humans and angiotensin-converting enzyme 2-overexpressing mice infected with SARS-CoV-2.

• The Korean Journal of Physiology and Pharmacology
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• v.26 no.5
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• pp.389-396
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• 2022

The increased expression of receptors for advanced glycation end-product (RAGE) is known as a key player in the progression of vascular remodeling. However, the precise signal pathways regulating RAGE expression in vascular smooth muscle cells (VSMCs) in the injured vasculatures are unclear. Given the importance of mitogen-activated protein kinase (MAPK) signaling in cell proliferation, we investigated the importance of MAPK signaling in high-mobility group box 1 (HMGB1)-induced RAGE expression in VSMCs. In HMGB1 (100 ng/ml)-stimulated human VSMCs, the expression of RAGE mRNA and protein was increased in association with an increase in AGE-induced VSMC proliferation. The HMGB1-induced RAGE expression was attenuated in cells pretreated with inhibitors for ERK (PD98059, 10 μM) and p38 MAPK (SB203580, 10 μM) as well as in cells deficient in ERK and p38 MAPK using siRNAs, but not in cells deficient of JNK signaling. In cells stimulated with HMGB1, the phosphorylation of ERK, JNK, and p38 MAPK was increased. This increase in ERK and p38 MAPK phosphorylation was inhibited by p38 MAPK and ERK inhibitors, respectively, but not by JNK inhibitor. Moreover, AGE-induced VSMC proliferation in HMGB1-stimulated cells was attenuated in cells treated with ERK and p38 MAPK inhibitors. Taken together, our results indicate that ERK and p38 MAPK signaling are involved in RAGE expression in HMGB1-stimulated VSMCs. Thus, the ERK/p38 MAPK-RAGE signaling axis in VSMCs was suggested as a potential therapeutic target for vascular remodeling in the injured vasculatures.

• Korean Journal of Veterinary Research
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• v.51 no.3
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• pp.239-241
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• 2011

In this study, we investigated the kinetics of tumor necrosis factor (TNF)-${\alpha}$, interleukin (IL)-6 and high mobility group box 1 (HMGB1) concentrations in a 48-h model of canine endotoxemia by lipopolysaccharide (LPS) injection. Four healthy beagles were slowly administered 1 mg/kg of LPS diluted in normal saline, while two others were administered normal saline as controls. Blood collection was performed at 0 h (baseline), 1 h and 3 h (for TNF-${\alpha}$), 6 h, 12 h, 24 h and 48 h of the experiment, and cytokine levels were determined using the sandwich ELISA method. Early increments of TNF-${\alpha}$ and IL-6 were observed (< 3 h), but HMGB1 levels increased the most at 12 h of the experiment and gradually decreased until 48 h. During the whole experiment, IL-6 and HMGB1 were sustained over 12 h of LPS injection, whereas TNF-${\alpha}$ decreased within 6 h of LPS injection. Taken together, canine HMGB1 levels increase relatively late (< 12 h) and sustained longer than TNF-${\alpha}$ and IL-6 in response to endotoxin. This is the first study to evaluate canine HMGB1 cytokine from endotoxemia in dogs.