HMGB1

Gene Summary

Gene:HMGB1; high mobility group box 1
Aliases: HMG1, HMG3, HMG-1, SBP-1
Location:13q12.3
Summary:This gene encodes a protein that belongs to the High Mobility Group-box superfamily. The encoded non-histone, nuclear DNA-binding protein regulates transcription, and is involved in organization of DNA. This protein plays a role in several cellular processes, including inflammation, cell differentiation and tumor cell migration. Multiple pseudogenes of this gene have been identified. Alternative splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Sep 2015]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:high mobility group protein B1
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (9)

Latest Publications: HMGB1 (cancer-related)

Lohani N, Rajeswari MR
Dichotomous Life of DNA Binding High Mobility Group Box1 Protein in Human Health and Disease.
Curr Protein Pept Sci. 2016; 17(8):762-775 [PubMed] Related Publications
The High mobility group box 1 (HMGB1) protein is an extremely versatile, highly conserved nuclear protein, with its unique intracellular and extracellular functions mediated by its relatively simple domain structure. Within the nucleus, HMGB1 binds to DNA minor groove in a nonspecific manner and causes bends in the double helix thus helps in recruiting a number of DNA binding protein and transcription factors, to facilitate transcription of various genes. HMGB1 also helps in DNA repair, chromatin remodeling, V (D) J recombination, and assembly of nucleosome on the chromatin. On contrary, under pathological conditions HMGB1 displays inflammatory response by interaction with specific cell surface receptors like RAGE, TLR-4, TLR9, and TLR2 and activates NF-kB downstream signaling pathways. The upregulation of HMGB1 is directly associated with the pathogenesis of cancer, sepsis, ischemia, hemorrhagic shock, anorexia, rheumatic disease, periodontal disease etc. Therefore, HMGB1 has been considered as a promising target in the treatment of various human diseases. The interest in HMGB1 is evident and reflected in the exponential increase in the recent publications, and therefore there is a need for an update on the understanding of the role of HMGB1 in pathogenesis and its potential application of HMGB1 as a therapeutic target in a number of human diseases.

Waki K, Yamada A
Blockade of high mobility group box 1 augments antitumor T-cell response induced by peptide vaccination as a co-adjuvant.
Cancer Sci. 2016; 107(12):1721-1729 [PubMed] Free Access to Full Article Related Publications
High mobility group box 1 (HMGB1) is a member of the family of damage-associated molecular patterns, which cause inflammation and trigger innate immunity through Toll-like receptors 2/4 and the receptor for advanced glycation end products. We examined the effect of glycyrrhizin, a selective inhibitor of HMGB1, on the induction of CTLs in mice. B6 mice, either OT-1 spleen cell-transferred or untransferred, were immunized with an s.c. injection of OVA257-264 peptide with topical imiquimod, and glycyrrhizin was mixed with the antigen peptide. Proliferation of OT-1 cells after immunization was enhanced by glycyrrhizin. The effect of glycyrrhizin was confirmed in other adjuvant systems, such as CpG oligonucleotide and monophosphoryl lipid A, but glycyrrhizin was not effective in Freund's incomplete adjuvant system. The augmenting effects of glycyrrhizin were also observed in other synthetic HMGB1 inhibitors, gabexate mesilate, nafamostat, and sivelestat. Thus, the effects are common to the HMGB1 inhibitors. Induction of CTLs detected by γ-interferon enzyme-linked immunospot assay was similarly augmented by glycyrrhizin. In a therapeutic vaccine model, glycyrrhizin inhibited the growth of s.c. transplanted EG.7 tumors. Expression of inflammatory cytokines in the skin inoculation site was downregulated by glycyrrhizin. These results suggest that HMGB1 inhibitors might be useful as a co-adjuvant for peptide vaccination with an innate immunity receptor-related adjuvant.

Bigagli E, De Filippo C, Castagnini C, et al.
DNA copy number alterations, gene expression changes and disease-free survival in patients with colorectal cancer: a 10 year follow-up.
Cell Oncol (Dordr). 2016; 39(6):545-558 [PubMed] Related Publications
BACKGROUND: DNA copy number alterations (CNAs) and gene expression changes have amply been encountered in colorectal cancers (CRCs), but the extent at which CNAs affect gene expression, as well as their relevance for tumor development, are still poorly defined. Here we aimed at assessing the clinical relevance of these parameters in a 10 year follow-up study.
METHODS: Tumors and normal adjacent colon mucosa, obtained at primary surgery from 21 CRC patients, were subjected to (i) high-resolution array CGH (a-CGH) for the detection of CNAs and (ii) microarray-based transcriptome profiling for the detection of gene expression (GE) changes. Correlations between these genomic and transcriptomic changes and their associations with clinical and histopathological parameters were assessed with the aim to identify molecular signatures associated with disease-free survival of the CRC patients during a 10 year follow-up.
RESULTS: DNA copy number gains were frequently detected in chromosomes 7, 8q, 13, 19, 20q and X, whereas DNA copy number losses were frequently detected in chromosomes 1p, 4, 8p, 15, 17p, 18, 19 and 22q. None of these alterations were observed in all samples. In addition, we found that 2,498 genes were up- and that 1,094 genes were down-regulated in the tumor samples compared to their corresponding normal mucosa (p < 0.01). The expression of 65 genes was found to be significantly associated with prognosis (p < 0.01). Specifically, we found that up-regulation of the IL17RA, IGF2BP2 and ABCC2 genes, and of genes acting in the mTOR and cytokine receptor pathways, were strongly associated with a poor survival. Subsequent integrated analyses revealed that increased expression levels of the MMP9, BMP7, UBE2C, I-CAM, NOTCH3, NOTCH1, PTGES2, HMGB1 and ERBB3 genes were associated with copy number gains, whereas decreased expression levels of the MUC1, E2F2, HRAS and SIRT3 genes were associated with copy number losses. Pathways related to cell cycle progression, eicosanoid metabolism, and TGF-β and apoptosis signaling, were found to be most significantly affected.
CONCLUSIONS: Our results suggest that CNAs in CRC tumor tissues are associated with concomitant changes in the expression of cancer-related genes. In other genes epigenetic mechanism may be at work. Up-regulation of the IL17RA, IGF2BP2 and ABCC2 genes, and of genes acting in the mTOR and cytokine receptor pathways, appear to be associated with a poor survival. These alterations may, in addition to Dukes' staging, be employed as new prognostic biomarkers for the prediction of clinical outcome in CRC patients.

Cebrián MJ, Bauden M, Andersson R, et al.
Paradoxical Role of HMGB1 in Pancreatic Cancer: Tumor Suppressor or Tumor Promoter?
Anticancer Res. 2016; 36(9):4381-9 [PubMed] Related Publications
Pancreatic cancer has a dismal prognosis and there is an increasing and unmet need to identify better diagnostic and therapeutic targets in order to ameliorate the course of the disease. HMGB1, a nuclear DNA-binding protein that acts as a transcription factor, is currently in the limelight. HMGB1 exhibits a dual role in pancreatic cancer; when intracellular, it acts as an anti-tumor protein stabilizing the genome, whereas extracellular HMGB1 behaves as a pro-tumor protein with cytokine, chemokine and growth factor functions. Although the exact mechanisms of HMGB1 in pancreatic cancer are still to be elucidated, the significance of this protein for processes, such as autophagy, immunogenic cell death, tumor growth, metastasis and resistance to chemotherapy, have become increasingly clear. In this review, we provide a systematic summary and review of the biological and clinical relevance of HMGB1 in pancreatic cancer.

Li Z, Block MS, Vierkant RA, et al.
The inflammatory microenvironment in epithelial ovarian cancer: a role for TLR4 and MyD88 and related proteins.
Tumour Biol. 2016; 37(10):13279-13286 [PubMed] Free Access to Full Article Related Publications
The tumor-associated inflammatory microenvironment may play a pivotal role in epithelial ovarian cancer (EOC) carcinogenesis and outcomes, but a detailed profile in patient-derived tumors is needed. Here, we investigated the expression of TLR4- and MyD88-associated markers in tumors from over 500 EOC patients using immunohistochemical staining. We demonstrate that high expression of TLR4 and MyD88 predicts poorer overall survival in patients with EOC; most likely, this is due to their association with serous histology and features of high tumor burden and aggressiveness, including stage, grade, and ascites at surgery. Combined TLR4 and MyD88 expression appears to serve as an independent risk factor for shortened survival time, even after covariate adjustment (both moderate HR 1.1 [95 % CI 0.7-1.8], both strong HR 2.1 [95 % CI 1.1-3.8], both weak as referent; p = 0.027). We reveal that in EOC tissues with elevated expression of both TLR4 and MyD88 and activated NF-κB signaling pathway, expression of hsp60, hsp70, beta 2 defensin, and HMGB1 are also enriched. In total, these results suggest that activation of TLR4/MyD88/NF-κB signaling by endogenous ligands may contribute to an inflammatory microenvironment that drives a more aggressive phenotype with poorer clinical outcome in EOC patients.

Chandrasekaran KS, Sathyanarayanan A, Karunagaran D
Downregulation of HMGB1 by miR-34a is sufficient to suppress proliferation, migration and invasion of human cervical and colorectal cancer cells.
Tumour Biol. 2016; 37(10):13155-13166 [PubMed] Related Publications
High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein known to be highly expressed in human cervical (CaCx) and colorectal (CRC) cancers, and sustained high levels of HMGB1 contribute to tumourigenesis and metastasis. HMGB1-targeted cancer therapy is of recent interest, and there are not many studies on miRNA-mediated HMGB1 regulation in these cancers. Since miRNA-based therapeutics for cancer is gaining importance in recent years, it was of interest to predict miRNAs targeting HMGB1. Based on the identification of a potential miR-34a response element in HMGB1-3' untranslated region (3'UTR) and an inverse correlation between HMGB1 and miR-34a expression levels in CaCx and CRC tissues, from a subset of the local population as well as a large sampling from TCGA database, experiments were performed to validate HMGB1 as a direct target of miR-34a in CaCx and CRC cells. Ectopic expression of miR-34a decreased the wild-type HMGB1-3'UTR luciferase activity but not that of its mutant in 3'UTR luciferase assays. While forced expression of miR-34a in CaCx and CRC cells inhibited HMGB1 mRNA and protein levels, proliferation, migration and invasion, inhibition of endogenous miR-34a enhanced these tumourigenic properties. siRNA-mediated HMGB1 suppression imitated miR-34a expression in reducing proliferation and metastasis-related events. Combined with the disparity in expression of miR-34a and HMGB1 in clinical specimens, the current findings would help in not only understanding the complexity of miRNA-target regulatory mechanisms but also in designing novel therapeutic interventions in CaCx and CRC.

Zheng H, Chen JN, Yu X, et al.
HMGB1 Enhances Drug Resistance and Promotes In Vivo Tumor Growth of Lung Cancer Cells.
DNA Cell Biol. 2016; 35(10):622-627 [PubMed] Related Publications
Drug resistance is an obstacle in the chemotherapeutic treatment of lung cancers. In the present study, the effects of high-mobility group box 1 (HMGB1) protein in chemotherapeutic resistance and the relationships between HMGB1 and chemotherapy drug-induced cell apoptosis or necrosis were clarified. We used cisplatin-sensitive A549 cells and cisplatin-resistant A549/DDP cells as cell models with IC50 of 11.58 and 46.95 μM, respectively. A549/DDP had higher level of HMGB1 compared with A549 cells. Interestingly, with the increasing concentration of DDP, HMGB1 was gradually located into cytoplasm in cisplatin-sensitive A549 cells. Moreover, interference with endogenous HMGB1 sensitized the effects of chemotherapeutic drugs, including 5-Fu, DDP, and OXA. Furthermore, results from an in vivo tumorigenesis experiment demonstrated that serum concentration of HMGB1 was much lower in the group inoculated with HMGB1 shRNA-transfected A549 cells than in the N.C. shRNA-transfected A549 inoculated group, as well as the tumor volume, suggesting that serum HMGB1 contributed to tumor growth in a mouse model. In conclusion, higher levels of HMGB1 probably contributed to chemotherapy drug resistance, and higher serum concentration of HMGB1 promoted in vivo tumor growth. The study would provide new clues to overcome drug resistance in chemotherapy of human lung cancers.

Lu L, Qiu C, Li D, et al.
MicroRNA-505 suppresses proliferation and invasion in hepatoma cells by directly targeting high-mobility group box 1.
Life Sci. 2016; 157:12-8 [PubMed] Related Publications
AIMS: MicroRNA-505 (miR-505) expressions have been reported to be altered in the serum of HCC patients. However, the effect and underlying mechanism of miR-505 in hepatoma cells remains poorly understood. The present study intended to investigate the expression levels and the probable role and molecular basis of miR-505 in hepatoma cells.
MAIN METHODS: Real-time PCR was used to determine the miR-505 expressions in hepatoma cell lines QGY-7703, SMMC-7721 and MHCC97. Furthermore, an up-or down-regulation of miR-505 was performed in MHCC97 by transfected with miR-505 mimics or anti-miR-505, respectively. Cell proliferation, cell invasion, and epithelial-mesenchymal transition were determined. Moreover, the target gene of miR-505 was also investigated.
KEY FINDINGS: The expressions of miR-505 were down-regulated in three hepatoma cell lines. MHCC97 possessed the lowest miR-505 levels among the three hepatoma cell lines. Furthermore, the up-regulation of miR-505 suppressed, whereas the down-regulation of miR-505 promoted proliferation, invasion and epithelial-mesenchymal transition in MHCC97. Moreover, miR-505 could directly bind to the 3'-untranslated region of High-Mobility Group Box 1. Notably, High-Mobility Group Box 1 knockdown apparently promoted cell proliferation and invasion in MHCC97.
SIGNIFICANCE: We investigated that MiR-505 regulates proliferation and invasion in MHCC97 cells via targeting High-Mobility Group Box 1.

Shimabukuro M, Sato H, Izaki H, et al.
Depot- and gender-specific expression of NLRP3 inflammasome and toll-like receptors in adipose tissue of cancer patients.
Biofactors. 2016; 42(4):397-406 [PubMed] Related Publications
Gender difference in obesity-associated cardiovascular complication could be derived from divergent chronic inflammation. We evaluated depot- and gender-specific regulation of the innate immune system in human adipose tissues. Pair samples were obtained from subcutaneous (SAT) and visceral adipose tissue (VAT) during elective surgery (Male: 35; Female: 27). Expressions of pro- and anti-inflammatory adipocytokines were evaluated by semi-quantitative qPCR. Adipose cell-size distribution was obtained from tissue samples fixed in osmium tetroxide and analyzed by Beckman Coulter Multisizer. Levels of adiponectin were higher in SAT and VAT of female than those of male (P < 0.001 and P = 0.011, respectively). NLRP3, IL1β-IL18, TLR2 were comparable in SAT and VAT between genders. However, TLR4 and TLR9 were increased in female SAT and VAT and HMGB1 in female VAT. Levels of adiponectin were not correlated with mean diameter of adipocyte (φ, μm) in SAT and VAT of male, but negatively well correlated in those of female (r = -0.392 and r = -0.616). Such negative correlations were also observed between levels of TLR2, TLR4, and HMGB1 and φ in female. Levels of NLRP3 and IL1β were positively correlated with φ in male, but not in female. In conclusion, Innate signals were differentially expressed in male and female adipose tissues, suggesting that the depot- and gender-specific signals could be related to gender difference in chronic inflammation. © 2016 BioFactors, 42(4):397-406, 2016.

Wang B, Yeh CB, Lein MY, et al.
Effects of HMGB1 Polymorphisms on the Susceptibility and Progression of Hepatocellular Carcinoma.
Int J Med Sci. 2016; 13(4):304-9 [PubMed] Free Access to Full Article Related Publications
Hepatocellular carcinoma (HCC) is a malignancy of liver and a leading cause of cancer mortality worldwide. Its management is compounded by biological and clinical heterogeneity. These interindividual genetic variations can modulate the effects of HCC treatment. High-mobility group box protein 1 (HMGB1) is a well investigated, ubiquitous nuclear protein found in eukaryotic cells that plays a multiple biological roles such as DNA stability, program cell death, immune response, and furthermore in cancer progression. In this report, we examined HMGB1 single nucleotide polymorphisms (SNPs) with multiple risk factors related to HCC susceptibility and clinicopathological characteristics. Four HMGB1 SNPs (rs1412125, rs2249825, rs1045411, and rs1360485) were assessed by using a TaqMan SNPs Genotyping in 324 patients with HCC and in 695 cancer-free controls. The results showed that HMGB1 SNP rs1045411 with CT or at least one T alleles has lower risk of HCC than wild-type (CC) carriers. Moreover, HMGB1 SNP rs1412125 with TT allele has a higher risk of distant metastasis compared with patients carrying at least one C allele. The present study is the first report to discuss the risk factors associated with HMGB1 SNPs in HCC progression in Taiwan.

Bukowska B, Rogalska A, Forma E, et al.
Why a Combination of WP 631 and Epo B is an Improvement on the Drugs Singly - Involvement in the Cell Cycle and Mitotic Slippage.
Asian Pac J Cancer Prev. 2016; 17(3):1299-308 [PubMed] Related Publications
Our previous studies clearly demonstrated that a combination of WP 631 and Epo B has higher activity against ovarian cancer cells than either of these compounds used separately. In order to fully understand the exact mechanism of action in combination, we assessed effects on the cell cycle of SKOV-3 cells. We evaluated three control points essential for WP 631 and Epo B action to determine which cell cycle-regulating proteins (CDK1/cyclin B complex, EpCAM or HMGB1) mediate activity. The effects of the drug on the cell cycle were measured based on the nuclear DNA content using flow cytometry. Expression of cell cycle-regulating genes was analyzed using real-time PCR. It was discovered that WP 631, at the tested concentration, did not affect the SKOV-3 cell cycle. Epo B caused significant G2/M arrest, whereas the drug combination induced stronger apoptosis and lower mitotic arrest than Epo B alone. This is very important information from the point of view of the fight against cancer, as, while mitotic arrest in Epo B-treated cells could be overcame after DNA damage repair, apoptosis which occurs after mitotic slippage in combination-treated cells is irreversible. It clearly explains the higher activity of the drug combination in comparison to Epo B alone. Epo B acts via the CDK1/cyclin B complex and has the ability to inhibit CDK1, which may be a promising strategy for ovarian cancer treatment in the future. The drug combination diminishes EpCAM and HMGB1 expression to a greater degree than either WP 631 and Epo B alone. Owing to the fact that the high expression of these two proteins is a poor prognostic factor for ovarian cancer, a decrease in their expression, observed in our studies, may result in improved efficacy of cancer therapy. The presented findings show that the combination of WP 631 and Epo B is a better therapeutic option than either of these drugs alone.

Lv W, Chen N, Lin Y, et al.
Macrophage migration inhibitory factor promotes breast cancer metastasis via activation of HMGB1/TLR4/NF kappa B axis.
Cancer Lett. 2016; 375(2):245-55 [PubMed] Related Publications
Macrophage migration inhibitory factor (MIF) is up-regulated in diverse solid tumors and acts as the critical link between immune response and tumorigenesis. In this study, we demonstrated that MIF overexpression promoted migration of breast cancer cells by elevating TLR4 expression. Further investigation evidenced that MIF induced ROS generation. MIF-induced ROS led to ERK phosphorylation, which facilitated HMGB1 release from the nucleus to the cytoplasm. MIF overexpression also induced caveolin-1 phosphorylation. Caveolin-1 phosphorylation contributed to HMGB1 secretion from the cytoplasm to the extracellular matrix. The extracellular HMGB1 activated TLR4 signaling including NF-κB phosphorylation, which was responsible for the transcription of Snail and Twist as well as MMP2 activation. Furthermore, MIF-induced caveolin-1-dependent HMGB1 secretion might control the recruitment of CD11b+ immune cells. Our data suggested that MIF affected the intrinsic properties of tumors and the host immune response in tumor microenvironment by regulating the TLR4/HMGB1 axis, leading to metastasis of breast cancer.

Yusein-Myashkova S, Stoykov I, Gospodinov A, et al.
The repair capacity of lung cancer cell lines A549 and H1299 depends on HMGB1 expression level and the p53 status.
J Biochem. 2016; 160(1):37-47 [PubMed] Related Publications
Elucidation of the cellular components responsive to chemotherapeutic agents as cisplatin rationalizes the strategy for anticancer chemotherapy. The removal of the cisplatin/DNA lesions gives the chance to the cancer cells to survive and compromises the chemotherapeutical treatment. Therefore, the cell repair efficiency is substantial for the clinical outcome. High mobility group box 1 (HMGB1) protein is considered to be involved in the removal of the lesions as it binds with high affinity to cisplatin/DNA adducts. We demonstrated that overexpression of HMGB1 protein inhibited cis-platinated DNA repair in vivo and the effect strongly depended on its C-terminus. We registered increased levels of DNA repair after HMGB1 silencing only in p53 defective H1299 lung cancer cells. Next, introduction of functional p53 resulted in DNA repair inhibition. H1299 cells overexpressing HMGB1 were significantly sensitized to treatment with cisplatin demonstrating the close relation between the role of HMGB1 in repair of cis-platinated DNA and the efficiency of the anticancer drug, the process being modulated by the C-terminus. In A549 cells with functional p53, the repair of cisplatin/DNA adducts is determined by а complex action of HMGB1 and p53 as an increase of DNA repair capacity was registered only after silencing of both proteins.

Ni P, Zhang Y, Liu Y, et al.
HMGB1 silence could promote MCF-7 cell apoptosis and inhibit invasion and metastasis.
Int J Clin Exp Pathol. 2015; 8(12):15940-6 [PubMed] Free Access to Full Article Related Publications
High mobility group box 1 (HMGB1), a non-histone nuclear protein, was associated with a variety of biological important processes, such as transcription, differentiation, extracellular signaling. As a cytokine or inflammatory mediator, more and more data showed that HMGB1 was involved in inflammatory diseases, cancers or autoimmune disease. However, few data focused on nucleic or cytoplasmic function of HMGB1. Therefore, the present study focused on cancer cells biological characteristics following HMGB1 silence. HMGB1 siRNAs were designed and chemically synthesized, and then transfected into the breast cancer cell line MCF-7 with lipofectamine 2000. The transcription and translation level of HMGB1 expression, proliferation, apoptosis, migration of MCF-7 were determined. The results demonstrated that HMGB1 silence inhibit invasion and migration and promote apoptosis of human breast cells; which indicated that HMGB1 silence might be a potential therapy targets.

Yun BH, Chon SJ, Choi YS, et al.
Pathophysiology of Endometriosis: Role of High Mobility Group Box-1 and Toll-Like Receptor 4 Developing Inflammation in Endometrium.
PLoS One. 2016; 11(2):e0148165 [PubMed] Free Access to Full Article Related Publications
Oxidative stress has been proposed as a potential factor associated with the establishment and progression of endometriosis. Although a few studies have shown possible mechanisms which may play roles in development, progression of endometriosis, few are known in regards of initiation of the disease, especially in the relationship with endometrium. The aim of our study was to investigate whether normal endometrium may be changed by Damage-associated molecular patterns (DAMPs), which may contribute developing pathologic endometrium to induce endometriosis. Endometrial tissues were obtained from 10 patients with fibroids undergoing hysterectomy at a university hospital. High mobility group box-1 (HMGB-1), which is a representative DAMP, has been chosen that may induce alteration in endometrium. In preceding immunohistochemistry experiments using paraffin-block sections from endometriosis (N = 33) and control (N = 27) group, retrospectively, HMGB-1 expression was shown in both epithelial and stromal cell. HMGB-1 expression was significantly increased in secretory phase of endometriosis group, comparing to the controls. To examine the alteration of endometrial stromal cell (HESC) by oxidative stress in terms of HMGB-1, cell proliferation and expression of its receptor, TLR4 was measured according to recombinant HMGB-1 use. Cell proliferation was assessed by CCK-8 assay; real-time PCR and western blotting were used to quantify Toll like receptor 4 (TLR4) mRNA and protein expression respectively. A TLR4 antagonist (LPS-RS) and an inhibitor of the NF-κB pathway (TPCA-1, an IKK-2 inhibitor) were used to confirm the relationships between HMGB-1, TLR4, and the NF-κB pathway. Passive release of HMGB-1 was significantly proportional to the increase in cell death (P<0.05). HESCs showed significant proliferation following treatment with rHMGB-1 (P<0.05), and increased TLR4 expression was observed following rHMGB-1 treatment (P<0.05) in a concentration-dependent manner. Treatment with a TLR4 antagonist and an NF-κB inhibitor resulted in suppression of rHMGB-1-induced HESC proliferation (P<0.05). Levels of IL-6 were significantly decreased following treatment with an NF-κB inhibitor (P<0.05). Our results support the development of altered, pathological endometrium resulted from oxidative stress in normal endometrium. These findings may provide important insights into the changes in endometrium linking the development and progression of endometriosis.

Huang K, Cui M, Ye F, et al.
Global profiling of the signaling network of papillary thyroid carcinoma.
Life Sci. 2016; 147:9-14 [PubMed] Related Publications
AIMS: Thyroid carcinoma is one of the most fast rising cancer diagnoses in the US. Papillary thyroid carcinoma (PTC) comprises 80% of thyroid carcinoma. The goal of our study is to identify regulatory proteins and signaling pathways altered in PTC.
MAIN METHODS: Protein Pathway Array (PPA) was applied to screen 65 signaling proteins and phosphoproteins in 27 pairs of PTC and surrounding benign tissues. Ingenuity Pathway Analysis (IPA) was applied to analyze the signaling pathway.
KEY FINDINGS: 11 were differentially expressed between tumors and surrounding tissues, 8 of which were up-regulated (cytokeratin 18, Stat 1, HMG-1, p-p70 S6 kinase, Raf-B, glutamine synthetase, p-PKC δ, and HDAC1), while 3 of which were down-regulated (cytokeratin 5, BECN1, and p-ERK). Further study showed that two proteins (p-p70 S6 kinase and cytokeratin 18) were associated with lymph node metastasis. The top 10 canonical pathways in PTC were identified to be involved in PTC.
SIGNIFICANCE: Taken together, there is a broad array of dysregulation of signaling proteins in PTC, suggesting a heterogeneous group of diseases.

Shrivastava S, Mansure JJ, Almajed W, et al.
The Role of HMGB1 in Radioresistance of Bladder Cancer.
Mol Cancer Ther. 2016; 15(3):471-9 [PubMed] Related Publications
Although radical cystectomy surgery is the standard-of-care for muscle-invasive bladder cancer, it entails complete removal of the bladder and surrounding organs which leads to substantial loss in the quality-of-life of patients. Radiotherapy, which spares the bladder, would be a more appropriate treatment modality if we can utilize molecular markers to select patients with better response to radiation. In this study, we investigate a protein called high mobility group box protein 1 (HMGB1) as a predictive marker for radiotherapy response in bladder cancer. Our in vitro results indicate a positive correlation between higher levels of HMGB1 protein and resistance to radiation in various cell lines. Upon HMGB1 protein knockdown, highly significant (>1.5-fold) sensitization to radiotherapy was achieved. We saw that loss of HMGB1 was associated with at least two times higher (P < 0.001) DNA damage in cell lines postradiation. Our results also depicted that autophagy was inhibited more than 3-fold (P < 0.001) upon HMGB1 knockdown, implicating its role in autophagy as another cause of bladder cancer radioresistance. Further validation was done in vivo by conducting mouse tumor xenograft experiments, where HMGB1 knockdown tumors showed a significantly better (P < 0.001) response to radiotherapy and decreased autophagy (shown by P62 staining) as compared with controls. The cumulative findings of our in vitro and in vivo studies highlight the significance of HMGB1 as a radiation response marker as well as its utility in radiosensitization of bladder cancer.

Huang J, Liu K, Song D, et al.
Krüppel-like factor 4 promotes high-mobility group box 1-induced chemotherapy resistance in osteosarcoma cells.
Cancer Sci. 2016; 107(3):242-9 [PubMed] Free Access to Full Article Related Publications
Osteosarcoma is the most common primary malignant bone tumor, and the frequent acquisition of chemoresistance is often an obstacle to achieving favorable outcomes during chemotherapy. Recently, Krüppel-like factor 4 (KLF4) has been shown to be associated with chemotherapy resistance in a few tumors; however, the involvement of KLF4 in chemotherapy resistance in osteosarcoma cells remains unknown. In this study, quantitative real-time PCR and western blot analysis revealed that KLF4 expression was significantly increased in response to cisplatin, methotrexate and doxorubicin treatment in osteosarcoma cells, and knockdown of KLF4 increased sensitivity to these anticancer drugs by decreasing cellular clonogenic ability and increasing apoptosis. Moreover, our data suggest that KLF4-regulated drug resistance might, at least partially, positively regulate high-mobility group box 1 (HMGB1), which was found to be a significant contributor to chemoresistance in osteosarcoma cells in our previous study. In summary, this study highlights the significance of KLF4/HMGB1 interaction in regulating chemotherapy resistance, and suggests that targeting KLF4/high-mobility group box 1 may be a therapeutic strategy for osteosarcoma chemotherapy.

Liao H, Xiao Y, Hu Y, et al.
Suppression of Cellular Proliferation and Invasion by HMGB1 Knockdown in Bladder Urothelial Carcinoma Cells.
Oncol Res. 2014; 22(5-6):235-45 [PubMed] Related Publications
HMGB1, which acts as a DNA chaperone to help maintain nuclear homeostasis, was reported to play a prominent role in cancer progression, angiogenesis, invasion, and metastasis development. Increased expression of HMGB1 has been observed in several tumor entities. However, the molecular mechanisms of HMGB1 in tumorigenesis of bladder cancer have rarely been reported. In the present study, real-time quantitative RT-PCR analysis revealed that the expression of HMGB1 in human bladder urothelial carcinoma (BUC) cells was much higher than that in human normal urethra epithelial cells. In order to investigate the role of HMGB1 in BUC cells, RNA interference and Talen-mediated gene knockout (KO) were used to knockdown and knockout HMGB1, respectively, in BUC cell lines BIU-87 and T24. HMGB1 knockdown/out greatly inhibited proliferation, invasion, and cell cycle G1/S transition of BUC cells. The decrease in cell viability caused by HMGB1 knockdown/out was due to an increase in apoptosis via Bax/Bcl-2, both of which were important molecules involved in the apoptotic pathway. We then investigated the effect of HMGB1 knockdown/out on the sensitivity of BUC cells treated with the anticancer drug cisplatin. Knockdown or knockout of HMGB1 rendered BUC cells more sensitive to cisplatin. The decreased expression of LC3-II and Beclin 1, which resulted in decreased levels of autophagy, could probably explain this phenomenon. Thus, HMGB1 may become a novel promising candidate for the prognosis and therapy for bladder cancer.

Xiao P, Liu WL
MiR-142-3p functions as a potential tumor suppressor directly targeting HMGB1 in non-small-cell lung carcinoma.
Int J Clin Exp Pathol. 2015; 8(9):10800-7 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: microRNAs (miRNAs) play a significant role in cancer development and progression by regulating the expression of oncogenes or tumor suppressor genes. Previous study using microarrays demonstrated that miR-142-3p was downregulated in patients with Non-small-cell lung carcinoma (NSCLC). However, the functional role of miR-142-3p in NSCLC is still unclear.
MATERIAL AND METHOD: Real-time quantitative PCR was applied to evaluate the expression level of miRNA-142-3p in NSCLC and normal samples. The cell proliferation of NSCLC cells was analyzed by MTT and colony formation assay after miR-142-3p transfection. Luciferase activities assay, cotransfection and Western blot were used to reveal that the predicted target genes of miR-125b were direct and specific.
RESULTS: In this study, we demonstrate miR-142-3p was downregulated in NSCLC tissues and cell lines. We demonstrated that the overexpression of miR-142-3p inhibits NSCLC cell proliferation and induced cell apoptosis. Furthermore, we demonstrate HMGB1 was a directly target of miR-142-3p in NSCLC cells, and confirmed the target specificity between miR-142-3p and the HMGB1 3'-untranslated region by luciferase reporter assay.
CONCLUSIONS: These results suggest that miR-142-3p may be a tumor suppressor through the downregulation of HMGB1 in NSCLC. miR-142-3p may be a tumor suppressor and a potential therapeutic agent for patients with NSCLC.

Ladoire S, Penault-Llorca F, Senovilla L, et al.
Combined evaluation of LC3B puncta and HMGB1 expression predicts residual risk of relapse after adjuvant chemotherapy in breast cancer.
Autophagy. 2015; 11(10):1878-90 [PubMed] Free Access to Full Article Related Publications
In spite of adjuvant chemotherapy, a significant fraction of patients with localized breast cancer (BC) relapse after optimal treatment. We determined the occurrence of cytoplasmic MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3B)-positive puncta, as well as the presence of nuclear HMGB1 (high mobility group box 1) in cancer cells within surgical BC specimens by immunohistochemistry, first in a test cohort (152 patients) and then in a validation cohort of localized BC patients who all received adjuvant anthracycline-based chemotherapy (1646 patients). Cytoplasmic LC3B(+) puncta inversely correlated with the intensity of SQSTM1 staining, suggesting that a high percentage cells of LC3B(+) puncta reflects increased autophagic flux. After setting optimal thresholds in the test cohort, cytoplasmic LC3B(+) puncta and nuclear HMGB1 were scored as positive in 27.2% and 28.6% of the tumors, respectively, in the validation cohort, while 8.7% were considered as double positive. LC3B(+) puncta or HMGB1 expression alone did not constitute independent prognostic factors for metastasis-free survival (MFS) in multivariate analyses. However, the combined positivity for LC3B(+) puncta and nuclear HMGB1 constituted an independent prognostic factor significantly associated with prolonged MFS (hazard ratio: 0.49 95% confidence interval [0.26-0.89]; P = 0.02), and improved breast cancer specific survival (hazard ratio: 0.21 95% confidence interval [0.05-0.85]; P = 0.029). Subgroup analyses revealed that within patients with poor-prognosis BC, HMGB1(+) LC3B(+) double-positive tumors had a better prognosis than BC that lacked one or both of these markers. Altogether, these results suggest that the combined positivity for LC3B(+) puncta and nuclear HMGB1 is a positive predictor for longer BC survival.

Chen Y, Lin C, Liu Y, Jiang Y
HMGB1 promotes HCC progression partly by downregulating p21 via ERK/c-Myc pathway and upregulating MMP-2.
Tumour Biol. 2016; 37(4):4399-408 [PubMed] Free Access to Full Article Related Publications
High-mobility group box 1 (HMGB1) was found to be over-expressed in many kinds of human cancer, which binds with several receptors and activates RAGE-Ras-MAPK, Toll-like receptors, NF-κB, and Src family kinase signaling pathways and plays a crucial role in tumorigenesis and cancer progression. However, the function and mechanism of HMGB1 in hepatocellular carcinoma (HCC) remain unclear. The aim of this study was to investigate the effect of HMGB1 on HCC progression and explore new molecular mechanism. HMGB1 transient knockdown, stable knockdown, and re-expression were performed by transfection with specific siRNA, shRNA, or expression vector in HCCLM3 cells. Results showed that transient knockdown HMGB1 prevented cell proliferation, promoted apoptosis, induced S phase arrest, and inhibited migration and invasion in vitro, and stable knockdown HMGB1 inhibited xenograft growth in Balb/c athymic mice in vivo. Molecular mechanism investigation revealed that knockdown HMGB1 significantly reduced the activation of MAPKs, including ERK1/2, p38, SAPK/JNK, as well as MAPKKs (MEK1/2, SEK1) and its substrates (c-Jun, c-Myc); downregulated NF-κB/p65 expression and phosphorylation level; decreased MMP-2 expression and activity; and upregulated p21 expression. Interestingly, c-Myc was firstly found to be involved in the promoting function of HMGB1 on HCC progression, which provided a novel clue for the inhibitory effect of HMGB1 on p21 expression by a p53-independent pathway. Collectively, these findings indicated that HMGB1 promoted HCC progression partly by enhancing the ERK1/2 and NF-κB pathways, upregulating MMP-2, and downregulating p21 via an ERK/c-Myc pathway.

Jiang Y, Shan S, Chi L, et al.
Methyl methanesulfonate induces necroptosis in human lung adenoma A549 cells through the PIG-3-reactive oxygen species pathway.
Tumour Biol. 2016; 37(3):3785-95 [PubMed] Related Publications
Methyl methanesulfonate (MMS) is an alkylating agent that can induce cell death through apoptosis and necroptosis. The molecular mechanisms underlying MMS-induced apoptosis have been studied extensively; however, little is known about the mechanism for MMS-induced necroptosis. Therefore, we first established MMS-induced necroptosis model using human lung carcinoma A549 cells. It was found that, within a 24-h period, although MMS at concentrations of 50, 100, 200, 400, and 800 μM can induce DNA damage, only at higher concentrations (400 and 800 μM) MMS treatment lead to necroptosis in A549 cells, as it could be inhibited by the specific necroptotic inhibitor necrostatin-1, but not the specific apoptotic inhibitor carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (Z-VAD-fmk). MMS-induced necroptosis was further confirmed by the induction of the necroptosis biomarkers including the depletion of cellular NADH and ATP and leakage of LDH. This necroptotic cell death was also concurrent with the increased expression of p53, p53-induced gene 3 (PIG-3), high mobility group box-1 protein (HMGB1), and receptor interaction protein kinase (RIP) but not the apoptosis-associated caspase-3 and caspase-9 proteins. Elevated reactive oxygen species (ROS) level was also involved in this process as the specific ROS inhibitor (4-amino-2,4-pyrrolidine-dicarboxylic acid (APDC)) can inhibit the necroptotic cell death. Interestingly, knockdown of PIG-3 expression by small interfering RNA (siRNA) treatment can inhibit the generation of ROS. Taken together, these results suggest that MMS can induce necroptosis in A549 cells, probably through the PIG-3-ROS pathway.

Zhou J, Chen X, Gilvary DL, et al.
HMGB1 induction of clusterin creates a chemoresistant niche in human prostate tumor cells.
Sci Rep. 2015; 5:15085 [PubMed] Free Access to Full Article Related Publications
Development of chemoresistance, especially to docetaxel (DTX), is the primary barrier to the cure of castration-resistant prostate cancer but its mechanism is obscure. Here, we report a seminal crosstalk between dying and residual live tumor cells during treatment with DTX that can result in outgrowth of a chemoresistant population. Survival was due to the induction of secretory/cytoplasmic clusterin (sCLU), which is a potent anti-apoptotic protein known to bind and sequester Bax from mitochondria, to prevent caspase 3 activation. sCLU induction in live cells depended on HMGB1 release from dying cells. Supernatants from DTX-treated DU145 tumor cells, which were shown to contain HMGB1, effectively induced sCLU from newly-plated DU145 tumor cells and protected them from DTX toxicity. Addition of anti-HMBG1 to the supernatant or pretreatment of newly-plated DU145 tumor cells with anti-TLR4 or anti-RAGE markedly abrogated sCLU induction and protective effect of the supernatant. Mechanistically, HMGB1 activated NFκB to promote sCLU gene expression and prevented the translocation of activated Bax to mitochondria to block cell death. Importantly, multiple currently-used chemotherapeutic drugs could release HMGB1 from tumor cells. These results suggest that acquisition of chemoresistance may involve the HMGB1/TLR4-RAGE/sCLU pathway triggered by dying cells to provide survival advantage to remnant live tumor cells.

Peng T, Hu M, Wu T, et al.
Effects of high‑mobility group box 1 knockdown on proliferation, migration and invasion of the HONE‑1 human nasopharyngeal carcinoma cell line.
Mol Med Rep. 2015; 12(5):7531-7 [PubMed] Related Publications
The present study was designed to investigate the effects of high‑mobility group box 1 (HMGB1) knockdown on the proliferation, migration and invasion of the HONE‑1 human nasopharyngeal carcinoma cell line and explore the possible underlying mechanisms. HMGB1-knockdown HONE‑1 cells were generated by lentiviral transfection, and HMGB1 expression was demonstrated to be obviously decreased in these cells. A Cell Counting kit‑8 assay was used to determine cell proliferation, while flow cytometric analysis was employed to determine the apoptotic rate. In addition, in vitro wound healing, cell adhesion and invasion assays were performed to evaluate the metastatic potential of the cells. Western blot analysis was used to determine the protein expression of apoptosis signaling proteins caspase‑3, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein, receptor for advanced glycation end products (RAGE) as well as phosphorylated and total extracellular signal-regulated kinase 1/2 in HONE‑1 cells. The results of the present study demonstrated that HMGB1 knockdown suppressed the proliferation, migration and invasion of HONE‑1 cells, the mechanisms of which may be associated with the induction of mitochondria‑mediated apoptosis and inhibition of HMGB1/RAGE pathways.

Rojas A, Delgado-López F, Perez-Castro R, et al.
HMGB1 enhances the protumoral activities of M2 macrophages by a RAGE-dependent mechanism.
Tumour Biol. 2016; 37(3):3321-9 [PubMed] Related Publications
The monocyte-macrophage lineage shows a high degree of diversity and plasticity. Once they infiltrate tissues, they may acquire two main functional phenotypes, being known as the classically activated type 1 macrophages (M1) and the alternative activated type 2 macrophages (M2). The M1 phenotype can be induced by bacterial products and interferon-γ and exerts a cytotoxic effect on cancer cells. Conversely, the alternatively activated M2 phenotype is induced by Il-4/IL13 and promotes tumor cell growth and vascularization. Although receptor for advanced glycation end-products (RAGE) engagement in M1 macrophages has been reported by several groups to promote inflammation, nothing is known about the functionality of RAGE in M2 macrophages. In the current study, we demonstrate that RAGE is equally expressed in both macrophage phenotypes and that RAGE activation by high-mobility group protein box1 (HMGB1) promotes protumoral activities of M2 macrophages. MKN45 cells co-cultured with M2 macrophages treated with HMGB1 at different times displayed higher invasive abilities. Additionally, conditioned medium from HMGB1-treated M2 macrophages promotes angiogenesis in vitro. RAGE-targeting knockdown abrogates these activities. Overall, the present findings suggest that HMGB1 may contribute, by a RAGE-dependent mechanism, to the protumoral activities of the M2 phenotype.

Wang L, Zhang H, Sun M, et al.
High mobility group box 1-mediated autophagy promotes neuroblastoma cell chemoresistance.
Oncol Rep. 2015; 34(6):2969-76 [PubMed] Related Publications
Neuroblastoma (NB) is one of the most common tumors in childhood. Unfortunately, the survival outcomes remain unsatisfactory since NB commonly develops multidrug resistance. Recent studies have demonstrated that the high mobility group box 1 (HMGB1)-mediated autophagy promotes chemoresistance in osteosarcoma, lung adenocarcinoma and ovarian cancer, but the exact molecular mechanism underlying HMGB1-mediated autophagy in NB has not been clearly defined. In the present study, we investigated the role of HMGB1 in the development of resistance to anticancer agents in NB. Anticancer agents including doxorubicin, cisplatin and etoposide each induced HMGB1 upregulation, promoted cytosolic HMGB1 translocation and the elevation of autophagic activity in human NB cells. RNA interference-mediated knockdown of HMGB1 restored the chemosensitivity of NB cells. Furthermore, mechanistic investigation revealed that HMGB1 promoted the proliferative activity and invasive potential of NB cells. HMGB1 enhanced drug resistance by inducing Beclin-1-mediated autophagy, an intracellular self-defense mechanism known to confer drug resistance. In addition, we found that HMGB1 facilitated autophagic progression and reduced oxidative stress induced by doxorubicin. Therefore, through its role as a regulator of autophagy, HMGB1 is a critical factor in the development of chemoresistance and tumorigenesis, and it may be a novel target for improving the efficacy of NB therapy.

Lai KK, Chan KT, Choi MY, et al.
14-3-3σ confers cisplatin resistance in esophageal squamous cell carcinoma cells via regulating DNA repair molecules.
Tumour Biol. 2016; 37(2):2127-36 [PubMed] Related Publications
Esophageal squamous cell carcinoma (ESCC) is the predominant type of esophageal cancer in Asia. Cisplatin is commonly used in chemoradiation for unresectable ESCC patients. However, the treatment efficacy is diminished in patients with established cisplatin resistance. To understand the mechanism leading to the development of cisplatin resistance in ESCC, we compared the proteomes from a cisplatin-resistant HKESC-2R cell line with its parental-sensitive counterpart HKESC-2 to identify key molecule involved in this process. Mass spectrometry analysis detected 14-3-3σ as the most abundant molecule expressed exclusively in HKESC-2R cells, while western blot result further validated it to be highly expressed in HKESC-2R cells when compared to HKESC-2 cells. Ectopic expression of 14-3-3σ increased cisplatin resistance in HKESC-2 cells, while its suppression sensitized SLMT-1 cells to cisplatin. Among the molecules involved in drug detoxification, drug transportation, and DNA repair, the examined DNA repair molecules HMGB1 and XPA were found to be highly expressed in HKESC-2R cells with high 14-3-3σ expression. Subsequent manipulation of 14-3-3σ by both overexpression and knockdown approaches concurrently altered the expression of HMGB1 and XPA. 14-3-3σ, HMGB1, and XPA were preferentially expressed in cisplatin-resistant SLMT-1 cells when compared to those more sensitive to cisplatin. In ESCC patients with poor response to cisplatin-based chemoradiation, their pre-treatment tumors expressed higher expression of HMGB1 than those with response to such treatment. In summary, our results demonstrate that 14-3-3σ induces cisplatin resistance in ESCC cells and that 14-3-3σ-mediated cisplatin resistance involves DNA repair molecules HMGB1 and XPA. Results from this study provide evidences for further work in researching the potential use of 14-3-3σ and DNA repair molecules HMGB1 and XPA as biomarkers and therapeutic targets for ESCC.

Tian PJ, Li BL, Shan YJ, et al.
Extraction of Peptidoglycan from L. paracasei subp. Paracasei X12 and Its Preliminary Mechanisms of Inducing Immunogenic Cell Death in HT-29 Cells.
Int J Mol Sci. 2015; 16(8):20033-49 [PubMed] Free Access to Full Article Related Publications
L. paracasei subp. paracasei X12 was previously isolated from a Chinese traditional fermented cheese with anticancer activities and probiotic potential. Herein, the integral peptidoglycan (X12-PG) was extracted by a modified trichloroacetic acid (TCA) method. X12-PG contained the four representative amino acids Asp, Glu, Ala and Lys, and displayed the similar lysozyme sensitivity, UV-visible scanning spectrum and molecular weight as the peptidoglycan standard. X12-PG could induce the production of apoptotic bodies observed by transmission electron microscopy (TEM). X12-PG could significantly induced the translocation of calreticulin (CRT) and the release of high mobility group box 1 protein (HMGB1), the two notable hallmarks of immunogenic cell death (ICD), with the endoplastic reticulum (ER) damaged and subsequently intracellular [Ca(2+)] elevated. Our findings implied that X12-PG could induce the ICD of HT-29 cells through targeting at the ER. The present results may enlighten the prospect of probiotics in the prevention of colon cancer.

Paek J, Lee M, Nam EJ, et al.
Clinical impact of high mobility group box 1 protein in epithelial ovarian cancer.
Arch Gynecol Obstet. 2016; 293(3):645-50 [PubMed] Related Publications
PURPOSE: The aim of this study was to confirm the expression of high mobility group box 1 (HMGB1) in patients with epithelial ovarian cancer (EOC) and to evaluate the prognostic significance of HMGB1.
METHODS: A total of 74 patients with EOC comprised our cohort. Retrospectively collected tissue microarray from EOC patients treated with debulking surgery followed by taxane and platinum chemotherapy were analyzed for evaluation of the prognostic significance of HMGB1. Expression of HMGB1 was assessed by immunohistochemistry.
RESULTS: The positive staining was detected in 80% of EOC patients and the rate of high HMGB1 expression was 42%. In advanced stage, patients with high HMGB1 expression showed a poorer prognosis than low HMGB1 expression group [median progression-free survival (PFS), 10.8 vs. 21.7 months, P = 0.005]. High HMGB1 expression was an independent predictor for PFS (P = 0.024).
CONCLUSIONS: HMGB1 expression is expected as a promising biomarker for EOC and further studies are needed to assess potential roles in EOC.

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