Gene Summary

Gene:HMGB1; high mobility group box 1
Aliases: HMG1, HMG3, HMG-1, SBP-1
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:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:high mobility group protein B1
Source:NCBIAccessed: 31 August, 2019


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 (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (9)

Latest Publications: HMGB1 (cancer-related)

Okuda T, Fujita M, Kato A
Significance of Elevated HMGB1 Expression in Pituitary Apoplexy.
Anticancer Res. 2019; 39(8):4491-4494 [PubMed] Related Publications
BACKGROUND/AIM: High-mobility group box 1 (HMGB1) is a nuclear DNA-binding protein that exerts a range of proinflammatory actions when it is secreted extracellularly. We hypothesized that HMGB1 released from damaged cells in pituitary apoplexy would exacerbate the neurological symptoms due to acute inflammation.
PATIENTS AND METHODS: All the patients included in this study suffered from non-functioning pituitary adenoma. Four patients with apoplexy and three patients without apoplexy were included in this study. They underwent endonasal transsphenoidal endoscopic surgery to resect the tumors. We conducted enzyme-linked immunosorbent assay (ELISA) to measure HMGB1 in the surgical specimens.
RESULTS: Patients with apoplexy expressed HMGB1 at significantly higher levels than those in the non-apoplexy group (p=0.0478).
CONCLUSION: HMGB1 may be involved in subacute inflammation of pituitary apoplexy. Further work is needed to elucidate the detailed biological significance of HMGB1 in this disease.

Yoon Y, Ku B, Lee K, et al.
Cold Atmospheric Plasma Induces HMGB1 Expression in Cancer Cells.
Anticancer Res. 2019; 39(5):2405-2413 [PubMed] Related Publications
BACKGROUND/AIM: Plasma medicine is a new field that provides great potential for the treatment of human diseases including cancer in addition to sterilizing the surface of skin and facilitating wound healing. Recently, non-thermal atmospheric plasma (or cold atmospheric plasma, CAP) was introduced, not only for denaturing cells and tissues, but also for operating under the threshold of thermal damage and for chemically inducing a specific response or modification.
MATERIALS AND METHODS: Microwave-mediated CAP was used in this study.
RESULTS: CAP increased high-mobility group box 1 protein (HMGB1) expression, thereby increasing HMGB-1 secretion. In addition, we observed that the calreticulin (CRT) protein was concentrated at the cellular membrane when plasma was treated, representing immunogenic cell death.
CONCLUSION: Overall, plasma treatment induces apoptosis via immunogenic cell death in cancer cells, implying a potential application to human cancer therapy and for the treatment of other human diseases.

Liu S, Zhang W, Liu K, Liu Y
LncRNA SNHG16 promotes tumor growth of pancreatic cancer by targeting miR-218-5p.
Biomed Pharmacother. 2019; 114:108862 [PubMed] Related Publications
Small Nucleolar RNA Host Gene (SNHG16) is a novel cancer-related long noncoding RNA (lncRNA) and functions as an oncogene in a variety of cancers. Nonetheless, the expression patterns, biological function, and potential mechanisms in SNHG16 in pancreatic cancer (PC) remain rarely known. An increase in expression of SNHG16 in PC samples against adjacent normal tissues was shown here. Increased SNHG16 was linked intimately to the tumor-node-metastasis (TNM) stage, distant metastasis, tumor differentiation, and poor overall survival. Loss-of-function experiments revealed that SNHG16 knockdown suppressed the proliferation, formation of colonies, ability to migrate and invade in vitro, along with a lowered growth of the tumor in a mouse model. Mechanistically, SNHG16 might serve as a sponge competitive endogenous RNA (ceRNA) for miR-218-5p, thereby playing a role in regulating the expression of high mobility group box 1 (HMGB1) expression, a known direct miR-218-5p target in PC cells. These results provide novel insight into PC tumorigenesis and suggest that SNHG16 could serve as a likely therapeutic intervention in PC.

Wang Y, Jiang Z, Yan J, Ying S
HMGB1 as a Potential Biomarker and Therapeutic Target for Malignant Mesothelioma.
Dis Markers. 2019; 2019:4183157 [PubMed] Free Access to Full Article Related Publications
Malignant mesothelioma (MM) is a rare, aggressive, and highly lethal cancer that is substantially induced by exposure to asbestos fibers. High-mobility group box 1 (HMGB1) is an intriguing proinflammatory molecule involved in MM. In this review, we describe the possible crucial roles of HMGB1 in carcinogenic mechanisms based on

Chang HY, Chen SY, Wu CH, et al.
Glycyrrhizin Attenuates the Process of Epithelial-to-Mesenchymal Transition by Modulating HMGB1 Initiated Novel Signaling Pathway in Prostate Cancer Cells.
J Agric Food Chem. 2019; 67(12):3323-3332 [PubMed] Related Publications
High mobility group box 1 (HMGB1) is upregulated in nearly every tumor type. Importantly, clinical evidence also proposed that HMGB1 is particularly increased in metastatic prostate cancer patients. Besides, a growing number of studies highlighted that HMGB1 could be a successful therapeutic target for prostate cancer patients. Glycyrrhizin is a novel pharmacological inhibitor of HMGB1 that may repress prostate cancer metastasis. This research was aimed to investigate the effect of glycyrrhizin on inhibition of HMGB1-induced epithelial-to-mesenchymal transition (EMT), a key step of tumor metastasis, in prostate cancer cells. In this study, HMGB1 knock-downed DU145 prostate cancer cells were used. Silencing the HMGB1 gene expression triggered a change of cell morphology to a more epithelial-like shape, which was accompanied by a reduction of Cdc42/GSK-3β/Snail and induction of E-cadherin levels estimated by immunoblotting. Furthermore, HMGB1 facilitated cell migration and invasion via downstream signaling, whereas HMGB1 targeting by 10 mM ethyl pyruvate effectively inhibited EMT characteristics. Interestingly, cell migration capacity induced by HMGB1 in DU145 cells was abolished in a dose-dependent effect of 25-200 μM glycyrrhizin treatment. In conclusion, glycyrrhizin successfully inhibited HMGB1-induced EMT phenomenon, which suggested that glycyrrhizin may serves as a therapeutic agent for metastatic prostate cancer.

Yadav SS, Kumar M, Varshney A, Yadava PK
KLF4 sensitizes the colon cancer cell HCT-15 to cisplatin by altering the expression of HMGB1 and hTERT.
Life Sci. 2019; 220:169-176 [PubMed] Related Publications
AIMS: Insensitivity of cancer cells to therapeutic drugs is the most daunting challenge in cancer treatment. The mechanism of developing chemo-resistance is only partly understood to date. In continuation of some earlier reports, we hypothesize that KLF4, a key transcription factors that also has a crucial role in maintaining the stemness in cancer cells, may offer a basis for chemo-resistance.
MAIN METHODS: Sensitivity of cells to cisplatin was analyzed by cell proliferation, colony formation, and cell growth assay. Cell cycle analysis and immunophenotyping were used to measure cell cycle arrest and level of reactive oxygen species respectively. Immunoblotting was used to analyze the change in expression hTERT and HMGB1 involved in KLF4 mediated cisplatin resistance.
KEY FINDINGS: We found that KLF4 expression sensitizes cancer cell to cisplatin cytotoxicity. Further, KLF4 promotes the cisplatin-mediated G2/M cell cycle arrest while KLF4 knocked down induces cisplatin-mediated S-phase arrest compared to control. Decreased level of reactive oxygen species (ROS) in cisplatin-treated and KLF4 knocked down HCT-15 cells compared to vector control, accounting for increased cell survival. Immuno-blotting showed that KLF4 positively regulates expression of the survival proteins hTERT and HMGB1 while in presence of cisplatin, expression of HMGB1 and hTERT is negatively regulated by KLF4.
SIGNIFICANCE: This study suggests the involvement of KLF4-HMGB1/hTERT signaling in offering the basis for chemo-resistance in colon cancer cells and KLF4 overexpression as a probable strategy for sensitizing drug-resistant cancer cells to chemotherapy. The present study opens up new avenues for cancer research and therapeutics.

Chen X, Cheng F, Liu Y, et al.
Toll-like receptor 2 and Toll-like receptor 4 exhibit distinct regulation of cancer cell stemness mediated by cell death-induced high-mobility group box 1.
EBioMedicine. 2019; 40:135-150 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: High-mobility group box 1 (HMGB1), a common extracellular damage associated molecular pattern molecule, is overexpressed in several solid tumors including pancreatic carcinoma. We previously observed that radiotherapy induced dying cells secrete HMGB1 and accelerate pancreatic carcinoma progression through an unclear mechanism.
METHODS: Using the Millicell system as an in vitro co-culture model, we performed quantitative reverse transcriptase-polymerase chain reaction, western blot and sphere forming ability analyses to access the effect of dying-cell-derived HMGB1 on CD133
FINDINGS: Radiation-associated, dying-cell-derived HMGB1 maintained stemness and contributed to CD133
INTERPRETATION: Our results show how irradiation-induced cell death might enhance the stemness of resident cancer cells, and indicate HMGB1-TLR2 signaling as a potential therapeutic target for preventing pancreatic cancer recurrence.

Zhang W, An F, Xia M, et al.
Increased HMGB1 expression correlates with higher expression of c-IAP2 and pERK in colorectal cancer.
Medicine (Baltimore). 2019; 98(3):e14069 [PubMed] Free Access to Full Article Related Publications
The aim of this study was to investigate the relationship between high-mobility group box 1 (HMGB1) and colorectal cancer (CRC).In this prospective study, patients with CRC undergoing primary surgery and healthy subjects (control group) were enrolled from July 2013 to December 2014. The serum HMGB1 concentration and HMGB1 mRNA expression were determined using enzyme-linked immunosorbent assay reverse transcription-polymerase chain reaction, respectively. Immunohistochemical analysis was performed to determine HMGB1, pERK, and c-inhibitor of apoptosis protein 2 (c-IAP2) protein expression levels in the cancer tissues.A total 144 patients with CRC and 50 healthy subjects underwent serum HMGB1 testing. Resected specimens of 50 patients were used for HMGB1 mRNA and protein expression analyses. Mean serum HMGB1 level in the patients with CRC was higher than that of the control group (8.42 μg/L vs 1.79 μg/L, P < .05). Mean serum HMGB1 level in the patients with CRC with distant metastasis was significantly higher than that of the controls (13.32 μg/L vs 7.37 μg/L, P < .05). The HMGB1 mRNA and protein expression levels in the CRC tissues were significantly higher than those in the adjacent normal mucosa. HMGB1 protein expression positively correlated with the lymph node metastasis. There were positive correlations between HMGB1 and c-IAP2 (r = 0.457, P < .05), HMGB1 and pERK (r = 0.461, P < .05), as well as pERK and c-IAP2 (r = 0.399, P < .05).HMGB1 expression in CRC correlates with distant and lymph node metastasis. It may inhibit apoptosis by inducing activation of pERK and c-IAP2.

Wang S, Chen Y, Yu X, et al.
miR-129-5p attenuates cell proliferation and epithelial mesenchymal transition via HMGB1 in gastric cancer.
Pathol Res Pract. 2019; 215(4):676-682 [PubMed] Related Publications
BACKGROUND: The miR-129-5p has been reported to be aberrant expression and exert vital roles in tumor progression of various malignancies. However, the effects on EMT in gastric cancer and its precise molecular mechanism in gastric cancer remain unclear.
METHODS AND MATERIALS: RT-qPCR was performed to evaluate the expression level of miR-129-5p and HMGB1 in cell lines. Cell proliferation was detected via CCK-8. The epithelial mesenchymal transition (EMT) related proteins and the expression of HMGB1 were detected by western blot analysis. Luciferase assays were used to validate binding seeds between miR-129-5p and HMGB1.
RESULTS: miR-129-5p was downregulated in gastric cancer cells compared with GES-1. At the same time EMT was promoted in gastric cancer cells compared to GES-1. Overexpression of miR-129-5p inhibited EMT and proliferation. MiR-129-5p negatively and directly targeted HMGB1. HMGB1 was upregulated in gastric cancer cells and HMGB1 knocked-down inhibited EMT and cell proliferation.
CONCLUSION: Taken together, upregulation of miR-129-5p associated with gastric cancer proliferation and EMT, and serves as a potential diagnostic and therapeutic target via miR-129-5p/HMGB1 pathway in gastric cancer.

Hung SC, Wang SS, Li JR, et al.
Effect of
Int J Med Sci. 2018; 15(14):1731-1736 [PubMed] Free Access to Full Article Related Publications
The high mobility group box 1 gene (

Zhang X, Yang X, Zhu S, et al.
Radiosensitization of esophageal carcinoma cells by knockdown of HMGB1 expression.
Oncol Rep. 2019; 41(3):1960-1970 [PubMed] Related Publications
Radiotherapy (RT) is a traditional and important treatment for carcinoma of the esophagus along with surgery and chemotherapy. High mobility group box 1 (HMGB1) plays a crucial part in inhibiting the apoptosis of cancer cells after irradiation treatment. The present study, was designed to analyze the function of HMGB1 in esophageal cancer progression and elucidate the effects of HMGB1 on the radiosensitivity of human esophageal cancer cell lines. In the present study, an immunohistochemical evaluation of HMGB1 was performed on 77 biopsies, and the results revealed that HMGB1 overexpression was positively correlated with gross tumor volume (GTV), tumor‑node‑metastasis (TNM) stage, T classification, distant metastasis, and relapse and negatively correlated with patient survival rates, suggesting that HMGB1 acts as a key factor in the development of esophageal cancer. An shRNA targeting HMGB1 was designed for the knockdown of HMGB1 in ECA109 and TE13 cells, and the transfection efficiency of the shRNA was assessed using quantitative real‑time reverse transcription polymerase chain reaction and western blot analysis. CCK‑8 and clonogenic assays were used to analyze the effect of HMGB1 on the proliferation and radiosensitivity, respectively, of esophageal cancer cells in vitro. The influence of HMGB1 on radiation‑induced changes in the migration, invasion, and cell cycle as well as apoptosis of tumor cells was examined by wound‑healing and Transwell assays and flow cytometry, respectively. In addition, xenograft tumor models were constructed to observe the effect of HMGB1 on tumor growth in vivo. The results of the study in vitro revealed that the proliferation of the HMGB1‑shRNA group decreased after irradiation, and the radiation treatment reduced the tumor volume of the xenograft model which was more marked in HMGB1‑shRNA group. Moreover, HMGB1 was involved in the phosphorylation of H2AX after irradiation, and HMGB1 knockdown blocked the cell cycle in the G0/G1 phase and increased apoptosis. HMGB1 deficiency was also correlated with the upregulation of p16, Bax and caspase‑9 and the downregulation of MMP‑2, MMP‑9, cyclin D1, CDK4, γH2AX and Bcl‑2. These data indicated that the overexpression of HMGB1 prior to treatment was correlated with poor clinical outcome in esophageal carcinoma and that knockdown HMGB1 expression in human esophageal cancer cell lines increased their radiosensitivity by allowing the induction of apoptosis and G0/G1 arrest after exposure to radiation.

Ding C, Yu H, Shi C, et al.
MiR-let-7e inhibits invasion and magration and regulates HMGB1 expression in papillary thyroid carcinoma.
Biomed Pharmacother. 2019; 110:528-536 [PubMed] Related Publications
Thyroid cancer keeps rapidly increasing worldwide and the most frequent type is papillary thyroid carcinoma (PTC). MicroRNAs (miRNAs) are proved dysregulated in many types of malignancies, including thyroid cancer. Although miR-let-7e has been implicated in several types of cancer regulation, relatively little is known about the function of miR-let-7e in PTC. In this study, we showed that the overexpression of miR-let-7e or knockdown of high mobility group box 1 (HMGB1) inhibited cell migration and invasion. MiR-let-7e downregulates HMGB1 expression by directly targeting the HMGB1 3'-UTR. Furthermore, HMGB1 reintroduction reversed the anti-proliferation, anti-migration, and anti-invasion roles of miR-let-7e. miR-let-7e might function as a tumor suppressor in papillary thyroid carcinoma through HMGB1. Therefore, our study demonstrates that miR-let-7e plays an important role in papillary thyroid carcinoma progression and might represent a new potential therapeutic target for treatment.

Tian S, Liu W, Pan Y, Zhan S
Long non-coding RNA Linc00320 inhibits glioma cell proliferation through restraining Wnt/β-catenin signaling.
Biochem Biophys Res Commun. 2019; 508(2):458-464 [PubMed] Related Publications
Recent efforts have revealed that numerous oncogenic lncRNAs have been found play pivotal role in Glioma progression while there is little know about anti-oncogenic lncRNAs in Glioma. In current study, we found a HMGB1 regulated lncRNA, Linc00320, is significantly decreased in Glioma malignant tissues and its low expression predicts poor prognosis. Moreover, we found that the nucleus localized Linc00320 inhibits Glioma cell proliferation both in vitro and in vivo. In addition, we found that Linc00320 binds to β-catenin and inhibits the activity of Wnt/β-catenin signaling by disrupting β-catenin binds to TCF4 in Glioma cells. Taken together, we firstly demonstrated the tumor suppressive lncRNA, Linc00320, is down-regulated in Glioma tissues and inhibits Glioma cell proliferation by restraining Wnt/β-catenin signaling through segregating β-catenin and TCF4 and revealed the novel HMGB1/Linc00320/β-catenin axis in Glioma progression.

Meng FJ, Wang S, Yan YJ, et al.
Recombined humanized endostatin-induced suppression of HMGB1 expression inhibits proliferation of NSCLC cancer cells.
Thorac Cancer. 2019; 10(1):90-95 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Recombined humanized endostatin (Rh-endostatin) exhibits a potent anti-cancer effect involving multiple molecular targets and signaling pathways. HMGB1 is a highly conserved DNA-binding protein involved in cancer development. The therapeutic effect of Rh-endostatin on HMGB1 has not been reported, thus we investigate the effect in non-small cell lung cancer (NSCLC) cells.
METHODS: Quantitative real-time PCR and Western blot were used to analyze the messenger RNA and protein expression of HMGB1 in A549 cancer cells, while enzyme-linked immunosorbent assay was used to detect the release of HMGB1. Western blot was performed to evaluate HMGB1 expression in SK-MES-1 and H661 NSCLC cells.
RESULTS: Rh-endostatin inhibited the proliferation of A549 cancer cells and distinctly downregulated the expression and release of HMGB1 in dose and time dependent manners. Rh-endostatin-induced HMGB1 downregulation was confirmed in different types of NSCLC cells.
CONCLUSION: These results demonstrate the general phenomenon that Rh-endostatin can induce HMGB1 suppression in a variety of NSCLC cells. Rh-endostatin may suppress HMGB1 expression and release in A549 cancer cells, thus inhibiting cell proliferation.

Qian F, Xiao J, Gai L, Zhu J
HMGB1-RAGE signaling facilitates Ras-dependent Yap1 expression to drive colorectal cancer stemness and development.
Mol Carcinog. 2019; 58(4):500-510 [PubMed] Related Publications
HMGB1-RAGE signaling plays an integral role in inflammation-driven carcinogenesis. In the present study, we showed that RAGE has direct association with K-Ras following HMGB1 exposure in colorectal cancer (CRC) cells. Immunofluorescence analysis revealed a significant co-localization between RAGE and K-Ras in HMGB1-exposed CRC cells. Moreover, we uncovered that HMGB1-mediated RAGE activation led to Yap1 accumulation in a Ras-dependent mechanism in CRC cells. HMGB1 activated the expression of Yap1 downstream stemness marker proteins CD44 and Sox2 in RAGE- and Ras-dependent manners. Furthermore, HMGB1 exposure led to the proliferation of CRC cells and the expansion of CRC stem cells. RAGE, Yap1 and CD44 were overexpressed in CRC specimens. Linear regression analysis revealed that the expression of RAGE was positively correlated with Yap1 in clinical CRC specimens. Both of RAGE and Yap1 expression were correlated with advanced histological grades, lymph node metastasis and TNM stages. Finally, we revealed that both of RAGE and Yap1 expression could predicted unfavorable prognosis in CRC patients. These findings implicated that HMGB1-RAGE signaling may promote Yap1 activation and CRC progression, shedding new light on the mechanisms underlying inflammation-driven CRC development.

Zhang X, Shi H, Yuan X, et al.
Tumor-derived exosomes induce N2 polarization of neutrophils to promote gastric cancer cell migration.
Mol Cancer. 2018; 17(1):146 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Exosomes are extracellular vesicles that mediate cellular communication in health and diseases. Neutrophils could be polarized to a pro-tumor phenotype by tumor. The function of tumor-derived exosomes in neutrophil regulation remains unclear.
METHODS: We investigated the effects of gastric cancer cell-derived exosomes (GC-Ex) on the pro-tumor activation of neutrophils and elucidated the underlying mechanisms.
RESULTS: GC-Ex prolonged neutrophil survival and induced expression of inflammatory factors in neutrophils. GC-Ex-activated neutrophils, in turn, promoted gastric cancer cell migration. GC-Ex transported high mobility group box-1 (HMGB1) that activated NF-κB pathway through interaction with TLR4, resulting in an increased autophagic response in neutrophils. Blocking HMGB1/TLR4 interaction, NF-κB pathway, and autophagy reversed GC-Ex-induced neutrophil activation. Silencing HMGB1 in gastric cancer cells confirmed HMGB1 as a key factor for GC-Ex-mediated neutrophil activation. Furthermore, HMGB1 expression was upregulated in gastric cancer tissues. Increased HMGB1 expression was associated with poor prognosis in patients with gastric cancer. Finally, gastric cancer tissue-derived exosomes acted similarly as exosomes derived from gastric cancer cell lines in neutrophil activation.
CONCLUSION: We demonstrate that gastric cancer cell-derived exosomes induce autophagy and pro-tumor activation of neutrophils via HMGB1/TLR4/NF-κB signaling, which provides new insights into mechanisms for neutrophil regulation in cancer and sheds lights on the multifaceted role of exosomes in reshaping tumor microenvironment.

Chen J, Li G
MiR-1284 enhances sensitivity of cervical cancer cells to cisplatin via downregulating HMGB1.
Biomed Pharmacother. 2018; 107:997-1003 [PubMed] Related Publications
BACKGROUND: Chemotherapy is one of the commonest therapeutic method for cervical cancer. There are some common chemotherapy drugs, such as cisplatin, docetaxel, paclitaxel and selenium nanoparticle. microRNAs (miRNAs) have been verified to be regulators in various human cancers. This study aims to investigate the effects of miR-1284 on the cisplatin sensitivity of cervical cancer cells.
METHODS: The levels of miR-1284 in different tissues and cell lines were detected through using qRT-PCR analysis. Kaplan Meier analysis was utilized to analyze the influence of miR-1284 expression on the overall survival rate of cervical cancer patients. The biological effects of miR-1284 on the progression and chemosensitivity of cervical cancer were tested through conducting functional assays. Mechanism investigations were used to prove the binding relation between miR-1284 and HMGB1. Rescue assays were applied to demonstrate the effects of miR-1284-HMGB1 axis on chemosensitivity of cervical cancer cells.
RESULTS: miR-1284 was down-expressed in cervical cancer tissues and cell lines. Patients with low level of miR-1284 had low overall survival rate. Upregulation of miR-1284 suppressed proliferation and invasion, while promoted apoptosis. Moreover, upregulated miR-1284 enhanced sensitivity of cervical cancer cells to cisplatin. HMGB1 was a target gene of miR-1284. HMGB1 reversed the effects of miR-1284 on the progression and chemosensitivity of cervical cancer cells.
CONCLUSION: miR-1284 enhances sensitivity of cervical cancer cells to cisplatin via targeting HMGB1.

Guo X, He D, Zhang E, et al.
HMGB1 knockdown increases MM cell vulnerability by regulating autophagy and DNA damage repair.
J Exp Clin Cancer Res. 2018; 37(1):205 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: With the development of novel therapeutic agents, the survival of multiple myeloma (MM) patients has much improved. However, the disease is incurable due to drug resistance. Previous studies have found that high-mobility group box 1 (HMGB1) is involved in inflammation, angiogenesis, DNA damage repair, and cancer invasion, progression, metastasis and drug resistance and that high HMGB1 expression is associated with poor MM prognosis, yet the role and mechanism of HMGB1 in MM remains unclear.
METHODS: Through gene expression and Oncomine database analyses, we found that HMGB1 is associated with a poor prognosis in MM patients. RNA interference together with gene array analysis, cell proliferation and apoptosis assays, autophagy detection assays, western blotting, and in vivo xenograft models were employed to evaluate the effect of HMGB1 and the mechanism involved in MM drug resistance.
RESULTS: MM cell lines and primary MM samples were found to express high levels of HMGB1, which was negatively associated with the 3-year survival of MM patients. HMGB1 knockdown in MM cells enhanced the inhibitory effect of chemotherapy with dexamethasone (Dex) via apoptosis induction. Furthermore, downregulation of HMGB1 activated the mTOR pathway, inhibited autophagy and increased DNA damage induced by Dex by modulating expression of related genes. In vivo, xenograft models showed that after Dex treatment, the tumor burden of HMGB1-knockdown mice was decreased compared with that of control mice.
CONCLUSIONS: Our research shows that HMGB1 participates in autophagy and DNA damage repair and that downregulation of HMGB1 enhances the sensitivity of MM cells to Dex, suggesting that HMGB1 may serve as a target for MM treatment.

Hashemi-Niasari F, Rabbani-Chadegani A, Razmi M, Fallah S
Synergy of theophylline reduces necrotic effect of berberine, induces cell cycle arrest and PARP, HMGB1, Bcl-2 family mediated apoptosis in MDA-MB-231 breast cancer cells.
Biomed Pharmacother. 2018; 106:858-867 [PubMed] Related Publications
Berberine, is a plant alkaloid, proved to have anticancer effect on various cancers. Theophylline (TH), a natural product, is widely used in the treatment of respiratory difficulties. The present study designed to elucidate the effects of theophylline and berberine combination on breast cancer cells cytotoxicity, gene expression and cell cycle. MTT assay revealed that berberine inhibited MDA-MB-231 breast cancer cells viability in a time and dose dependent manner (IC

Zhang DY, Zou XJ, Cao CH, et al.
Identification and Functional Characterization of Long Non-coding RNA
Theranostics. 2018; 8(14):3751-3765 [PubMed] Free Access to Full Article Related Publications
Long non-coding RNAs (lncRNAs) have recently been identified as critical regulators in tumor initiation and development. However, the function of lncRNAs in human hepatocellular carcinoma (HCC) remains largely unknown. Our study was designed to explore the biological function and clinical implication of lncRNA

Wu K, Zhang H, Fu Y, et al.
TLR4/MyD88 signaling determines the metastatic potential of breast cancer cells.
Mol Med Rep. 2018; 18(3):3411-3420 [PubMed] Free Access to Full Article Related Publications
The influence of Toll‑like receptor (TLR)4/myeloid differentiation factor (MyD)88 signaling on the invasion and metastasis of cancer cells has been previously reported. The purpose of the present study was to determine the role of TLR4/MyD88 in breast cancer cell migration and invasion, and to discover novel therapeutic targets for breast cancer treatment. TLR4, MyD88 and high mobility group box 1 (HMGB1) mRNA expression levels were assessed in highly invasive human MDA‑MB‑231 breast cancer cells, breast cancer cells with a low rate of invasion (MCF‑7) and normal human MDA‑Kb2 mammary gland cells by reverse transcription‑quantitative polymerase chain reaction. The protein expression levels of these markers were detected by western blotting and immunofluorescence. Randomly selected breast cancer and paracarcinoma tissues were used to measure TLR4 and MyD88 protein expression levels by immunohistochemistry. The mRNA and protein expression levels of TLR4 and MyD88 were significantly higher in MDA‑MB‑231 cells compared with either MCF‑7 cells or MDA‑Kb2 cells. The mRNA and protein expression levels of HMGB1 were comparable in the two breast cancer cell lines, with no statistical difference (P>0.05). TLR4 and MyD88 protein expression levels were also significantly higher in breast cancer tissues compared with paracarcinoma tissues (P<0.05). TLR4 and MyD88 protein expression levels were positively correlated with axillary lymph node metastasis and histological grade (P<0.05). TLR4/MyD88 expression levels were positively correlated with the metastasis of breast cancer cells. TLR4/MyD88 may be useful as a novel biomarker to evaluate the prognosis and treatment of patients with breast cancer.

Huang M, Geng Y, Deng Q, et al.
Translationally controlled tumor protein affects colorectal cancer metastasis through the high mobility group box 1-dependent pathway.
Int J Oncol. 2018; 53(4):1481-1492 [PubMed] Free Access to Full Article Related Publications
Recently, accumulating evidence from clinical and experimental researches have suggested that translationally controlled tumor protein (TCTP) and high mobility group box 1 (HMGB1) are implicated in colorectal cancer (CRC) metastasis. However, whether there is an interconnection between these two tumor-promoting proteins and how they affect CRC metastasis remain to be fully elucidated. In the present study, the expression level of TCTP in CRC tissues was assessed by immunohistochemical staining and immunoblotting, and the serum concentration of HMGB1 in patients with CRC was detected by enzyme-linked immunosorbent assay. In vitro, following the modulation of TCTP expression in colon cancer LoVo cells, the translocation behavior of HMGB1 was observed by immunofluorescence assay. Furthermore, the activity of nuclear factor-κB (NF-κB) in LoVo cells was evaluated by immunoblotting and luciferase assay, and the invasion ability of LoVo cells after different treatments was determined using cell invasion assay. In vivo, xenograft tumor model was established and the correlation of TCTP and HMGB1 expression in xenografted tumors was studied by immunohistochemical examination. The results revealed that the expression level of TCTP in CRC tissue and the serum concentration of HMGB1 in patients with CRC were significantly increased, and there was a strong positive correlation between them. In vitro experiments showed that the overexpression of TCTP on LoVo cells resulted in the release of HMGB1 from the nucleus to the cytoplasm and into the extracellular space. In addition, the overexpression of TCTP led to the activation of NF-κB in LoVo cells, and this effect was reversed by treatment with antibodies targeting HMGB1 or to its receptors Toll-like receptor 4 (TLR4) and receptor for advanced glycation end products advanced glycation end products (RAGE). Furthermore, inhibition of the HMGB1-TLR4/RAGE-NF-κB pathway significantly inhibited the TCTP-stimulated invasion of LoVo cells. In vivo experiments demonstrated that the overexpression of TCTP in nude mice promoted the development and spread of xenografted tumors, and concurrently enhanced the expression of HMGB1 in tumor tissues. Collectively, these findings suggested that TCTP promotes CRC metastasis through regulating the behaviors of HMGB1 and the downstream activation of the NF-κB signaling pathway.

Li XY, Liang CH, Yang YJ, et al.
No association between HMGB1 polymorphisms and cancer risk: evidence from a meta-analysis.
Biosci Rep. 2018; 38(5) [PubMed] Free Access to Full Article Related Publications
The aim of the present study was to determine whether High mobility group box 1 (HMGB1) polymorphism was associated with cancer susceptibility. PubMed, Embase, and ISI Web of Science were extensively searched without language restriction. Data were extracted using a standardized data collection sheet after two reviewers scanned studies independently. The association between HMGB1 polymorphism and cancer risks was indicated as odds ratio (OR) along with its related 95% confidence interval (95%CI). Meta-analysis was conducted via RevMan 5.3 software. A total of ten studies comprising 4530 cases and 5167 controls were included in our study. Meta-analysis revealed no statistical association between

Jiang C, Qu X, Ke H, et al.
Association between the HMGB1/TLR4 signaling pathway and the clinicopathological features of ovarian cancer.
Mol Med Rep. 2018; 18(3):3093-3098 [PubMed] Related Publications
In the present study, the expression levels of high‑mobility group protein B1 (HMGB1), Toll‑like receptor 4 (TLR4), nuclear factor (NF)‑κB and tumor necrosis factor (TNF)‑α in malignant epithelial ovarian cancer (MEOC) were investigated in regards to several clinicopathological characteristics. A total of 20 patients with MEOC who underwent surgery were recruited in the present study. The mRNA and protein expression of HMGB1, TLR4, NF‑κB and TNF‑α was determined in patients with MEOC and compared with expression levels in 20 patients diagnosed with benign ovarian cysts (BOC). It was demonstrated that the mRNA and protein expression of HMGB1, TLR4, NF‑κB and TNF‑α in MEOC was significantly increased, compared with the BOC group (P<0.01). The gene and protein expression of HMGB1, TLR4, NF‑κB and TNF‑α was significantly increased in the advanced tumor stage and poorly differentiated group (P<0.01). The present study suggested that the HMGB1/TLR4 signaling pathway was overactive in MEOC, and was associated with MEOC tumor cell proliferation, invasion and metastasis. Furthermore, this may have been mediated via NF‑κB signaling.

Palanissami G, Paul SFD
RAGE and Its Ligands: Molecular Interplay Between Glycation, Inflammation, and Hallmarks of Cancer-a Review.
Horm Cancer. 2018; 9(5):295-325 [PubMed] Related Publications
Risk of cancer especially of colon, breast, and pancreas is high in diabetic and obese patients, with potential involvement of augmented expression of RAGE (receptor for advanced glycation end products) and its ligands, namely AGEs (advanced glycation end products), HMGB1 (high-mobility group box 1 protein), and S100 group of proteins. Studies have reported the involvement of RAGE activation by its ligands in growth and survival of cancers, including metastasis and poor prognosis. We propose that this receptor-ligand axis provides the molecular link between certain pre-existing states as hypoxia, hyperglycemia, glycation, inflammation, oxidative stress, and onset of cancers. The chronic inflammatory, hyperglycemic milieu accompanied by glycoxidative stress as in diabetes and obesity, concomitant with the formation of RAGE ligands, instigates RAGE and cancer stem cells, leading to the oncogenic transformation of normal and pre-malignant tissues towards development of neoplasms. We have aimed to elucidate the complete signalling map initiated upon RAGE-ligand splicing, from oncogenesis to progression, epithelial-mesenchymal transition, invasion, cancer stem cell renewal, chemo-resistance, and cancer relapse. We have attributed the complex molecular functions of RAGE-ligand signalling cues to every aspect of cancer promotion, explaining the central network in bridging glycation, inflammation, oxidation, and the hallmarks of cancer. Underlining the substantial requisite for anti-neoplastic agents targeting RAGE and its ligands, we have explicitly discoursed RAGE and its allied components (AGEs, soluble RAGE, RAGE gene polymorphisms) as potential diagnostic and prognostic biomarkers for prompt detection of cancers and implication in impending RAGE-ligand directed, novel combinatorial, and targeted onco-therapeutics.

Di X, He G, Chen H, et al.
High-mobility group box 1 protein modulated proliferation and radioresistance in esophageal squamous cell carcinoma.
J Gastroenterol Hepatol. 2019; 34(4):728-735 [PubMed] Related Publications
BACKGROUND AND AIM: The high-mobility group box 1 (HMGB1) protein plays an important role in a lot of biological behaviors, including DNA damage repair, gene transcription, cell replication, and cell death, and its expression is higher in many solid tumors tissues than in their adjacent normal tissues, and it is always involved in tumor proliferation, metastasis, therapeutic tolerance, and poor prognosis. However, HMGB1 in proliferation and radioresistance of esophageal squamous cell carcinoma (ESCC) remains poorly understood. In this study, the effect of HMGB1 on proliferation, cell death, DNA damage repair and radioresistance, and its underlying mechanism was investigated in human ESCC.
METHODS: The immunohistochemistry scores of tumor and adjacent normal tissues in ESCC tissue microarray were analyzed. Stable HMGB1 knockdown cell lines were constructed using Kyse150 and Kyse450 cells. Cell viability, radioresistance, apoptosis, autophagy, and DNA damage were determined using CCK-8, 5-ethynyl-2'-deoxyuridine, clonogenic survival assay, immunofluorescence, flow cytometry, and western blot assays.
RESULTS: Differential analyses showed that the expression of HMGB1 in esophageal cancer tissue was significantly higher than that in adjacent normal tissues. The downregulation of HMGB1 could effectively inhibit proliferation, increase radiosensitivity, impair DNA damage repair abilities, reduce autophagy, and increase apoptosis rates in ESCC cells after irradiation.
CONCLUSIONS: HMGB1 is expected to be a potential target for ESCC therapy and radiosensitization.

Lv S, Guan M
miRNA-1284, a regulator of HMGB1, inhibits cell proliferation and migration in osteosarcoma.
Biosci Rep. 2018; 38(4) [PubMed] Free Access to Full Article Related Publications
Previous literatures have reported the role of human micro RNA-1284 (hsa-miR-1284, in short miR-1284) in diverse cancers. However, its biological function in osteosarcoma pathogenesis remains unknown. In the present study, we investigated the potential role of miR-1284 in osteosarcoma. Expression of miR-1284 and high mobility group box 1 (HMGB1) were examined in 80 tissues obtained from 40 patients. MiR-1284 level was measured in five osteosarcoma cell lines. Relative luciferase activity and HMGB1 expression were examined in MG-63 and U2OS cells transfected with wild-type or mutant 3'-UTR of HMGB1 in the presence of miR-1284 mimics or miR-NC. Cell viability, colony formation, and cell migration were measured in MG-63, U2OS and hFOB 1.19 cells, which were transfected with miR-1284 mimics or miR-NC. In the rescue experiments, recombinant HMGB1 plasmid was transfected into MG-63 and U2OS cells, and cell viability and migration were determined again. Our results indicated that relative level of miR-1284 was lower in tumor tissues compared with its adjacent tissues and it was found suppressed at lower levels in MG-63 and U2OS cell lines. Expression of HMGB1 is significantly elevated in tumor tissues and negatively correlated with miR-1284 expression. MiR-1284 exerted its function by directly binding to 3'-UTR of HMGB1 and regulates expression of HMGB1. The overexpression of miR-1284 inhibited the cell proliferation and migration, and altered the protein expression of epithelial-mesenchymal transition (EMT)-associated genes (E-cadherin, N-cadherin, Vimentin, and Snail), which was reversed by HMGB1 overexpression. In conclusion, miR-1284 can function as a new regulator to inhibit osteosarcoma cell proliferation and migration by targeting HMGB1.

Ando K, Sakoda M, Ueno S, et al.
Clinical Implication of the Relationship Between High Mobility Group Box-1 and Tumor Differentiation in Hepatocellular Carcinoma.
Anticancer Res. 2018; 38(6):3411-3418 [PubMed] Related Publications
BACKGROUND/AIM: High mobility group box-1 (HMGB1) induces the release of proinflammatory cytokines and chemokines as a late-acting mediator of inflammation. Hepatocellular carcinoma (HCC) is a typical inflammation-related cancer. However, little is known about the relationship between HCC and HMGB1 and its receptor RAGE (receptor for advanced glycation end products). This study analyzes the clinicopathological relevance of HMGB1 expression level and the effect of HMGB1 expression on the characteristics of HCC.
MATERIALS AND METHODS: Samples from 75 HCC patients including 13 with positive hepatitis B surface antigen and 36 with hepatitis C antibody were studied. The expression of HMGB1 in paired cancer and non-cancerous tissues from patients with HCC was assessed using reverse-transcription polymerase chain reaction (RT-PCR) and western blotting. Quantitative RT-PCR data were analyzed in association with the clinicopathological factors of patients with HCC.
RESULTS: The expression of HMGB1 mRNA in HCC was high in well-differentiated tumors, but declined as tumors dedifferentiated to moderately and poorly differentiated HCC. The levels of HMGB1 mRNA showed a negative correlation with the presence of portal invasion (p=0.005) and the rise of serum PIVKA-II (p=0.034). There was no clear correlation between HMGB1 expression and proliferation activity of HCC using Ki-67 staining.
CONCLUSION: In HCC, HMGB1 expression level correlated inversely with tumor differentiation. The RAGE-HMGB1 interaction may play a greater role in the early stages of HCC tumorigenesis than during cancer development.

Zhang J, Shao S, Han D, et al.
High mobility group box 1 promotes the epithelial-to-mesenchymal transition in prostate cancer PC3 cells via the RAGE/NF-κB signaling pathway.
Int J Oncol. 2018; 53(2):659-671 [PubMed] Free Access to Full Article Related Publications
High mobility group box 1 (HMGB1), a critical damage-associated molecular pattern molecule, has been implicated in several inflammatory diseases and cancer types. The overexpression of HMGB1 protein occurs in prostate cancer, and is closely associated with the proliferation and aggressiveness of tumor cells. However, the underlying mechanisms of HMGB1-induced tumor metastasis in prostate cancer remain unclear. In the present study, it was demonstrated that the expression of HMGB1 was high in prostate cancer samples, particularly in the metastatic tissues. Furthermore, recombinant HMGB1 (rHMGB1) enhanced the invasive and metastatic capabilities of the prostate cancer cells. Molecular phenotype alterations of epithelial-to-mesenchymal transition (EMT) and elevated expression levels of matrix metalloproteinase (MMP)-1, -3 and -10 were observed. In addition, advanced glycosylation end-product specific receptor (RAGE) and its downstream molecule nuclear factor (NF)-κB pathway were activated during rHMGB1-induced metastasis. Silencing RAGE or NF-κB reversed the upregulation of MMP and EMT marker expression levels, thus reducing the migration and invasiveness of tumor cells. Taken together, these results suggest that highly expressed HMGB1 drives EMT and the overexpression of MMP-1, -3, -10 via the RAGE/NF-κB signaling pathways, which facilitates the metastasis of prostate cancer and may be a potential therapeutic target for metastatic prostate cancer.

Lu L, Zhang D, Xu Y, et al.
miR-505 enhances doxorubicin-induced cytotoxicity in hepatocellular carcinoma through repressing the Akt pathway by directly targeting HMGB1.
Biomed Pharmacother. 2018; 104:613-621 [PubMed] Related Publications
Compelling evidence has suggested the relevance of miRNAs in resistance to chemotherapeutic agents in HCC. miR-505 was reported to be downregulated and function as a tumor suppressor in HCC cells by binding to high-mobility group box 1 (HMGB1). Whether miR-505/HMGB1 axis was involved in ADM cytotoxicity in HCC remains to be addressed. The aim of this study was to explore the effect of miR-505/HMGB1 axis on ADM cytotoxicity in HCC cells. MTT, flow cytometry analysis, and caspase-3 activity assays were conducted to assess ADM-induced cytotoxicity. The protein level of phosphorylation of histone H2 AX at Ser139 (γH2AX) was detected to evaluate DNA damage. The effects of miR-505 and HMGB1 on the protein kinase B (Akt) pathway were determined by examining the protein levels of phosphorylated Akt (p-Akt), Akt, phosphorylated glycogen synthase kinase-3β (p-GSK-3β), and GSK-3β. We found that HMGB1 knockdown and miR-505 overexpression exacerbated ADM-induced cell viability inhibition, enhanced ADM-induced apoptosis, and increased caspase-3 activity in ADM-treated HCC cells. However, HMGB1 overexpression reversed the effects of miR-505 on ADM-induced cytotoxicity in HCC cells. HMGB1 knockdown and miR-505 overexpression promoted ADM-induced DNA damage in HCC cells, which was abated by HMGB1 overexpression. On a molecular mechanism level, HMGB1 silencing and miR-505 overexpression inactivated the Akt pathway in HCC cells, while exogenous HMGB1 resisted miR-505-induced Akt pathway inactivation. In conclusion, miR-505 overexpression enhanced ADM-induced cytotoxicity in HCC cells, at least partly by targeting HMGB1 and inactivating the Akt pathway.

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