High High Mobility Group Box 1 Research Articles

HMGB1 overexpression correlates with poor prognosis in early-stage squamous cervical cancer.

High mobility group box 1 (HMGB1) is associated with tumor progression and a poor prognosis; microtubule-associated protein 1 light chain 3 (LC3) plays a critical role in autophagy. However, the roles of HMGB1 and LC3 in squamous cervical cancer (SCC) remain unclear. An array of 166 early-stage SCC, 62 cervical intraepithelial neoplasia (CIN), and 50 normal cervical tissue samples was assessed. HMGB1 and LC3 protein levels were examined by immunohistochemistry, and the associations of HMGB1 and LC3 levels with clinicopathological characteristics evaluated, to assess their prognosis significance. High nuclear HMGB1 levels were detected in 72.9% SCC cases; 16% cases showed cytoplasmic expression of HMGB1 in cancer cells with low nuclear expression. Interestingly, HMGB1 levels in SCC samples were significantly higher than CIN and control specimens, while lower LC3 expression was found in SCC samples (P < 0.001). Nuclear HMGB1 expression was weakly negatively correlated to LC3 amounts (r = -0.254, P = 0.001). High nuclear HMGB1 levels were associated with vascular metastasis (P < 0.05). In addition, cytoplasmic HMGB1 expression was associated with lymph node metastasis (P < 0.05). Furthermore, high nuclear HMGB1 levels and cytoplasmic HMGB1 expression predicted poor overall survival (OS) and disease-free survival (DFS). Meanwhile, high LC3 expression was associated with favorable prognosis. Multivariate analysis showed that both nuclear and cytoplasmic HMGB1 expressions were independent prognostic factors for overall- and disease-free survival, along with nodule metastasis. HMGB1 overexpression plays a significant role in SCC progression. Both nuclear and cytoplasmic HMGB1 are independent factors for poor prognosis in early-stage SCC.

HMGB1 Level in Cerebrospinal Fluid as a Marker of Treatment Outcome in Patients with Acute Hydrocephalus Following Aneurysmal Subarachnoid Hemorrhage

Attempts to clarify mechanisms of early brain injury in subarachnoid hemorrhage (SAH) revealed a high-mobility group box 1 (HMGB1) protein involvement in sterile inflammation initiated by aneurysm rupture. This study aims at assessing the prognostic value of HMGB1 in comparison with traditional biomarkers. Ten patients with Fisher grade 4 SAH and acute hydrocephalus underwent endovascular coiling and ventriculostomy. HMGB1 level was measured in cerebrospinal fluid (CSF) samples collected on first, fifth, and 10th day. HMGB1 level in first sample was correlated with treatment outcome assessed in Glasgow outcome scale (GOS) at 3 months. Obtained results were compared with plasma inflammatory markers, clinical grading scales, and imaging grading scales. HMGB1 level in consecutive samples was analyzed in search of concentration trends correlating with patients' outcome. HMGB1 level in CSF of SAH patients, in contrast to control group, is significantly elevated (P < .001). Good (GOS > 3) and poor (GOS ≤ 3) outcome patients differ significantly in HMGB1 level on admission (P < .01). The strongest correlation to patients' outcome was found for Hunt and Hess scale (R = -.887, P < .01), HMGB1 level (R = -.859, P < .01), and World Federation of Neurological Surgeons scale (R = -.832, P < .01). Constant and high HMGB1 level of 10 ng/mL or more in consecutive CSF samples identifies nonsurvivors. HMGB1 protein is elevated in SAH patients. Changes in the concentration of HMGB1 in consecutive samples of the CSF correlate with outcome. Our results encourage further proteomic investigation.

Increased HMGB1 and cleaved caspase-3 stimulate the proliferation of tumor cells and are correlated with the poor prognosis in colorectal cancer.

BackgroundDying tumor cells after irradiation could promote the proliferation of living tumor cells might cause tumor relapse and treatment failure. Our previous study showed that activated caspase-3 after irradiation probably participates in tumor repopulation. In this study, we investigated whether high mobility group box 1(HMGB1) is also involved in tumor repopulation.MethodsColorectal tumor cells were irradiated. The cleaved caspase-3 (CC3) in irradiated tumor cells and HMGB1 in the supernatant of irradiated tumor cells were detected by Western blot. A large number of irradiated colorectal tumor cells (feeder cells) were then co-cultured with a small number of luciferase-labeled living colorectal tumor cells (reporter cells) and proliferation of reporter cells was measured by bioluminescence imaging. The CC3 and HMGB1 protein expression in colorectal tumor and peritumoral tissues were detected by immunohistochemistry and their correlation with prognosis were analyzed.ResultsThe irradiated colorectal tumor cells underwent apoptosis and necrosis and produced CC3 in tumor cells and HMGB1 in the supernatant of cultured cells. The increased expression of secretory HMGB1 correlated with CC3 level and proliferating cell nuclear antigen (PCNA) after irradiation in vitro. The irradiated dying cells remarkably stimulated living tumor cell proliferation. Interestedly, immunohistochemistry staining showed that positive HMGB1, CC3, and Ki67 expression were significantly higher in colorectal tumor tissues than in peritumoral tissues (p <0.01). The Kaplan-Meier survival analysis revealed that high HMGB1, CC3, and Ki67 levels were significantly associated with poor prognosis (p <0.05, p <0.01). Multivariate analysis using Cox proportional hazards model showed that TNM staging and HMGB1 were independent prognostic factors in patients with colorectal cancer (CRC) (p <0.01, p <0.001).ConclusionBoth apoptotic and necrotic cells could stimulate proliferation of living tumor cells, and the increased expression of CC3 and HMGB1 in tumor cells could be new markers for poor prognosis in colorectal cancer patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0166-1) contains supplementary material, which is available to authorized users.

High mobility group box-1 and its clinical value in breast cancer.

BackgroundHigh mobility group box-1 (HMGB1) is a factor regulating malignant tumorigenesis, proliferation, and metastasis, and is associated with poor clinical pathology in various human cancers. We investigated the differential concentrations of HMGB1 in tissues and sera, and their clinical value for diagnosis in patients with breast cancer, benign breast disease, and healthy individuals.MethodsHMGB1 levels in tumor tissues, adjacent normal tissues, and benign breast disease tissues was detected via immunohistochemistry. Serum HMGB1 was measured using an enzyme-linked immunosorbent assay in 56 patients with breast cancer, 25 patients with benign breast disease, and 30 healthy control subjects. The clinicopathological features of the patients were compared. Tissues were evaluated histopathologically by pathologists.ResultsHMGB1 levels in the tissues and sera of patients with breast cancer were significantly higher than those in patients with benign breast disease or normal individuals. The 56 cancer patients were classified as having high tissue HMGB1 levels (n=41) or low tissue HMGB1 levels (n=15), but the corresponsive serum HMGB1 in these two groups was not significantly different. HMGB1 levels in breast cancer tissues significantly correlated with differentiation grade, lymphatic metastasis, and tumor-node-metastasis stage, but not patient age, tumor size, or HER-2/neu expression; no association between serum HMGB1 levels and these clinicopathological parameters was found. The sensitivity and specificity of tissue HMGB1 levels for the diagnosis of breast cancer were 73.21% and 84.00%, respectively, while positive and negative predictive values were 91.11% and 58.33%.ConclusionHMGB1 might be involved in the development and progression of breast cancer and could be a supportive diagnostic marker for breast cancer. Serum HMGB1 could be a useful serological biomarker for diagnosis and screening of breast cancer.

Immunohistochemical detection of high-mobility group box 1 correlates with resistance of preoperative chemoradiotherapy for lower rectal cancer: a retrospective study.

BackgroundHigh-mobility group box 1 (HMGB1) is a nucleoprotein that is related to inflammation. It has been implicated in a variety of biologically important processes, including transcription, DNA repair, differentiation, development, and extracellular signaling. Recently, its important role in the process of tumor invasion, metastasis, and resistance to anti-cancer therapies has been demonstrated. In this study, we aimed to investigate the correlation of HMGB1 expression and resistance of rectal cancer patients to chemoradiotherapy (CRT) prior to curative operation.MethodsWe retrospectively reviewed the data of 75 lower rectal cancer patients without complete pathological response who had received preoperative CRT and had undergone curative resection at the University of Tokyo Hospital between May 2003 and June 2010. HMGB1 expression in surgically resected specimens was evaluated using immunohistochemical detection and specimens were classified into high or low HMGB1 expression groups. Clinicopathologic features, degree of tumor reduction, regression of tumor grade, and patient survival were compared between the groups using non-paired Student’s t-tests and Kaplan-Meier analysis.ResultsA total of 52 (69.3%) patients had high HMGB1 expression, and 23 (30.7%) had low expression. HMGB1 expression was significantly correlated with histologic type (P = 0.02), lymphatic invasion (P = 0.02), and venous invasion (P = 0.05). Compared to patients with low HMGB1 expression, those with high expression had a poorer response to CRT, in terms of tumor reduction ratio (42.2 versus 28.9%, respectively; P <0.01) and post-CRT histological tumor regression grade (56.5 versus 30.8% grade 2; respectively; P = 0.03). However, no significant correlation was found between HMGB1 expression and recurrence-free and overall survival rates.ConclusionsHMGB1 expression may be one of the key factors regulating the response of rectal cancer to preoperative CRT in terms of tumor invasiveness and resistance to therapy.

Acute pulmonary exacerbation and lung function decline in patients with cystic fibrosis: high-mobility group box 1 (HMGB1) between inflammation and infection

Airway inflammation plays a central role in cystic fibrosis (CF) lung disease, and biomarkers of inflammation, such as high-mobility group box 1 (HMGB1) could be used to monitor disease activity. The main aim of this study was to confirm the role of HMGB1 in CF patients, correlating its serum and sputum levels with pulmonary function and inflammation. Serum and sputum HMGB1 were evaluated in a cohort of 31 CF patients and 30 non-smoking healthy subjects (HS group). Acute pulmonary exacerbation events and lung function decline have been also evaluated during a 3-year follow-up period. Serum HMGB1 levels were significantly higher than those measured in HS, such as sputum HMGB1. Kaplan-Meier survival curves revealed that patients with high HMGB1 values experienced a significantly faster evolution to decline of lung function. A multiple Cox regression analysis assessed that an increase of serum HMGB1 was associated with 5% increased risk of pulmonary disease progression, whereas elevated sputum HMGB1 was related to a 10% increased risk of lung function decline. In CF patients, HMGB1 closely reflects the entity of pulmonary impairment and represents a strong and independent risk marker for progression of lung function decline.

Clinical value of serum HMGB1 in diagnosis and prognosis of laryngeal squamous cell carcinoma.

Laryngeal squamous cell carcinoma (LSCC) is one of the most common malignancies in the head and neck region. Recently, aberrantly expressed high-mobility group box 1 (HMGB1) has received a great deal of attention as a potential biomarker for cancer diagnosis and prognosis. Therefore, the aim of this study was to estimate HMGB1 levels in serum in LSCC patients and healthy controls and evaluated the potential of serum HMGB1 as a noninvasive biomarker for diagnosis and prognosis in LSCC. Serum HMGB1 levels were analyzed in 71 LSCC patients and 50 healthy controls. The serum HMGB1 level was significantly higher in LSCC patients compared with the healthy controls (4.81 ± 2.33 vs. 3.21 ± 1.08 ng/mL, P < 0.001). High serum HMGB1 was significantly associated with T classification (P = 0.005), N classification (P = 0.002), and clinical stage (P = 0.001). The area under ROC curve was 0.716, and the sensitivity and specificity were 42.3 and 92.0%, respectively. The Kaplan-Meier plots showed that patients with high serum HMGB1 had a poorer overall survival than those with low serum HMGB1 (P = 0.036). Serum HMGB1 levels are significantly associated with the progression of LSCC. In this population, HMGB1 has a poor sensitivity, but a high specificity for the diagnosis of LSCC. Serum HMGB1 level has potential as a biomarker for the prognosis in LSCC patients.

The association of HMGB1 expression with clinicopathological significance and prognosis in hepatocellular carcinoma: a meta-analysis and literature review.

BackgroundHepatocellular carcinoma (HCC) is the fifth most common cancer, and it is the second most common cancer-related mortality globally. The prognostic value of high mobility group box 1 (HMGB1) remains controversial. The purpose of this study is to conduct a meta-analysis and literature review to evaluate the association of HMGB1 expression with the prognosis of patients with HCC.MethodsA detailed literature search was made in Medline, Google Scholar and others for related research publications. The data were extracted and assessed by two reviewers independently. Analysis of pooled data were performed, Hazard Ratio (HR) and mean difference with corresponding confidence intervals (CIs) were calculated and summarized respectively.Results10 relevant articles were included for this meta-analysis study. HMGB1 mRNA levels in HCC were significantly higher than those in normal (p<0.00001) and para-tumor tissues (p = 0.002) respectively. The protein levels of HMGB1 in HCC were significantly higher than those in para-tumor tissues (p = 0.005). Two studies reported the serum HMGB1 levels in patients with HCC of TNM stages, and indicating significantly different between stage I and II, stage II and III, as well as stage III and IV (two studies showed p<0.01 and p<0.001 respectively). The overall survival (OS) was significantly shorter in HCC patients with high HMGB1 expression compared those with low HMGB1 expression and the pooled HR was 1.31 with 95% CI 1.20–1.44, Z = 5.82, p<0.0001. Two additional studies showed that there were higher serum HMGB1 levels in patients with chronic hepatitis than those in healthy people (p<0.05).ConclusionsThe results of this meta-analysis suggest that HMGB1 mRNA and protein tissue levels in the patients with HCC are significantly higher than those in para-tumor and normal liver tissues respectively. Tissue HMGB1 overexpression is a potential biomarker for HCC diagnosis, and it is significantly associated with the prognosis of patients with HCC.

Clinical significance of hmgb1 expression in human gastric cancer.

High mobility group box 1 (HMGB1) has been proved to be implicated in a variety of cell physiological and pathological behaviors including immune response, inflammation and cancer. Accumulating evidence suggests that HMGB1 plays a critical role in the development and progression of multiple malignancies. However, the clinical significance and prognosis of HMGB1 expression in some cancers remain controversial. The present study aimed to investigate whether overexpression of HMGB1 is an independent prognostic factor in patients with gastric cancer. The correlation of HMGB1 expression with clinicopathologic characteristics and prognosis was assessed by immunohistochemical assay through tissue microarray procedure in 50 primary gastric cancer cases. Our results indicated that the positive expression of HMGB1 was significantly increased in the nucleus of gastric cancer tissues compared with the adjacent non-cancerous tissues (ANCT) (64.0&#x0025; vs 44.0&#x0025;, P=0.025), but was not linked to the clinicopathologic features, including the TNM stage (P=0.533) and metastatic lymph node (P=0.771), in patients with gastric cancer. Kapalan-Meier and log-rank analysis demonstrated that overexpression of HMGB1 did not exert significant impact on the overall survival of patients with gastric cancer (P=0.805). Furthermore, Cox regression analysis showed that high HMGB1 protein expression did not represent an independent risk factor for patients with gastric cancer (P=0.677). Taken together, our findings suggest that high expression of HMGB1 is not correlated with the clinicopathologic characteristics of gastric cancer, and cannot serve as an independent prognostic biomarker for patients with gastric cancer.

High HMGB1 level is associated with poor outcome of septicemic melioidosis

A high level of HMGB1 (high-mobility group box 1) - a late onset inflammatory mediator - is a marker of lethal sepsis in several infectious diseases. The level of HMGB1 in the plasma of Burkholderia pseudomallei-infected patients was investigated together with the severity of the disease. The neutralization of HMGB1 to improve survival was also tested in a mouse model. HMGB1 levels in the plasma of 77 septic patients, 40 with B. pseudomallei infection and 37 with other bacterial infections, were determined by ELISA. Neutralizing antibody against purified recombinant HMGB1 was prepared in rabbits (rab-a-HMGB1) and its potential as an adjunct therapy was evaluated in B. pseudomallei-infected Balb/c mice treated with suboptimal doses of ceftazidime. The plasma from B. pseudomallei-infected patients showed significantly higher HMGB1 levels than the plasma from other septic patients (median 11.1 ng/ml vs. 7.1 ng/ml). The HMGB1 level was significantly higher in patients with melioidosis who died than in those who survived (median 14.8 ng/ml vs. 9.2 ng/ml). Moreover, the HMGB1 level was significantly correlated with the clinical severity score (SOFA score). In the mouse study, although the rab-a-HMGB1 by itself could not improve the survival outcome of B. pseudomallei-infected mice, it could nevertheless enhance the effectiveness of suboptimal doses of ceftazidime in the treatment of these animals. The level of HMGB1 in septic melioidosis patients can be used as a marker of late severe sepsis. Neutralizing antibody to HMGB1 may be used as an adjunct therapy to improve the outcome of melioidosis.

Abundant expression of HMGB1 in human T-cell lymphotropic virus type I-infected T-cell lines and high plasma levels of HMGB1 in patients with adult T-cell leukemia.

High mobility group box 1 (HMGB1) functions as a chromatin-associated nuclear protein and an extracellular signaling molecule. The concentration of HMGB1 protein and the expression of HMGB1 mRNA were analyzed by ELISA and polymerase chain reaction (PCR), respectively. The present study reports high plasma HMGB1 levels in patients with adult T-cell leukemia [ATL; which is caused by infection with human T-cell lymphotropic virus type I (HTLV-I)] compared with normal controls. In addition, HMGB1 was highly expressed in HTLV-I-infected T-cell lines compared with uninfected T-cell lines. The HTLV-I oncoprotein, Tax, induced extracellular release of HMGB1 in T cells. The results suggest that HMGB1 is a potential biomarker and a therapeutic target for ATL.

Circulatinng high-mobility group box 1 levels are associated with presence of thin-cap fibroatheroma in coronary culprit lesion determined by optical coherence tomography

Purpose: Biomarkers predicting the presence of Thin-Cap Fibroatheroma (TCFA), the primary type of vulnerable plaque, have not been established. Recently, High-Mobility Group Box 1 (HMGB1), a damage-associated molecular pattern molecule derived from necrotic cells and activated macrophages, has been shown to contribute to the progression of atherosclerosis. The aim of this study was to assess whether circulating serum HMGB1 can predict the presence of TCFA as determined by Optical Coherence Tomography (OCT). Methods: Forty-eight patients (69±9 years, 39 males) with 40 stable and 8 unstable angina pectoris were enrolled. Culprit lesion morphology was assessed by OCT and Intravascular Ultrasound (IVUS) before Percutaneous Coronary Intervention (PCI). By OCT, the TCFA was defined as a plaque with lipid contents in >90° and with thinnest part of the fibrous cap measuring <65μm. Cross-sectional vessel, lumen, plaque area, and remodeling index were measured using IVUS. Circulating serum levels of HMGB1 and high sensitive C-Reactive Protein (hsCRP) were measured before PCI and compared with plaque characteristics. Serum HMGB1 levels were categorized into low (lowest tertile), intermediate (middle tertile), and high (highest tertile) groups. Results: Nineteen patients with TCFA and 29 patients without TCFA were identified. Levels of HMGB1 were significantly higher in patients with TCFA than those without TCFA (9.64±5.52 vs. 5.95±3.68 ng/mL; p = 0.008). There were no significant differences in hsCRP levels between patients with and without TCFA. Levels of HMGB1, but not hsCRP, correlated inversely with fibrous cap thickness (r = -0.30, p = 0.04) and positively with remodeling index (r = 0.45, p = 0.001). The frequency of TCFA was 13, 50, and 56% in low, intermediate, and high HMGB1 group, respectively (p = 0.024). Multivariate logistic regression analysis showed that HMGB1 level was the independent factor associated with TCFA existence (odds ratio, 1.19; 95% confidence interval, 1.02 to 1.40; p = 0.032). The area under the receiver-operating characteristics curve for HMGB1 level for prediction of TCFA was 0.73 (p = 0.008). The optimal cut-off value of HMGB1 for predicting TCFA was 6.40 ng/mL (sensitivity 74%, specificity 62%). Conclusions: Higher serum HMGB1 level was associated with the presence of TCFA, thinner fibrous cap thickness, and greater remodeling index at coronary culprit lesions. These findings suggest that circulating HMGB1 may be a useful marker reflecting the plaque vulnerability.

Circulating nucleosomes and immunogenic cell death markers HMGB1, sRAGE and DNAse in patients with advanced pancreatic cancer undergoing chemotherapy

Serum biomarkers are urgently needed for patient stratification and efficient treatment monitoring in pancreatic cancer (PC). Within a prospective diagnostic observation study, blood samples were obtained from 78 patients with advanced PC before and weekly during the course of palliative chemotherapy. Circulating nucleosomes and immunogenic cell death markers, high-mobility group box 1 (HMGB1), soluble receptors of advanced glycation end products (sRAGE) and DNAse activity, were measured by enzyme-linked immunosorbent assay and correlated with results of radiological staging after 2 months of treatment, with time to progression (TTP) and overall survival (OS). Median TTP and OS of PC patients were 3.9 and 7.7 months, respectively. Pretherapeutic baseline biomarker levels did not correlate with objective response; however, nucleosome levels on day (d) 28 were higher (p = 0.048) and sRAGE levels at time of staging (d56) were lower in progressive patients (p = 0.046). Concerning estimation of prognosis, high nucleosome levels (d7, d14, d21 and d56), low sRAGE levels (d56) and DNAse activity courses (d0-d7) correlated with TTP, whereas high nucleosomes (d7, d14 and d56), high HMGB1 (d21 and d56) and DNAse (d0-d7) were associated with OS. After adjustment to Karnofsky performance score, nucleosomes and HMGB1 (both d56) and DNAse (d0-d7) remained independent prognostic factors. Thus, courses of circulating nucleosomes and immunogenic cell death markers HMGB1 and sRAGE show prognostic relevance in PC patients undergoing chemotherapy.

Urinary HMGB1 levels are associated with CD4+ T-cells in urine in patients with ANCA-associated vasculitis and active nephritis

Background High mobility group box 1 (HMGB1) is a nuclear non-histone protein that acts as an alarmin when released in the extra-cellular medium by necrotic or activated cells. High serum HMGB1 levels have been found in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and active nephritis as well as in patients with granulomatosis with polyangiitis (GPA) and predominant granulomatous manifestations. High serum and urinary HMGB1 levels have also been found in patients with systemic lupus erythematosus (SLE) and active nephritis. Objectives To evaluate serum and urinary levels of HMGB1, CD4+ T-cells and effector memory T-cells (CD4+ T EM )in peripheral blood (PB) and urine from patients with AAV and active nephritis. Methods 24 AAV patients with active nephritis and 10 healthy controls (HC) were evaluated in a cross-sectional study. Clinical diagnosis of GPA or microscopic polyangiitis (MPA) was made according to the European Medicines Agency algorithm whereas patients with isolated renal involvement, ANCA positivity and/or biopsy-proven pauci immune necrotizing glomerulonephritis were classified as renal limited vasculitis (RLV). Serum and urinary levels of HMGB1 were measured by Western blot while CD4+ T-cells and CD4+ T EM cells (CD4+CD45+RO+CCR7-) in urine were analyzed by flow cytometry. Disease activity was evaluated according to the Birmingham Vasculitis Activity Score (BVAS). Results Median urinary intensity of HMGB1 was significantly higher in AAV patients when compared to HC [5.15 (IQR 3.52-9.25) vs. 2.58 (1.88-4.24); P =0.006] whereas no difference was found among different AAV subsets regarding median urinary intensity of HMGB1 [GPA: 4.1 (2.6-16.4) vs. MPA: 5.1 (4.4-5.6) vs. RLV 5.7 (1.4-13.6); P =0.951] and HMGB1/creatinine ratio [GPA: 0.93 (0.29-3.91) vs. MPA: 1.29 (0.90-1.89) vs. RLV 0.54 (0.14-1.28); P =0.186]. In urine of AAV patients, median CD4+ T-cells was 125.00 (58.93-429.28) cells/ml and CD4+ T EM cells was 93.24 (43.21-343.37) cells/ml. Urine levels of HMGB1 were positively correlated with CD4+ T-cell counts in urine (rho: 0.454; P =0.014) and with CD4+ T EM cells in urine (rho: 0.378; P =0.049) while a tendency for a negative correlation between urinary HMGB1 and CD4+ T-cells in PB (rho: -0.307; P =0.083). No correlation could be found between urine levels of HMGB1 and 24 hour proteinuria (rho: 0.065; P =0.390), creatinine clearance (rho: -0.049; P =0.832), BVAS (rho: -0.203; P =0.171) and serum HMGB1 (rho: -0.046; P =0.419). Conclusions Urine HMGB1 levels are increased in AAV patients with active nephritis when compared to HC and are associated with CD4+ T-cells in urine suggesting that urine HMGB1 is a biomarker for renal activity in AAV.

Serum high mobility group box‐1 is a powerful diagnostic and prognostic biomarker for pancreatic ductal adenocarcinoma

Extracellular high mobility group box-1 (HMGB1) contributes to tumor growth and invasiveness. We evaluated the diagnostic and prognostic ability of serum HMGB1 for pancreatic ductal adenocarcinoma (PDAC). Serum HMGB1 measured by enzyme-linked immunosorbent assay (ELISA) were compared among normal, chronic pancreatitis, PDAC group in both training (n = 25, each group) and independent validation set (n = 45, each group). To determine the usability of serum HMGB1 as a diagnostic predictor of PDAC, receiver operating characteristic (ROC) curves with sensitivity/specificity and logistic regression were evaluated. To assess the HMGB1-associated prognosis of PDAC, Kaplan-Meier survival and Cox proportional-hazards regression were applied. Serum HMGB1 was correlated with presence and advanced-stage of PDAC. Logistic regression exhibited serum HMGB1 was a remarkable biomarker to predict PDAC as a single or multiple-markers; sensitivity/specificity of serum HMGB1 were superior to carbohydrate antigen (CA) 19-9 or carcinoembryonic antigen (CEA) in both training and independent datasets. Kaplan-Meier survival analysis showed PDAC patients with high serum HMGB1 levels (>30 ng/mL; median survival, 192 days) had a worse prognosis than patients with low HMGB1 levels (≤30 ng/mL; 514 days) by log-rank (P = 0.017). Cox proportional-hazards model showed the relative hazard ratios in high-serum HMGB1 group was 3.077 compared with the low-serum HMGB1 group. In conclusion, serum HMGB1 is a desirable diagnostic and prognostic biomarker for PDAC compared with pre-existing PDAC biomarkers, CA19-9 and CEA.

High-Mobility Group Box 1–Mediated Matrix Metalloproteinase-9 Expression in Non–Small Cell Lung Cancer Contributes to Tumor Cell Invasiveness

High-mobility group box 1 (HMGB1) is a versatile protein with intranuclear and extracellular functions. It is involved in invasion and metastasis in various human malignancies. However, the role of HMGB1 in non-small cell lung cancer (NSCLC) is unclear. We hypothesized that HMGB1 expression is a determinant of cellular invasiveness and metastasis in lung cancer. We examined HMGB1 expression in 48 NSCLC specimens by quantitative real-time PCR. High HMGB1 expression was significantly associated with clinically advanced stages (stage III-IV) (P < 0.05) and was correlated to expression of matrix metalloproteinase-9 (MMP-9) (P < 0.05). Patients with high levels of HMGB1 expression had poorer clinical prognosis. The expression level of MMP-9 and metastatic ability in vitro were significantly higher in an HMGB1-overexpressing human NSCLC cell lines (A549 and H23). The treatment with HMGB1 small interfering RNA reduced MMP-9 expression and the cellular metastatic ability in NSCLC cells. We also demonstrated that phosphoinositide 3-kinase/Akt and NF-κB-related pathways contributed to the HMGB1-induced MMP-9 expression and cellular metastatic ability.

Overexpression of high-mobility group box 1 correlates with tumor progression and poor prognosis in human colorectal carcinoma

High-mobility group box 1 (HMGB1) has been implicated in a variety of biologically important processes, including transcription, DNA repair, V(D)J recombination, differentiation, development, and extracellular signaling. The increased expression of HMGB1 has been described in colorectal cancer (CRC). However, there is no report about the correlation of HMGB1 with clinicopathologic features, including the survival of patients with CRC. In present study, we investigated HMGB1 expression and its prognostic significance in CRC by performing immunohistochemical analysis, using a total of 192 paraffin-embedded archival CRC samples. Moreover, disruption of endogenous HMGB1 protein through a siRNA knockdown technique was performed to investigate the possible role of HMGB1 in the process of tumor invasion and metastasis. Overexpression of HMGB1 was shown in 55.7% cases. Statistical analysis showed that HMGB1 expression was positively correlated with tumor invasion (P = 0.048), lymph node metastasis (P = 0.011), distant metastasis (P = 0.031), and Duke's stage (P = 0.029) of CRC patients. Patients with higher HMGB1 expression had shorter overall survival time, whereas patients with lower level of HMGB1 had better survival. Multivariate analysis suggested that HMGB1 expression might be an independent prognostic indicator for the survival of patients with CRC. Disruption of endogenous HMGB1 protein through a siRNA knockdown technique was shown to suppress substantially the invasion ability of SW620 cells. Our results suggest that HMGB1 protein is a valuable marker for progression of CRC patients. High HMGB1 expression is associated with poor overall survival in patients with CRC.

The expression of HMGB1 protein and its receptor RAGE in human malignant tumors

High Mobility Group Box 1 (HMGB1) is a nuclear non-histone protein discovered to be released in the extracellular medium as a response to various stimuli and implicated in cancerogenesis. High HMGB1 levels are reported in a variety of tumor types, but there are few data relating HMGB1 to the histological grade or to a particular cell type and cellular localization. We studied the expression of HMGB1 protein in malignant human tumors of different differentiation level and in tumor metastasis. In all tumor tissues, the protein level is elevated. In moderately differentiated carcinomas, the localization of the protein is perinuclear, while in the low differentiated; there is a tendency for non-specific nuclear localization. HMGB1 protein and its receptor RAGE are identified as a ligand-receptor pair that plays an important role in regulating the invasiveness of tumor cells. RAGE is not produced in all of the tested tumor specimens. We found high level of expression in hepatocellular, colorectal, and breast cribriform carcinomas, but not in malignant testicular specimens. Probably, the RAGE synthesis is related to distinctive tumor types. In metastatic cells, RAGE exhibits higher level of expression losing its specific granular cytosolic pattern characteristic for the primary tumors.

Activation of gene expression in human neutrophils by high mobility group box 1 protein.

High mobility group box 1 (HMGB1) protein, a DNA binding protein that stabilizes nucleosomes and facilitates transcription, was recently identified as a late mediator of endotoxin lethality. High serum HMGB1 levels in patients with sepsis are associated with increased mortality, and administration of HMGB1 produces acute inflammation in animal models of lung injury and endotoxemia. Neutrophils occupy a critical role in mediating the development of endotoxemia-associated acute lung injury, but previously it was not known whether HMGB1 could influence neutrophil activation. In the present experiments, we demonstrate that HMGB1 increases the nuclear translocation of NF-kappaB and enhances the expression of proinflammatory cytokines in human neutrophils. These proinflammatory effects of HMGB1 in neutrophils appear to involve the p38 MAPK, phosphatidylinositol 3-kinase/Akt, and ERK1/2 pathways. The mechanisms of HMGB1-induced neutrophil activation are distinct from endotoxin-induced signals, because HMGB1 leads to a different profile of gene expression, pattern of cytokine expression, and kinetics of p38 activation compared with LPS. These findings indicate that HMGB1 is an effective stimulus of neutrophil activation that can contribute to development of a proinflammatory phenotype in diseases characterized by excessively high levels of HMGB1.