Role of high-mobility group box 1 in cancer. / 高迁移率族蛋白B1在肿瘤中的作用.

High-mobility group box 1 (HMGB1) is a non-histone nuclear protein in most eukaryocytes. Inside the nucleus, HMGB1 plays an important role in several DNA events such as DNA repair, transcription, telomere maintenance, and genome stability. While outside the nucleus, it fulfils more complicated functions, including promoting cell proliferation, inflammation, angiogenesis, immune tolerance and immune escape, which may play a pro-tumoral role.Meanwhile, HMGB1 acts as an anti-tumoral protein by regulating immune cell recruitment and inducing immunogenic cell death (ICD) during the carcinogenesis process. Therefore, abnormal expression of HMGB1 is associated with oncogenesis, development, and metastasis of cancer, which may play a dual role of pro-tumor and anti-tumor.

Association between Thyroid Disease and Severe Coronavirus Disease 2019 (COVID-19) Infection: A Meta-Analysis.

BACKGROUND: COVID-19 has resulted in an emerging respiratory infection with a pandemical diffusion since December 2019. We aimed to elucidate whether the presence of thyroid disease might increase the risk of severe COVID-19 infection. METHODS: Studies reporting seriously ill in COVID-19 patients with and without thyroid disease combined were searched and 11 relevant studies were subjected to our analysis, and pooled odds ratios (ORs) together with 95% confidence intervals (CIs) were calculated by using STATA and Review Manager Software. RESULTS: In total, 2,995 COVID-19 patients were included in this study. The pooled ORs were calculated using a fixed-effects model according to the heterogeneity. The pooled results revealed that thyroid disease was associated with severe COVID-19 infection in patients (OR = 2.14, 95 % CI: 1.23-3.72, P = 0.007). In the subgroup analysis by type of thyroid disease, hypothyroidism was positively associated with risks of severe COVID-19 infection (OR = 4.78, 95 % CI: 1.59-14.36, P = 0.005), however, no obvious difference was found in the risk regarding the severe COVID-19 infection amongst hyperthyroidism or unclassified thyroid disease. In addition, subgroup analysis stratified by ethnic groups demonstrated that thyroid disease was linked to the risks of severe COVID-19 infection in Asian patients (OR = 2.41, 95 % CI: 1.30-4.48, P = 0.005) rather than non-Asian (OR = 1.31, 95 % CI: 0.35-4.87, P = 0.684). CONCLUSION: This study indicates a correlation between thyroid disease and severe COVID-19 infection.

Phosphorylation of islet-1 serine 269 by CDK1 increases its transcriptional activity and promotes cell proliferation in gastric cancer.

BACKGROUND: Despite recent advances in diagnostic and therapeutic approaches for gastric cancer (GC), the survival of patients with advanced GC remains very low. Islet-1 (ISL1) is a LIM-homeodomain transcription factor, which is upregulated and promotes cell proliferation in GC. The exact mechanism by which ISL1 influences GC development is unclear. METHODS: Co-immunoprecipitation (co-IP) and glutathione S-transferase (GST)-pulldown assays were employed to evaluate the interaction of ISL1 with CDK1. Western blot and immunohistochemistry analyses were performed to evaluate the ability of CDK1 to phosphorylate ISL1 at Ser 269 in GC cell and tissue specimens. Chromatin immunoprecipitation (ChIP), ChIP re-IP, luciferase reporter, and CCK-8 assays were combined with flow cytometry cell cycle analysis to detect the transactivation potency of ISL1-S269-p and its ability to promote cell proliferation. The self-stability and interaction with CDK1 of ISL1-S269-p were also determined. RESULTS: ISL1 is phosphorylated by CDK1 at serine 269 (S269) in vivo. Phosphorylation of ISL1 by CDK1 on serine 269 strengthened its binding on the cyclin B1 and cyclin B2 promoters and increased its transcriptional activity in GC. Furthermore, CDK1-dependent phosphorylation of ISL1 correlated positively with ISL1 protein self-stability in NIH3T3 cells. CONCLUSIONS: ISL1-S269-p increased ISL1 transcriptional activity and self-stability while binding to the cyclinB1 and cyclinB2 promoters promotes cell proliferation. ISL1-S269-p is therefore crucial for tumorigenesis and potentially a direct therapeutic target for GC.

Association of Polymorphism rs1045411 in the HMGB1 Gene with Cancer Risk: Evidence from a Meta-analysis.

The high-mobility group box protein 1 (HMGB1) rs1045411 polymorphism has been demonstrated to be associated with cancer risk in some studies. However, the results regarding this topic are inconsistent. A meta-analysis was applied to elucidate the association between the HMGB1 rs1045411 polymorphism and cancer risk. Ten relevant studies were subjected to our analysis, and pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. In total, of 3,918 cases and 5,296 controls were included in this study. The pooled ORs were calculated using a random-effects or fixed-effects model according to the heterogeneity. The pooled results revealed that TT genotype was significantly related to increased cancer risk in the comparisons of TT vs. CC+TC (OR=1.35; 95% CI: 1.09-1.67; p=0.005). Though no statistical significance was achieved between HMGB1 rs1045411 polymorphism and cancer risk in other four genetic models (T vs. C: OR=1.08, 95% CI 0.90-1.30; TC vs. CC: OR=1.01, 95% CI 0.82-1.24; CC vs. TC+TT: OR=0.95, 95% CI 0.77-1.18; TT vs. CC: OR=1.42; 95% CI 0.98-2.05), a trend of increased risk could be drawn. In the subgroup analysis by type of malignancy and ethnicity, no obvious difference was found in the tumour risk regarding the HMGB1 rs1045411 polymorphism amongst the cancer types except for breast cancer (OR=1.94; 95% CI: 1.05-3.59; p=0.03) and hepatocellular carcinoma (OR=1.82; 95% CI: 1.15-2.88; p=0.01), while rs1045411 polymorphism was positively associated with risks of cancer amongst Hans (OR=1.37; 95% CI: 1.11-1.69; p=0.004) rather than Caucasians (OR=0.89; 95% CI: 0.26-3.02; p=0.01). These results suggest that the HMGB1 rs1045411 polymorphism might be associated with increased cancer risk.

Evidence from an updated meta-analysis of the prognostic impacts of postoperative radiotherapy and chemotherapy in patients with anaplastic thyroid carcinoma.

BACKGROUND: Radiotherapy and chemotherapy are the two important postoperative management approaches for anaplastic thyroid carcinoma (ATC), and several studies have suggested that postoperative radiotherapy and chemotherapy can prolong the survival of patients with ATC. However, the results remain inconsistent. OBJECTIVE: A meta-analysis was performed to address whether postoperative radiotherapy and chemotherapy could prolong the survival of patients with ATC. METHODS: Relevant studies were included, and pooled hazard ratios (HRs) together with 95% confidence intervals (CIs) were calculated. RESULTS: Ten relevant studies on factors that affect the prognosis for ATC were included in this meta-analysis, evaluating a total of 1,163 patients. The pooled HR for overall survival (OS) was calculated using a random-effects model. The pooled results demonstrated that for all patients with resectable ATC, the combination of surgery and radiotherapy significantly reduced the risk of death compared with surgery alone (HR =0.51, 95% CI: 0.36-0.73, Z=3.66, P=0.0002). To investigate the prognostic impacts of chemotherapy in patients with ATC, we also calculated the pooled HR of chemotherapy for OS using a random-effects model; however, the pooled results suggested that chemotherapy did not prolong the survival of ATC patients compared with controls (HR =0.63, 95% CI: 0.33-1.21, Z=1.39, P=0.17). CONCLUSION: This study provided evidence that currently, for patients with ATC, postoperative radiotherapy may prolong survival; in contrast, chemotherapy did not improve long-term survival.

Association between an elevated level of HMGB1 and non-small-cell lung cancer: a meta-analysis and literature review.

BACKGROUND: HMGB1 has been overexpressed in the tissues or serum of patients with non-small-cell lung cancer (NSCLC) in several studies. However, the results remain inconsistent. OBJECTIVE: The aim of this study was to perform a meta-analysis to investigate the relationship between elevated level of HMGB1 and NSCLC. METHODS: Associated studies were included, and the pooled risk difference and mean difference (MD) together with 95% confidence interval (CI) were calculated. RESULTS: A total of ten relevant studies on HMGB1 expression were included in this meta-analysis. The pooled results suggested that the expression of HMGB1 in NSCLC tissues was notably higher than those in corresponding nontumor normal tissues by using immu-nohistochemistry (risk difference =0.38, 95% CI: 0.28-0.48, Z=7.67, P<0.00001, I (2)=0%), Western blot (MD =0.27, 95% CI: 0.06-0.47, Z=2.57, P<0.01), or real-time polymerase chain reaction (MD =15.15, 95% CI: 14.8-15.5, Z=2.08, P=0.04). Serum HMGB1 levels were similarly significantly higher in patients with NSCLC than those in healthy controls. The pooled MDs of HMGB1 in patients with NSCLC compared with healthy controls were 17.54 with 95% CI: 10.99-24.09, Z=5.25, P<0.00001. Two of the included studies were fully reviewed without performing meta-analysis due to the different detection methods used. The protein level of HMGB1 in patients with NSCLC of tumor, nodes, and metastasis (TNM) stages III-IV was higher than that of TNM stages I-II (P<0.047 and P<0.001, respectively). CONCLUSION: The expression levels of HMGB1 in both tissues and serum of patients with NSCLC were statistically higher than those of normal lung samples, which indicated that elevated levels of HMGB1 can reveal changes that correlated with disease progression, or even the risk of NSCLC disease progression. The elevated level of HMGB1 could also be considered as a potential biomarker for the diagnosis of patients with NSCLC.

IL-17 promotes Type 1 T cell response through modulating dendritic cell function in acute allograft rejection.

IL-17 is a cytokine that produced by various type of cell. Previous studies have been shown that IL-17 plays a critical role in the pathogenesis of different diseases. However, few studies have addressed the source and mechanism of IL-17 in the development of allograft rejection response. In this study, we present that the IL-17 expression reaches the strongest response at the early stage of cardiac allograft rejection, and was elevated earlier than DC maturation. The IL-17 is predominantly produced by CD3(+) T cells, whereas CD11c, CD11b, and NK1.1 positive cells rarely expressed IL-17. It is worth noting that blockade of endogenous IL-17 activity suppressed DC maturation, decreased inflammatory cytokines and impaired Th1 immune response during acute allograft rejection. Furthermore, adoptive transfer with DCs from IL-17-treated mice had a significant longer allograft survival time and decreased number of IFN-γ produced by T cells. Consistently, in an in vitro experiment, recombinant IL-17 significantly up-regulate co-stimulatory molecules of bone marrow derived dendritic cells (BMDCs), and IL-17-treated BMDCs show that an increased capacity to enhance T cell function was also observed. In conclusion, our data provide clear evidence that the early elevated level of IL-17 contributes to allograft rejection through modulating dendritic cell function.

High-mobility group box 1 accelerates early acute allograft rejection via enhancing IL-17+ γδ T-cell response.

Th17 and γδ T cells are the dominant IL-17-producing cell. We previously reported that high-mobility group box 1 (HMGB1) is critical in inducing IL-17-producing alloreactive T cells during early stage of acute allograft rejection. However, the role of γδ T cells during this process and its implication in HMGB1-mediated allograft rejection are not fully understood. Here, we use a murine model of cardiac allograft transplantation to further study the role of HMGB1 and IL-17-producing γδ T cells in acute allograft rejection. It was found that the expression of HMGB1 was increased in allograft, while blockade of HMGB1 suppressed IL-17(+) γδ T-cell response and inhibited the gene transcription of IL-23 and IL-1ß. Furthermore, in vitro HMGB1 indirectly promoted the development of IL-17(+) γδ T cells by stimulating dendritic cells to produce IL-23 and IL-1ß, meanwhile depletion of γδ T cells in vivo prolonged allograft survival and reduced the level of IL-17 in serum. In conclusion, our findings inferred that increased HMGB1 expression could enhance IL-17(+) γδ T-cell response by promoting the secretion of IL-23 and IL-1ß, while IL-17(+) γδ T cells contribute to the early stage of acute allograft rejection.

Interleukin-33 ameliorates experimental colitis through promoting Th2/Foxp3⁺ regulatory T-cell responses in mice.

Crohn's disease (CD) is characterized by the activation of Th1 and Th17 cells and deficiency of regulatory T cells (Tregs), leading to intestine tissue injury and destruction. As a novel cytokine of the interleukin (IL)-1 family, the role and underlying mechanisms of IL-33 in CD remain poorly understood. Here, we assess the effects and mechanisms of IL-33 on the trinitrobenzene sulfonic acid (TNBS)-induced experimental colitis that mimics human CD. We found that IL-33 levels were increased in the TNBS-treated mice, whereas recombinant IL-33 (rIL-33) administration substantially ameliorated TNBS-mediated colonic tissue injury and clinical symptoms of colitis. The protective effect of rIL-33 was partly associated with the markedly increased induction of Th2-type cytokines. Importantly, rIL-33 treatment resulted in prominently upregulated Foxp3 expression in the TNBS-treated mice, and depletion of Tregs significantly abrogated the impact of IL-33 on reducing the development of colitis. Notably, the level of CD103⁺ dendritic cells (DCs), which promotes development of Tregs, is also increased in mesenteric lymph node and lamina propria of rIL-33-treated mice. The impact of rIL-33 on CD103⁺ DC induction was the result of indirectly upregulating intestine epithelial cells that produce thymic stromal lymphopoietin and retinoic acid but do not directly act on DCs. In conclusion, our data provide clear evidence that IL-33 plays a protective role in TNBS-induced colitis, which is closely related to a Th1-to-Th2/Treg switch. Thus, IL-33 is a promising candidate for the development of new treatments for CD.