scholarly journals HoxA10 Facilitates SHP-1-Catalyzed Dephosphorylation of p38 MAPK/STAT3 To Repress Hepatitis B Virus Replication by a Feedback Regulatory Mechanism

2019 ◽  
Vol 93 (7) ◽  
Author(s):  
Qingyu Yang ◽  
Qi Zhang ◽  
Xuewu Zhang ◽  
Lei You ◽  
Wenbiao Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cirrhosis ◽  
Chronic Hepatitis ◽  
Hepatitis B ◽  
P38 Mapk ◽  
Regulatory Mechanism ◽  
Human Hepatocytes ◽  
Hbv Infection ◽  
Hbv Replication ◽  
B Virus

ABSTRACTHepatitis B virus (HBV) infection is the leading cause of chronic hepatitis B (CHB), liver cirrhosis (LC), and hepatocellular carcinoma (HCC). This study reveals a distinct mechanism underlying the regulation of HBV replication. HBV activates homeobox A10 (HoxA10) in human hepatocytes, leukocytes, peripheral blood mononuclear cells (PBMCs), HepG2-NTCP cells, leukocytes isolated from CHB patients, and HBV-associated HCC tissues. HoxA10 in turn represses HBV replication in human hepatocytes, HepG2-NTCP cells, and BALB/c mice. Interestingly, we show that during early HBV infection, p38 mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) were activated to facilitate HBV replication; however, during late HBV infection, HoxA10 was induced to attenuate HBV replication. Detailed studies reveal that HoxA10 binds to p38 MAPK, recruits SH2-containing protein tyrosine phosphatase 1 (SHP-1) to facilitate SHP-1 in catalyzing dephosphorylation of p38 MAPK/STAT3, and thereby attenuates p38 MAPK/STAT3 activation and HBV replication. Furthermore, HoxA10 binds to the HBV enhancer element I (EnhI)/X promoter, competes with STAT3 for binding of the promoter, and thereby represses HBV transcription. Taken together, these results show that HoxA10 attenuates HBV replication through repressing the p38 MAPK/STAT3 pathway by two approaches: HoxA10 interacts with p38 MAPK and recruits SHP-1 to repress HBV replication, and HoxA10 binds to the EnhI/X promoter and competes with STAT3 to attenuate HBV transcription. Thus, the function of HoxA10 is similar to the action of interferon (IFN) in terms of inhibition of HBV infection; however, the mechanism of HoxA10-mediated repression of HBV replication is different from the mechanism underlying IFN-induced inhibition of HBV infection.IMPORTANCETwo billion people have been infected with HBV worldwide; about 240 million infected patients developed chronic hepatitis B (CHB), and 650,000 die each year from liver cirrhosis (LC) or hepatocellular carcinoma (HCC). This work elucidates a mechanism underlying the control of HBV replication. HBV infection activates HoxA10, a regulator of cell differentiation and cancer progression, in human cells and patients with CHB and HCC. HoxA10 subsequently inhibits HBV replication in human tissue culture cells and mice. Additionally, HoxA10 interacts with p38 MAPK to repress the activation of p38 MAPK and STAT3 and recruits and facilitates SHP-1 to catalyze the dephosphorylation of p38 MAPK and STAT3. Moreover, HoxA10 competes with STAT3 for binding of the HBV X promoter to repress HBV transcription. Thus, this work reveals a negative regulatory mechanism underlying the control of HBV replication and provides new insights into the development of potential agents to control HBV infection.

scholarly journals Anti-Hepatitis B Virus X Protein in Sera Is One of the Markers of Development of Liver Cirrhosis and Liver Cancer Mediated by HBV

2009 ◽  
Vol 2009 ◽  
pp. 1-6 ◽  
Author(s):  
Hang Zhang ◽  
Lian-Ying Wu ◽  
Shuai Zhang ◽  
Li-Yan Qiu ◽  
Nan Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cirrhosis ◽  
Chronic Hepatitis ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Enzyme Linked Immunosorbent Assay ◽  
X Protein ◽  
Hbv Replication ◽  
B Virus ◽  
Circulating Antibody

Hepatitis B virus X protein (HBx) plays a crucial role in the development of hepatocellular carcinoma (HCC). However, the significance of circulating antibody to hepatitis B virus X antigen (anti-HBx) in sera remains unclear. In the present study, we examined the titers of anti-HBx (IgG) in the sera from 173 patients with chronic hepatitis B (CHB), 106 liver cirrhosis (LC), and 61 HCC by enzyme-linked immunosorbent assay (ELISA), respectively. Our data showed that the positive rates of anti-HBx were higher in sera of LC (40.6%) and HCC (34.4%) than those of CHB (10.4%),P<.05. In all 40 patients with anti-HBx+ out of 340 patients, 39 (97.5%) were HBsAg/HBeAg/anti-HBc+ and 1 (2.5%) was anti-HBs+ (P<.01), suggesting that anti-HBx in sera is a marker of HBV replication rather than a protective antibody. Thus, our findings reveal that circulating anti-HBx in sera is one of the markers of development of LC and HCC mediated by HBV.

scholarly journals Significant association of thrombocytopenia with chronic active hepatitis B virus infection in a tertiary care hospital of an intermediate prevalence HBV country

2019 ◽  
Vol 5 (3) ◽  
pp. 207-211
Author(s):  
Muayad A Merza ◽  
Sagvan Kareem Taha ◽  
Sara Muhsin Ibrahim ◽  
Ahmed Tayar Sadeeq ◽  
Mahabad R Abdulrahman
Keyword(s):  
Liver Cirrhosis ◽  
Chronic Hepatitis ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
Chronic Active Hepatitis ◽  
Hbv Infection ◽  
Care Hospital ◽  
Younger Age ◽  
B Virus

Thrombocytopenia is a relatively uncommon extra-hepatic manifestation of uncomplicated chronic hepatitis B virus (HBV) infection. This study has two aims: to assess the prevalence of thrombocytopenia in non-cirrhotic patients with chronic hepatitis B (CHB); and to determine the association of certain variables with thrombocytopenia in Duhok province. It is a case control study conducted in Azadi Teaching Hospital during June 2016 - May 2019. Chronic active hepatitis B was defined according to the following parameters: the presence of detectable hepatitis B surface antigen (HBsAg) in the blood longer than six months, positive or negative HBeAg, HBV-DNA level >2000 IU/ml, elevated ALT, and/or at least moderate histopathological fibrosis. Thrombocytopenia was defined as platelet counts below 150,000/μl. The obtained results were analyzed by entering data into Microsoft Excel 2010. A total of 379 CHB patients and 200 cases as control were enrolled in this study. Their mean ages were 33.62 ± 14.48 and 40.72 ± 18.56 for HBV and control cases, respectively. There were 236 (62.27%) males in the HBV patients and 109 (54.50%) males in the control group. Comparing both groups, significant association was found between HBV and younger age, cigarette smoking, and alcohol consumption. Chronic active hepatitis B without liver cirrhosis was strongly associated with an increased rate of thrombocytopenia. This finding is paramount as it is statistically significant (P = 0.042). Significant association with younger age and Syrian nationality was found more in CHB patients with thrombocytopenia compared to non-thrombocytopenic. In conclusion, chronic active hepatitis B is strongly associated with thrombocytopenia. As hypersplenism resulting from liver cirrhosis was excluded in our patients, the cause of thrombocytopenia is due to other mechanisms. Therefore, it is important to consider CHB in the differential diagnosis of patients presenting with isolated thrombocytopenia. Older age and Syrian nationality were predictors for developing thrombocytopenia in chronic active HBV infection. Asian J. Med. Biol. Res. June 2019, 5(3): 207-211

scholarly journals Association of STAT3 and STAT4 polymorphisms with susceptibility to chronic hepatitis B virus infection and risk of hepatocellular carcinoma: a meta-analysis

2019 ◽  
Vol 39 (6) ◽  
Author(s):  
Han Shi ◽  
Hongyan He ◽  
Suvash Chandra Ojha ◽  
Changfeng Sun ◽  
Juan Fu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Chronic Hepatitis ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
Meta Analysis ◽  
Hbv Infection ◽  
Chronic Hbv Infection ◽  
B Virus ◽  
Chronic Hbv

Abstract Background: It has been reported that polymorphisms of signal transducer and activator of transcription (STAT) 3 and STAT4 might be associated with susceptibility to hepatitis B virus (HBV) infection and risk of chronic hepatocellular carcinoma (HCC). Owing to limitation of sample size and inconclusive results, we conducted a meta-analysis to clarify the association. Methods: We identified relevant studies by a systematic search of Medline/PubMed, Embase, Web of Science and the Cochrane Library up to 20 February 2019. The strength of the association measured by odds ratios (OR) with 95% confidence intervals (CIs) was studied. All the statistical analyses were conducted based on Review Manager 5.3 software. Results: A total of 5242 cases and 2717 controls from five studies were included for the STAT3 polymorphism, 5902 cases and 7867 controls from nine studies for the STAT4 polymorphism. Our results suggested that STAT3 rs1053004 polymorphism was a significant risk factor of chronic HBV infection (C vs. T: OR = 1.17, 95% CI: 1.07–1.29, PA=0.0007; CC + CT vs. TT: OR = 1.38, 95% CI: 1.09–1.76, PA=0.008). Validation with all the genetic models revealed that rs7574865 polymorphism of STAT4 gene was closely associated with chronic HBV infection (PA<0.01) and chronic hepatitis B (CHB)-related HCC (PA<0.05). Meanwhile, the authenticity of the above meta-analysis results was confirmed by trial sequential analysis (TSA). Conclusions: The meta-analysis showed that STAT3 rs1053004 polymorphism may be the risk for developing chronic HBV infection but not associated with HCC. The present study also indicates that STAT4 rs7574865 polymorphism increased the risk of chronic HBV infection and HCC.

scholarly journals Studies on Mutual Relationship between Anti-HBx and sFas, IL-10 or IL-12 in Sera of Cases with Chronic Hepatitis B Infection

2014 ◽  
Vol 3 (2) ◽  
pp. 49-53
Author(s):  
Ai-kun Ding ◽  
Li-wei Guo ◽  
Yong-kong Wang ◽  
Wei Liu ◽  
Cheng Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cirrhosis ◽  
Chronic Hepatitis ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
Sandwich Elisa ◽  
Hbv Infection ◽  
Mutual Relationship ◽  
Chronic Hbv Infection ◽  
Chronic Hbv

Abstract Objective To study the mutual relationship between anti-HBx and IL-10, IL-12 or soluble Fas (sFas) in sera of patients with chronic HBV infection and to explore the importance of anti-HBx detection as well as its role in the development of chronic HBV infection. Methods Total of 90 cases with chronic HBV infection were randomly selected, including 10 of asymptomatic carriers (ASC), 28 of chronic hepatitis B (CHB), 26 of liver cirrhosis (LC) and 26 patients of hepatocellular carcinoma (HCC). Their clinical data and blood samples were collected, and serum was prepared and stored at -73℃. Anti-HBx was detected with an indirect ELISA established in our earlier research, and levels of IL-10, IL-12 and Fas were determined with commercial double-antibody sandwich ELISA kits. The mutual relationship between anti-HBx and IL-10, IL-12 or sFas in serum were analyzed with the software SPSS 20.0. Results All levels of IL-10, IL-12 and sFas in peripheral blood showed a rising trend with development of chronic HBV infection. The levels of IL-10 in ASC, CHB, LC and HCC groups were 13.93 ± 14.40 ng/L, 39.38 ± 20.77 ng/L, 69.06 ± 46.37 ng/L and 62.82 ± 23.42 ng/L, respectively, levels of IL-12 in the 4 groups were 15.64 ± 23.04 ng/L, 68.50 ± 23.14 ng/L, 76.83 ± 12.82 ng/L and 83.74 ± 24.88 ng/L, respectively, and levels of sFas were 58.17 ± 77.42 ng/L, 179.88 ± 104.36 ng/L, 249.22 ± 107.80 ng/L and 252.98 ± 87.65 ng/L, respectively. Twenty-seven out of 90 patients showed a positive result for anti-HBx detection, including 1 in ASC, 4 in CHB, 12 in LC and 10 in HCC group. The levels of IL-10, IL-12 and sFas were higher in anti-HBx positive group than in negative group. Statistical analysis demonstrated significant differences of IL-10 and IL-12 between the two groups (P < 0.05), but the differences of sFas had no statistical significance (P = 0.094). Conclusions Anti-HBx antibody is not protective, and is closely related to IL-10, IL-12 and sFas. It may be an important serum indicator for aggravation from chronic hepatitis B to liver cirrhosis or hepatocellular carcinoma in patients with chronic HBV infection.

scholarly journals Spectrum of Disease Conditions Seen at the Gastroenterology Clinic of a Tertiary Health Facility in South-Western Nigeria

2020 ◽  
pp. 77-87
Author(s):  
Oguntoye Oluwatosin Oluwagbenga ◽  
Yusuf Musah ◽  
Olowoyo Paul ◽  
Soje Michael Osisiogu ◽  
Oguntoye Oluwafunmilayo Adenike ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cirrhosis ◽  
Chronic Hepatitis ◽  
Hepatitis B ◽  
Viral Infection ◽  
Medical Condition ◽  
Hepatitis B Virus Infection ◽  
Medical Conditions ◽  
B Virus ◽  
Hepatitis B Viral Infection

Background: Globally, gastrointestinal medical conditions are common and a considerable number of patients will require specialist consultation for the diagnosis, management and follow-up care. Aim: To determine the spectrum of disease conditions seen at the Gastroenterology clinic of Federal Teaching Hospital, Ido-Ekiti in south-western Nigeria. Methods: This was a retrospective cohort study of all patients who attended the Gastroenterology clinic between January 2015 and December 2019 (a period of 5 years). The Age, Gender and Diagnosis were obtained from the Clinic Register. A total of 679 patients attended the clinic over the period and they were all recruited into the study. The data obtained was analyzed using the Statistical Package for the Social Sciences (SPSS) version 21.0. Descriptive statistics used included frequency tables, means and standard deviations. Results: A total number of 679 patients attended the Gastroenterology clinic during the period under review out of which 353 (52.0%) were males and 326 (48.0%) were females with a male to female ratio of 1.08 to 1. The age range of the patients was 10 to 93 years with a mean (±SD) of 43.8 (±16.32) and median of 40.0 years. The commonest medical condition seen at our clinic was Chronic Hepatitis B viral infection (38.1%), followed by Acid Peptic Disorders (27.0%), Liver cirrhosis (5.2%), Non-Alcoholic Fatty Liver Disease (5.0%) and Hepatocellular carcinoma (4.1%). Hepatocellular carcinoma was the commonest malignancy seen at our clinic followed by Gastric cancer (2.5%), Colorectal cancer (1.9%) and Cholangiocarcinoma (0.7%). Pancreatic cancer and Oesophageal cancer were seen at our clinic at the same frequency (0.6% each). Primary Biliary Cirrhosis, Achalasia and Irritable Bowel Syndrome were the least frequently seen (0.1% each) medical conditions at our clinic. Acute Hepatitis B viral infection constituted 2.9% while Chronic Hepatitis C viral infection constituted 2.4% of the cases seen. The other medical conditions seen at our clinic include Alcoholic Liver Disease (2.4%), Abdominal Tuberculosis (0.7%), Toxin-induced Hepatitis (0.6%), Haemorrhoids (0.6%), Ulcerative Colitis (0.4%) and Diverticular Disease (0.3%). Conclusion: The commonest medical condition seen at our Gastroenterology clinic was Chronic Hepatitis B virus infection followed by Acid Peptic Disorders both of which are largely preventable and the commonest malignancy seen at our clinic was Hepatocellular carcinoma. Hepatitis B virus infection is highly prevalent in our environment and it is a risk factor for chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Efforts must be enhanced by all stakeholders to curb the spread of this virus and thereby limit its sequelae.

scholarly journals Identification and Analysis of the Blood lncRNA Signature for Liver Cirrhosis and Hepatocellular Carcinoma

2020 ◽  
Vol 11 ◽  
Author(s):  
Qi Xia ◽  
Zheyue Shu ◽  
Ting Ye ◽  
Min Zhang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Feature Selection ◽  
Liver Cirrhosis ◽  
Chronic Hepatitis ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
Hbv Infection ◽  
Support Vector ◽  
Chronic Hepatitis B Virus ◽  
Healthy Control

As one of the most common malignant tumors, hepatocellular carcinoma (HCC) is the fifth major cause of cancer-associated mortality worldwide. In 90% of cases, HCC develops in the context of liver cirrhosis and chronic hepatitis B virus (HBV) infection is an important etiology for cirrhosis and HCC, accounting for 53% of all HCC cases. To understand the underlying mechanisms of the dynamic chain reactions from normal to HBV infection, from HBV infection to liver cirrhosis, from liver cirrhosis to HCC, we analyzed the blood lncRNA expression profiles from 38 healthy control samples, 45 chronic hepatitis B patients, 46 liver cirrhosis patients, and 46 HCC patients. Advanced machine-learning methods including Monte Carlo feature selection, incremental feature selection (IFS), and support vector machine (SVM) were applied to discover the signature associated with HCC progression and construct the prediction model. One hundred seventy-one key HCC progression-associated lncRNAs were identified and their overall accuracy was 0.823 as evaluated with leave-one-out cross validation (LOOCV). The accuracies of the lncRNA signature for healthy control, chronic hepatitis B, liver cirrhosis, and HCC were 0.895, 0.711, 0.870, and 0.826, respectively. The 171-lncRNA signature is not only useful for early detection and intervention of HCC, but also helpful for understanding the multistage tumorigenic processes of HCC.

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