Hepatocellular carcinoma in individuals with HBV infection or HBV–HCV co-infection in a low endemic country

Objective: Our study aims to detect the sensitivity of the new biomarker miR-212 existing in serum exosomes along with other hepatocellular carcinoma biomarkers such as AFP (alpha-fetoprotein), CA125 (carbohydrate antigen-ca125), and Hbx protein in the diagnosis of HBV-related liver diseases. We also aim to study the roles of these biomarkers in the progression of chronic hepatitis B and provide scientific data to show the clinical value of these biomarkers. Methods: We selected 200 patients with HBV-infection (58 cases of chronic hepatitis B, 47 cases of hepatocellular carcinoma, 30 cases of compensatory phase cirrhosis, and 65 cases of decompensatory phase cirrhosis), 31 patients with primary liver cancer without HBV infection, and 70 healthy individuals as the control group. The expression level of serum AFP and CA125 was detected with electrochemiluminescence immunoassay. The expression level of the Hbx protein was detected with ELISA. Meanwhile, the expression level of miR-212 in serum was analyzed with RT-qPCR. We collected patients’ clinical information following the Child-Pugh classification and MELD score criterion, and statistical analysis was made between the expression level of miR-212 and the collected clinical indexes. Lastly, we predicted the target genes of the miR-212 and its functions using bioinformatics methods such as cluster analysis and survival prediction. Results: Compared to the control group, the expression level of miR-212 in HBV infected patients was remarkably increased (P<0.05), especially between the HBV-infection Hepatocellular carcinoma group and the non-HBVinfection liver cancer group (P<0.05). The expression of miR-212 was increased in patients’ Child-Pugh classification, MELD score, and TNM staging. Moreover, the sensitivity and specificity of miR-212 were superior to AFP, CA125, and HBx protein. Conclusion: There is a linear relationship between disease progression and expression level of miR-212 in the serum of HBV infected patients. This demonstrates that miR-212 plays a significant role in liver diseases. miR-212 is expected to be a new biomarker used for the diagnosis and assessment of patients with HBV-infection-related liver diseases.

Download Full-text

Clinical value evaluation of microRNA-324-3p and other available biomarkers in patients with HBV-infection-related hepatocellular carcinoma

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab108 ◽

2021 ◽

Author(s):

Li Zhao ◽

Qian Yang ◽

Jianbo Liu

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Hepatitis B ◽

Diagnostic Performance ◽

Cox Regression ◽

Hbv Infection ◽

Healthy Controls ◽

Survival Prognosis ◽

Diagnosis And Prognosis ◽

Hcc Cells

Abstract Background Patients with hepatitis B virus (HBV) infection are at high risk of hepatocellular carcinoma (HCC). This study aimed to evaluate the expression of microRNA-324-3p (miR-324-3p) in HBV-related HCC, and explore the clinical significance of serum miR-324-3p and other available biomarkers in the diagnosis and prognosis of HBV-related HCC. Methods Expression of miR-324-3p in HBV-infection-related cells and patients was estimated using quantitative real-time PCR. The receiver operating characteristic (ROC) curves were constructed to evaluate the diagnostic performance of serum miR-324-3p, AFP and PIVKA-II in the differentiation of HBV-related HCC from healthy controls and chronic hepatitis B (CHB). The relationship between serum miR-324-3p and patients’ clinical features was assessed using Chi-square test, and the value of miR-324-3p to predict overall survival prognosis was evaluated using Kaplan-Meier methods and Cox regression assay in patients with HBV-related HCC. Results HBV-related HCC cells had significantly increased miR-324-3p compared with normal and HBV-unrelated HCC cells, and serum miR-324-3p in HCC patients with HBV infection was also higher than that in healthy controls and CHB. Serum miR-324-3p had relatively high diagnostic accuracy for the screening of HCC case with HBV infection, and the combination of miR-324-3p, AFP and PIVKA-II showed the improved diagnostic performance. Additionally, high serum miR-324-2p in HBV-related HCC patients was associated with cirrhosis, tumor size, clinical stage and poor overall survival prognosis. Conclusion Serum increased miR-324-3p may be involved in the progression of HBV-related hepatitis to HCC, and may serve as a candidate biomarker for the diagnosis and prognosis of HBV-related HCC.

Download Full-text

Genetic variants of programmed cell death 1 are associated with HBV infection and liver disease progression

Scientific Reports ◽

10.1038/s41598-021-87537-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Nghiem Xuan Hoan ◽

Pham Thi Minh Huyen ◽

Mai Thanh Binh ◽

Ngo Tat Trung ◽

Dao Phuong Giang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Death ◽

Liver Disease ◽

Programmed Cell Death ◽

Disease Progression ◽

Infection Risk ◽

Hbv Infection ◽

Liver Disease Progression ◽

Increased Risk ◽

Programmed Cell Death 1

AbstractThe inhibitory effects of programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) modulates T-cell depletion. T-cell depletion is one of the key mechanisms of hepatitis B virus (HBV) persistence, in particular liver disease progression and the development of hepatocellular carcinoma (HCC). This case–control study aimed to understand the significance of PD-1 polymorphisms (PD-1.5 and PD-1.9) association with HBV infection risk and HBV-induced liver disease progression. Genotyping of PD-1.5 and PD-1.9 variants was performed by direct Sanger sequencing in 682 HBV-infected patients including chronic hepatitis (CHB, n = 193), liver cirrhosis (LC, n = 183), hepatocellular carcinoma (HCC, n = 306) and 283 healthy controls (HC). To analyze the association of PD-1 variants with liver disease progression, a binary logistic regression, adjusted for age and gender, was performed using different genetic models. The PD-1.9 T allele and PD-1.9 TT genotype are significantly associated with increased risk of LC, HCC, and LC + HCC. The frequencies of PD-1.5 TT genotype and PD-1.5 T allele are significantly higher in HCC compared to LC patients. The haplotype CT (PD-1.5 C and PD-1.9 T) was significantly associated with increased risk of LC, HCC, and LC + HCC. In addition, the TC (PD-1.5 T and PD-1.9 C) haplotype was associated with the risk of HCC compared to non-HCC. The PD-1.5 CC, PD-1.9 TT, genotype, and the CC (PD-1.5 C and PD-1.9) haplotype are associated with unfavorable laboratory parameters in chronic hepatitis B patients. PD-1.5 and PD1.9 are useful prognostic predictors for HBV infection risk and liver disease progression.

Download Full-text

Creation of a Six-fingered Artificial Transcription Factor That Represses the Hepatitis B Virus HBx Gene Integrated into a Human Hepatocellular Carcinoma Cell Line

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057112463066 ◽

2012 ◽

Vol 18 (4) ◽

pp. 378-387 ◽

Cited By ~ 7

Author(s):

Xinghui Zhao ◽

Zhanzhong Zhao ◽

Junwei Guo ◽

Peitang Huang ◽

Xudong Zhu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Transcription Factor ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Cell Line ◽

Hbv Infection ◽

Luciferase Reporter ◽

Artificial Transcription Factor ◽

Chronic Hepatitis B Virus ◽

B Virus

Chronic hepatitis B virus (HBV) infection is an independent risk factor for the development of hepatocellular carcinoma (HCC). The HBV HBx gene is frequently identified as an integrant in the chromosomal DNA of patients with HCC. HBx encodes the X protein (HBx), a putative viral oncoprotein that affects transcriptional regulation of several cellular genes. Therefore, HBx may be an ideal target to impede the progression of HBV infection–related HCC. In this study, integrated HBx was transcriptionally downregulated using an artificial transcription factor (ATF). Two three-fingered Cys2-His2 zinc finger (ZF) motifs that specifically recognized two 9-bp DNA sequences regulating HBx expression were identified from a phage-display library. The ZF domains were linked into a six-fingered protein that specified an 18-bp DNA target in the Enhancer I region upstream of HBx. This DNA-binding domain was fused with a Krüppel-associated box (KRAB) transcriptional repression domain to produce an ATF designed to downregulate HBx integrated into the Hep3B HCC cell line. The ATF significantly repressed HBx in a luciferase reporter assay. Stably expressing the ATF in Hep3B cells resulted in significant growth arrest, whereas stably expressing the ATF in an HCC cell line lacking integrated HBx (HepG2) had virtually no effect. The targeted downregulation of integrated HBx is a promising novel approach to inhibiting the progression of HBV infection–related HCC.

Download Full-text

Discovery of novel hepatitis B virus (HBV) antivirals and analysis of mechanisms of action of HBV-targeting agents

10.32469/10355/70421 ◽

2017 ◽

Author(s):

◽

Andrew Douglas Huber

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Treatment Options ◽

Mechanisms Of Action ◽

Hbv Infection ◽

Viral Inhibition ◽

University Of Missouri ◽

Chronic Hepatitis B Virus ◽

B Virus

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Chronic hepatitis B virus (HBV) infection leads to liver disease, cirrhosis, and hepatocellular carcinoma. Globally, an estimated 50% of all hepatocellular carcinoma cases are linked to chronic HBV infection. More than 240 million people are chronically infected, and there are 0.5-1 million deaths per year due to HBVrelated liver conditions. HBV treatment options rarely cure infections and are associated with adverse side effects that often outweigh the potential benefits of treatment. New treatments, therefore, are highly desired for HBV therapy. Towards this goal, we have developed novel compounds targeting two viral targets and assessed the mechanisms of action by which these compounds act. We have developed systems for the discovery and evaluation of compounds that inhibit 2 distinct steps in the HBV life cycle. Using these systems, we have developed potent inhibitors of HBV replication that have potential to become clinically used HBV drugs. Furthermore, we have used our methods to evaluate which properties of these compounds are likely to result in better viral inhibition. The work described in this thesis has led to at least 2 new compound groups for potential use as HBV antivirals and provides insight into mechanisms by which potent antivirals can be achieved.

Download Full-text

Epidemiology of Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) Related Hepatocellular Carcinoma

The Open Virology Journal ◽

10.2174/1874357901812010026 ◽

2018 ◽

Vol 12 (1) ◽

pp. 26-32 ◽

Cited By ~ 66

Author(s):

Arnolfo Petruzziello

Keyword(s):

Risk Factors ◽

Hepatocellular Carcinoma ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Hbv Infection ◽

Sub Saharan Africa ◽

Liver Cancers ◽

B Virus

Introduction:Hepatocellular carcinoma (HCC) is one of the most prevalent primary malignant tumors and accounts for about 90% of all primary liver cancers. Its distribution varies greatly according to geographic location and it is more common in middle and low- income countries than in developed ones especially in Eastern Asia and Sub Saharan Africa (70% of all new HCCs worldwide), with incidence rates of over 20 per 100,000 individuals.Explanation:The most important risk factors for HCC are Hepatitis B Virus (HBV) infection, Hepatitis C Virus (HCV) infection, excessive consumption of alcohol and exposition to aflatoxin B1. Its geographic variability and heterogeneity have been widely associated with the different distribution of HBV and HCV infections worldwide.Chronic HBV infection is one of the leading risk factors for HCC globally accounting for at least 50% cases of primary liver tumors worldwide. Generally, while HBV is the main causative agent in the high incidence HCC areas, HCV is the major etiological factor in low incidence HCC areas, like Western Europe and North America.Conclusion:HBV-induced HCC is a complex, stepwise process that includes integration of HBV DNA into host DNA at multiple or single sites. On the contrary, the cancerogenesis mechanism of HCV is not completely known and it still remains controversial as to whether HCV itself plays a direct role in the development of tumorigenic progression.

Download Full-text

The Associated Ion between the VDR Gene Polymorphisms and Susceptibility to Hepatocellular Carcinoma and the Clinicopathological Features in Subjects Infected with HBV

BioMed Research International ◽

10.1155/2013/953974 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 11

Author(s):

Xing Yao ◽

Huazong Zeng ◽

Guolei Zhang ◽

Weimin Zhou ◽

Qiang Yan ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Smoking Status ◽

Clinicopathological Features ◽

Hbv Infection ◽

Advanced Tumor Stage ◽

Vdr Gene ◽

Genotype Frequencies ◽

Advanced Tumor ◽

Vdr Gene Polymorphisms ◽

Chronic Hepatitis B Virus

Aim. To evaluate the possible association between the vitamin D receptor (VDR), single-nucleotide polymorphisms (SNPs), and hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection.Method. 968 chronic HBV infection patients were enrolled, of which 436 patients were diagnosed HCC patients, and 532 were non-HCC patients. The clinicopathological characteristics of HCC were evaluated. The genotypes of VDR gene at FokI, BsmI, ApaI, and TaqI were determined.Results. The genotype frequencies of VDR FokI C>T polymorphism were significantly different between HCC and non-HCC groups. HCC patients had a higher prevalence of FokI TT genotype than non-HCC subjects. With FokI CC as reference, the TT carriage had a significantly higher risk for development of HCC after adjustments with age, sex, HBV infection time,α-fetoprotein, smoking status, and alcohol intake. In addition, we also found that the TT genotype carriage of FokI polymorphisms were associated with advanced tumor stage, presence of cirrhosis, and lymph node metastasis. The SNP at BsmI, ApaI, and TaqI did not show positive association with the risk and clinicopathological features of HCC.Conclusion. The FokI C>T polymorphisms may be used as a molecular marker to predict the risk and to evaluate the disease severity of HCC in those infected with HBV.

Download Full-text

Elevated serum soluble CD14 levels in chronic HBV infection are significantly associated with HBV-related hepatocellular carcinoma

Tumor Biology ◽

10.1007/s13277-015-4423-x ◽

2015 ◽

Vol 37 (5) ◽

pp. 6607-6617 ◽

Cited By ~ 4

Author(s):

Na Li ◽

Qianqian Zhu ◽

Cuiling Yang ◽

Fang Li ◽

Zhihua Zhou ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Elevated Serum ◽

Hbv Infection ◽

Soluble Cd14 ◽

Chronic Hbv Infection ◽

Chronic Hbv

Download Full-text

Tenofovir Is Associated With Lower Risk of Hepatocellular Carcinoma Than Entecavir in Patients With Chronic HBV Infection in China

Gastroenterology ◽

10.1053/j.gastro.2019.09.025 ◽

2020 ◽

Vol 158 (1) ◽

pp. 215-225.e6 ◽

Cited By ~ 36

Author(s):

Terry Cheuk-Fung Yip ◽

Vincent Wai-Sun Wong ◽

Henry Lik-Yuen Chan ◽

Yee-Kit Tse ◽

Grace Chung-Yan Lui ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Lower Risk ◽

Hbv Infection ◽

Chronic Hbv Infection ◽

Chronic Hbv

Download Full-text

Surgical Resection Significantly Promotes the Overall Survival of Patients with Hepatocellular Carcinoma: A Propensity Score Matching Analysis

10.21203/rs.3.rs-148506/v1 ◽

2021 ◽

Author(s):

Pei-Min Hsieh ◽

Hung-Yu Lin ◽

Chao-Ming Hung ◽

Gin-Ho Lo ◽

I-Cheng Lu ◽

...

Keyword(s):

Risk Factors ◽

Hepatocellular Carcinoma ◽

Overall Survival ◽

Propensity Score ◽

Propensity Score Matching ◽

Surgical Resection ◽

Cox Regression ◽

Survival Rates ◽

Hbv Infection ◽

Cox Regression Analysis

Abstract Background: The benefits of surgical resection (SR) for various Barcelona Clinic Liver Cancer (BCLC) stages of hepatocellular carcinoma (HCC) remain unclear. We investigated the risk factors of overall survival (OS) and survival benefits of SR over nonsurgical treatments in patients with HCC of various BCLC stages.Methods: Overall, 2316 HCC patients were included, and their clinicopathological data and OS were recorded. OS was analyzed by the Kaplan-Meier method and Cox regression analysis. Propensity score matching (PSM) analysis was performed.Results: In total, 66 (2.8%), 865 (37.4%), 575 (24.8%) and 870 (35.0%) patients had BCLC stage 0, A, B, and C disease, respectively. Furthermore, 1302 (56.2%) of all patients, and 37 (56.9%), 472 (54.6%), 313 (54.4%) and 480 (59.3%) of patients with BCLC stage 0, A, B, and C disease, respectively, died. The median follow-up duration time was 20 (range 0-96) months for the total cohort and was subdivided into 52 (8-96), 32 (1-96), 19 (0-84), and 12 (0-79) months for BCLC stages 0, A, B, and C cohorts, respectively. The risk factors for OS were 1) SR and cirrhosis; 2) SR, cirrhosis, and Child-Pugh (C-P) class; 3) SR, hepatitis B virus (HBV) infection, and C-P class; and 4) SR, HBV infection, and C-P class for the BCLC stage 0, A, B, and C cohorts, respectively. Compared to non-SR treatment, SR resulted in significantly higher survival rates in all cohorts. The 5-year OS rates for SR vs non-SR were 44.0% vs 28.7%, 72.2% vs 42.6%, 42.6% vs 36.2, 44.6% vs 23.5%, and 41.4% vs 15.3% (all p-values<0.05) in the total and BCLC stage 0, A, B, and C cohorts, respectively. After PSM, SR resulted in significantly higher survival rates compared to non-SR treatment in various BCLC stages.Conclusion: SR conferred significant survival benefits to patients with HCC of various BCLC stages and should be considered a recommended treatment for select HCC patients, especially patients with BCLC stage B and C disease.

Download Full-text