Blood glucose fluctuates severely in the diabetes (DM) and tumor microenvironment. Our previous works have found Hepatitis B virus X protein (HBx) differentially regulated metastasis and apoptosis of hepatoma cells depending on glucose concentration. We here aimed to explore whether HBx played dual roles in the angiogenesis of hepatocellular carcinoma varying on different glucose levels.
Materials and Methods
We collected conditioned medium from HBx-overexpressing cells cultured with two solubilities of glucose, and then applied to EA.hy926 cells. Alternatively, a co-culture cell system was established with hepatoma cells and EA.hy926 cells. We analyzed the angiogenesis of EA.hy926 cells with CCK8, wound-healing, transwell-migartion and tube formation experiment. ELISA was conducted to detect the secretion levels of angiogenesis-related factors. siRNAs were used to detect the P53-VEGF axis.
Results
HBx expressed in hepatoma cells suppressed VEGF secretion, and subsequently inhibited the proliferation, migration and tube formation of EA.hy926 cells in a high glucose condition, while attenuating these in the lower glucose condition. Furthermore, the p53-VEGF axis was required for the dual role of HBx in angiogenesis. Additionally, HBx mainly regulated the nuclear p53.
Conclusions
These data suggest that the dual roles of HBx confer hepatoma cells to remain in a glucose-rich environment and escape from the glucose-low milieu through tumor vessels, promoting liver tumor progression overall. We exclusively revealed the dual role of HBx on the angiogenesis of liver tumors, which may shed new light on the mechanism and management strategy of HBV- and DM-related hepatocellular carcinoma.
{"title":"Hepatitis B virus X protein differentially regulates the angiogenesis of Hepatocellular Carcinoma through p53-VEGF axis according to glucose levels","authors":"Guitao Xiao , Xiaoyun Huang , Tingxuan Huang , Zhixin Chen , Yuehong Huang , Rongfeng Huang , Xiaozhong Wang","doi":"10.1016/j.aohep.2024.101543","DOIUrl":"10.1016/j.aohep.2024.101543","url":null,"abstract":"<div><h3>Introduction and Objectives</h3><p>Blood glucose fluctuates severely in the diabetes (DM) and tumor microenvironment. Our previous works have found Hepatitis B virus X protein (HBx) differentially regulated metastasis and apoptosis of hepatoma cells depending on glucose concentration. We here aimed to explore whether HBx played dual roles in the angiogenesis of hepatocellular carcinoma varying on different glucose levels.</p></div><div><h3>Materials and Methods</h3><p>We collected conditioned medium from HBx-overexpressing cells cultured with two solubilities of glucose, and then applied to EA.hy926 cells. Alternatively, a co-culture cell system was established with hepatoma cells and EA.hy926 cells. We analyzed the angiogenesis of EA.hy926 cells with CCK8, wound-healing, transwell-migartion and tube formation experiment. ELISA was conducted to detect the secretion levels of angiogenesis-related factors. siRNAs were used to detect the P53-VEGF axis.</p></div><div><h3>Results</h3><p>HBx expressed in hepatoma cells suppressed VEGF secretion, and subsequently inhibited the proliferation, migration and tube formation of EA.hy926 cells in a high glucose condition, while attenuating these in the lower glucose condition. Furthermore, the p53-VEGF axis was required for the dual role of HBx in angiogenesis. Additionally, HBx mainly regulated the nuclear p53.</p></div><div><h3>Conclusions</h3><p>These data suggest that the dual roles of HBx confer hepatoma cells to remain in a glucose-rich environment and escape from the glucose-low milieu through tumor vessels, promoting liver tumor progression overall. We exclusively revealed the dual role of HBx on the angiogenesis of liver tumors, which may shed new light on the mechanism and management strategy of HBV- and DM-related hepatocellular carcinoma.</p></div>","PeriodicalId":7979,"journal":{"name":"Annals of hepatology","volume":"29 6","pages":"Article 101543"},"PeriodicalIF":3.7,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1665268124003375/pdfft?md5=e5108f85d7a786e2689d8e7855c5a7eb&pid=1-s2.0-S1665268124003375-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-29DOI: 10.1016/j.aohep.2024.101544
Adnan Malik , Sadia Javaid , Muhammad Imran Malik , Shahbaz Qureshi
Introduction and Objectives
Metabolic dysfunction-associated steatotic liver disease (MASLD) formerly known as Nonalcoholic fatty liver disease (NAFLD) is a common chronic disease. Identifying MASLD risk factors could help early intervention and reduce the burden of the disease. Previous studies investigated the association between sarcopenia and NAFLD. Several trials were published after the last meta-analysis with indecisive results. This is an updated meta-analysis which aims to assess the association between sarcopenia, MASLD, and MASLD-related fibrosis.
Materials and Methods
Relevant trials published on PubMed, Web of Science, Scopus, and Cochrane Library databases until October 2022 were included. We included studies in which skeletal mass index (SMI) or sarcopenia was compared between patients with and without NAFLD now MASLD. Also, studies comparing fibrosis between MASLD patients with and without sarcopenia were included. Data were pooled as odds ratios (ORs) and 95 % confidence intervals (CIs) using Review Manager Software.
Results
A total of 25 studies were included. The incidence of sarcopenia was significantly higher in MASLD than controls (OR, 1.25; 95 % CI, 1.08-1.44; P = 0.003). SMI odds showed no significant difference between MASLD patients and controls (OR, 1.02; 95 % CI, 0.91-1.15; P = 0.7). MASLD patients with sarcopenia had higher odds of fibrosis than MASLD patients without sarcopenia (OR, 1.49; 95 % CI, 1.03-2.14; P = 0.03).
Conclusions
Sarcopenia increased MASLD's probability and was associated with a higher probability of liver fibrosis in MASLD patients. However, SMI had no predictive value of MASLD occurrence.
{"title":"Relationship between sarcopenia and metabolic dysfunction-associated steatotic liver disease (MASLD): A systematic review and meta-analysis","authors":"Adnan Malik , Sadia Javaid , Muhammad Imran Malik , Shahbaz Qureshi","doi":"10.1016/j.aohep.2024.101544","DOIUrl":"10.1016/j.aohep.2024.101544","url":null,"abstract":"<div><h3>Introduction and Objectives</h3><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) formerly known as Nonalcoholic fatty liver disease (NAFLD) is a common chronic disease. Identifying MASLD risk factors could help early intervention and reduce the burden of the disease. Previous studies investigated the association between sarcopenia and NAFLD. Several trials were published after the last meta-analysis with indecisive results. This is an updated meta-analysis which aims to assess the association between sarcopenia, MASLD, and MASLD-related fibrosis.</p></div><div><h3>Materials and Methods</h3><p>Relevant trials published on PubMed, Web of Science, Scopus, and Cochrane Library databases until October 2022 were included. We included studies in which skeletal mass index (SMI) or sarcopenia was compared between patients with and without NAFLD now MASLD. Also, studies comparing fibrosis between MASLD patients with and without sarcopenia were included. Data were pooled as odds ratios (ORs) and 95 % confidence intervals (CIs) using Review Manager Software.</p></div><div><h3>Results</h3><p>A total of 25 studies were included. The incidence of sarcopenia was significantly higher in MASLD than controls (OR, 1.25; 95 % CI, 1.08-1.44; P = 0.003). SMI odds showed no significant difference between MASLD patients and controls (OR, 1.02; 95 % CI, 0.91-1.15; P = 0.7). MASLD patients with sarcopenia had higher odds of fibrosis than MASLD patients without sarcopenia (OR, 1.49; 95 % CI, 1.03-2.14; P = 0.03).</p></div><div><h3>Conclusions</h3><p>Sarcopenia increased MASLD's probability and was associated with a higher probability of liver fibrosis in MASLD patients. However, SMI had no predictive value of MASLD occurrence.</p></div>","PeriodicalId":7979,"journal":{"name":"Annals of hepatology","volume":"29 6","pages":"Article 101544"},"PeriodicalIF":3.7,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1665268124003387/pdfft?md5=840ab2b9fd6c63babd4fff6b502d77d2&pid=1-s2.0-S1665268124003387-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-29DOI: 10.1016/j.aohep.2024.101541
Facundo Maiorana , Magali Neschuk , María Virginia Caronia , Karina Elizondo , Adolfo Schneider , Georgina Veron , Pedro D Zapata , Fernando Javier Barreyro
Introduction and Objectives
Recent studies have suggested an association between H. pylori and metabolic dysfunction associated steatotic liver disease (MASLD). We aim to evaluate the association of H. pylori virulence genes with non-invasive markers of liver injury and fibrosis in MASLD subjects.
Patients and Methods
A total of 362 dyspeptic patients who underwent gastroscopy were selected. Biochemical, clinical parameters, ultrasound, FIB-4 score, liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE), gastric biopsies, and H. pylori virulence genes (cagA, vacA) were evaluated.
Results
A cohort comprised of 61 % women and 39 % men with a median age of 52 (40–60) years. MASLD was observed in 42 %, and H. pylori-positive in 45 %. No differences were observed regarding H. pylori status at co-morbid metabolic conditions. In MASLD cohort, H. pylori-positive was associated with higher AST, ALT, FIB-4 and LSM. Indeed, carriers of cagA/vacA-s1/m1-positive allelic combination were associated with higher AST, ALT, FIB-4 and LSM but not cagA/vacA-s1/m1-negative. The OR for high-risk of significant/advanced- fibrosis by VCTE (≥8 kPa) with H. pylori-positive was 2.56 (95 % CI, 1.2–5.75) and for cagA/vacA-s1/-m1-positive allelic carriers was 4.01 (95 % CI, 1.38–11.56), but non-significant association in cagA/vacA-s1/-m1-negative. After adjusting for age, gender, diabetes, BMI and hypertension the OR for VCTE ≥8 kPa with H. pylori-positive was 2.43 (95 % CI, 1.88–12.44), and cagA/vacA-s1/m1-positive allelic carriers was 4.06 (95 % CI, 1.22–14.49).
Conclusions
In our cohort of functional dyspepsia (FD) patients with MASLD, H. pylori was associated with non-invasive markers of liver injury and fibrosis. Carriers of cagA/vacA-s1/m1-positive allelic combination showed an independent risk of significant/advanced fibrosis by VCTE.
{"title":"Helicobacter pylori cagA/vacAs1-m1 strain is associated with high risk of fibrosis in metabolic-dysfunction-associated steatotic liver disease","authors":"Facundo Maiorana , Magali Neschuk , María Virginia Caronia , Karina Elizondo , Adolfo Schneider , Georgina Veron , Pedro D Zapata , Fernando Javier Barreyro","doi":"10.1016/j.aohep.2024.101541","DOIUrl":"10.1016/j.aohep.2024.101541","url":null,"abstract":"<div><h3>Introduction and Objectives</h3><p>Recent studies have suggested an association between <em>H. pylori</em> and metabolic dysfunction associated steatotic liver disease (MASLD). We aim to evaluate the association of <em>H. pylori</em> virulence genes with non-invasive markers of liver injury and fibrosis in MASLD subjects.</p></div><div><h3>Patients and Methods</h3><p>A total of 362 dyspeptic patients who underwent gastroscopy were selected. Biochemical, clinical parameters, ultrasound, FIB-4 score, liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE), gastric biopsies, and <em>H. pylori</em> virulence genes (cagA, vacA) were evaluated.</p></div><div><h3>Results</h3><p>A cohort comprised of 61 % women and 39 % men with a median age of 52 (40–60) years. MASLD was observed in 42 %, and <em>H. pylori</em>-positive in 45 %. No differences were observed regarding <em>H. pylori</em> status at co-morbid metabolic conditions. In MASLD cohort, <em>H. pylori</em>-positive was associated with higher AST, ALT, FIB-4 and LSM. Indeed, carriers of cagA/vacA-s1/m1-positive allelic combination were associated with higher AST, ALT, FIB-4 and LSM but not cagA/vacA-s1/m1-negative. The OR for high-risk of significant/advanced- fibrosis by VCTE (≥8 kPa) with <em>H. pylori</em>-positive was 2.56 (95 % CI, 1.2–5.75) and for cagA/vacA-s1/-m1-positive allelic carriers was 4.01 (95 % CI, 1.38–11.56), but non-significant association in cagA/vacA-s1/-m1-negative. After adjusting for age, gender, diabetes, BMI and hypertension the OR for VCTE ≥8 kPa with <em>H. pylori</em>-positive was 2.43 (95 % CI, 1.88–12.44), and cagA/vacA-s1/m1-positive allelic carriers was 4.06 (95 % CI, 1.22–14.49).</p></div><div><h3>Conclusions</h3><p>In our cohort of functional dyspepsia (FD) patients with MASLD, <em>H. pylori</em> was associated with non-invasive markers of liver injury and fibrosis. Carriers of cagA/vacA-s1/m1-positive allelic combination showed an independent risk of significant/advanced fibrosis by VCTE.</p></div>","PeriodicalId":7979,"journal":{"name":"Annals of hepatology","volume":"29 6","pages":"Article 101541"},"PeriodicalIF":3.7,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1665268124003351/pdfft?md5=04c9bcbd2115e0c3d900a09fc780b896&pid=1-s2.0-S1665268124003351-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-22DOI: 10.1016/j.aohep.2024.101539
Maria Stella Franzè , Paul Vigneron , Anna Sessa , Carlo Saitta , Julia Chalaye , Vania Tacher , Alain Luciani , Hélène Regnault , Ancuta Bejan , Rami Rhaiem , Daniele Sommacale , Vincent Leroy , Raffaele Brustia , Giovanni Raimondo , Giuliana Amaddeo
Selective internal radiation therapy (SIRT) has emerged as a viable endovascular treatment strategy for hepatocellular carcinoma (HCC). According to the Barcelona Clinic Liver Cancer (BCLC) classification, SIRT is currently recommended for early- and intermediate-stage HCC that is unsuitable for alternative locoregional therapies. Additionally, SIRT remains a recommended treatment for patients with advanced-stage HCC and portal vein thrombosis (PVT) without extrahepatic metastasis. Several studies have shown that SIRT is a versatile and promising treatment with a wide range of applications. Consequently, given its favourable characteristics in various scenarios, SIRT could be an encouraging treatment option for patients with HCC across different BCLC stages. Over the past decade, an increasing number of studies have focused on better understanding the prognostic factors associated with SIRT to identify patients who derive the most benefit from this treatment or to refine the optimal technical procedures of SIRT. Several variables can influence treatment decisions, with a growing emphasis on a personalised approach. This review, based on the literature, will focus on the prognostic factors associated with the effectiveness of radioembolization and related complications. By comprehensively analysing these factors, we aimed to provide a clearer understanding of how to optimise the use of SIRT in managing HCC patients, thereby enhancing outcomes across various clinical scenarios.
{"title":"Prognostic factors influencing outcomes in hepatocellular carcinoma patients undergoing selective internal radiation therapy","authors":"Maria Stella Franzè , Paul Vigneron , Anna Sessa , Carlo Saitta , Julia Chalaye , Vania Tacher , Alain Luciani , Hélène Regnault , Ancuta Bejan , Rami Rhaiem , Daniele Sommacale , Vincent Leroy , Raffaele Brustia , Giovanni Raimondo , Giuliana Amaddeo","doi":"10.1016/j.aohep.2024.101539","DOIUrl":"10.1016/j.aohep.2024.101539","url":null,"abstract":"<div><p>Selective internal radiation therapy (SIRT) has emerged as a viable endovascular treatment strategy for hepatocellular carcinoma (HCC). According to the Barcelona Clinic Liver Cancer (BCLC) classification, SIRT is currently recommended for early- and intermediate-stage HCC that is unsuitable for alternative locoregional therapies. Additionally, SIRT remains a recommended treatment for patients with advanced-stage HCC and portal vein thrombosis (PVT) without extrahepatic metastasis. Several studies have shown that SIRT is a versatile and promising treatment with a wide range of applications. Consequently, given its favourable characteristics in various scenarios, SIRT could be an encouraging treatment option for patients with HCC across different BCLC stages. Over the past decade, an increasing number of studies have focused on better understanding the prognostic factors associated with SIRT to identify patients who derive the most benefit from this treatment or to refine the optimal technical procedures of SIRT. Several variables can influence treatment decisions, with a growing emphasis on a personalised approach. This review, based on the literature, will focus on the prognostic factors associated with the effectiveness of radioembolization and related complications. By comprehensively analysing these factors, we aimed to provide a clearer understanding of how to optimise the use of SIRT in managing HCC patients, thereby enhancing outcomes across various clinical scenarios.</p></div>","PeriodicalId":7979,"journal":{"name":"Annals of hepatology","volume":"30 1","pages":"Article 101539"},"PeriodicalIF":3.7,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1665268124003338/pdfft?md5=69a179c75b056d162814acdfcaaddbc1&pid=1-s2.0-S1665268124003338-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-15DOI: 10.1016/j.aohep.2024.101540
Yuan Xu , Bei Zhang , Fan Zhou , Ying-ping Yi , Xin-Lei Yang , Xiao Ouyang , Hui Hu
Introduction and Objectives
The increasing incidence of hepatocellular carcinoma (HCC) in China is an urgent issue, necessitating early diagnosis and treatment. This study aimed to develop personalized predictive models by combining machine learning (ML) technology with a demographic, medical history, and noninvasive biomarker data. These models can enhance the decision-making capabilities of physicians for HCC in hepatitis B virus (HBV)-related cirrhosis patients with low serum alpha-fetoprotein (AFP) levels.
Patients and Methods
A total of 6,980 patients treated between January 2012 and December 2018 were included. Pre-treatment laboratory tests and clinical data were obtained. The significant risk factors for HCC were identified, and the relative risk of each variable affecting its diagnosis was calculated using ML and univariate regression analysis. The data set was then randomly partitioned into validation (20 %) and training sets (80 %) to develop the ML models.
Results
Twelve independent risk factors for HCC were identified using Gaussian naïve Bayes, extreme gradient boosting (XGBoost), random forest, and least absolute shrinkage and selection operation regression models. Multivariate analysis revealed that male sex, age >60 years, alkaline phosphate >150 U/L, AFP >25 ng/mL, carcinoembryonic antigen >5 ng/mL, and fibrinogen >4 g/L were the risk factors, whereas hypertension, calcium <2.25 mmol/L, potassium ≤3.5 mmol/L, direct bilirubin >6.8 μmol/L, hemoglobin <110 g/L, and glutamic-pyruvic transaminase >40 U/L were the protective factors in HCC patients. Based on these factors, a nomogram was constructed, showing an area under the curve (AUC) of 0.746 (sensitivity = 0.710, specificity=0.646), which was significantly higher than AFP AUC of 0.658 (sensitivity = 0.462, specificity=0.766). Compared with several ML algorithms, the XGBoost model had an AUC of 0.832 (sensitivity = 0.745, specificity=0.766) and an independent validation AUC of 0.829 (sensitivity = 0.766, specificity = 0.737), making it the top-performing model in both sets. The external validation results have proven the accuracy of the XGBoost model.
Conclusions
The proposed XGBoost demonstrated a promising ability for individualized prediction of HCC in HBV-related cirrhosis patients with low-level AFP.
{"title":"Development of machine learning-based personalized predictive models for risk evaluation of hepatocellular carcinoma in hepatitis B virus-related cirrhosis patients with low levels of serum alpha-fetoprotein","authors":"Yuan Xu , Bei Zhang , Fan Zhou , Ying-ping Yi , Xin-Lei Yang , Xiao Ouyang , Hui Hu","doi":"10.1016/j.aohep.2024.101540","DOIUrl":"10.1016/j.aohep.2024.101540","url":null,"abstract":"<div><h3>Introduction and Objectives</h3><p>The increasing incidence of hepatocellular carcinoma (HCC) in China is an urgent issue, necessitating early diagnosis and treatment. This study aimed to develop personalized predictive models by combining machine learning (ML) technology with a demographic, medical history, and noninvasive biomarker data. These models can enhance the decision-making capabilities of physicians for HCC in hepatitis B virus (HBV)-related cirrhosis patients with low serum alpha-fetoprotein (AFP) levels.</p></div><div><h3>Patients and Methods</h3><p>A total of 6,980 patients treated between January 2012 and December 2018 were included. Pre-treatment laboratory tests and clinical data were obtained. The significant risk factors for HCC were identified, and the relative risk of each variable affecting its diagnosis was calculated using ML and univariate regression analysis. The data set was then randomly partitioned into validation (20 %) and training sets (80 %) to develop the ML models.</p></div><div><h3>Results</h3><p>Twelve independent risk factors for HCC were identified using Gaussian naïve Bayes, extreme gradient boosting (XGBoost), random forest, and least absolute shrinkage and selection operation regression models. Multivariate analysis revealed that male sex, age >60 years, alkaline phosphate >150 U/L, AFP >25 ng/mL, carcinoembryonic antigen >5 ng/mL, and fibrinogen >4 g/L were the risk factors, whereas hypertension, calcium <2.25 mmol/L, potassium ≤3.5 mmol/L, direct bilirubin >6.8 μmol/L, hemoglobin <110 g/L, and glutamic-pyruvic transaminase >40 U/L were the protective factors in HCC patients. Based on these factors, a nomogram was constructed, showing an area under the curve (AUC) of 0.746 (sensitivity = 0.710, specificity=0.646), which was significantly higher than AFP AUC of 0.658 (sensitivity = 0.462, specificity=0.766). Compared with several ML algorithms, the XGBoost model had an AUC of 0.832 (sensitivity = 0.745, specificity=0.766) and an independent validation AUC of 0.829 (sensitivity = 0.766, specificity = 0.737), making it the top-performing model in both sets. The external validation results have proven the accuracy of the XGBoost model.</p></div><div><h3>Conclusions</h3><p>The proposed XGBoost demonstrated a promising ability for individualized prediction of HCC in HBV-related cirrhosis patients with low-level AFP.</p></div>","PeriodicalId":7979,"journal":{"name":"Annals of hepatology","volume":"29 6","pages":"Article 101540"},"PeriodicalIF":3.7,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S166526812400334X/pdfft?md5=82d35e2d0a0e066c7691927642b98ea4&pid=1-s2.0-S166526812400334X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hepatocellular carcinoma (HCC) is one of the deadliest cancers. For patients with advanced HCC, liver function decompensation often occurs, which leads to poor tolerance to chemotherapies and other aggressive treatments. Therefore, it remains critical to develop effective therapeutic strategies for HCC. Etiological factors for HCC are complex and multifaceted, including hepatitis virus infection, alcohol, drug abuse, chronic metabolic abnormalities, and others. Thus, HCC has been categorized as a “genomically unstable” cancer due to the typical manifestation of chromosome breakage and aneuploidy, and oxidative DNA damage. In recent years, immunotherapy has provided a new option for cancer treatments, and the degree of genomic instability positively correlates with immunotherapy efficacies. This article reviews the endogenous and exogenous causes that affect the genomic stability of liver cells; it also updates the current biomarkers and their detection methods for genomic instabilities and relevant applications in cancer immunotherapies. Including genomic instability biomarkers in consideration of cancer treatment options shall increase the patients’ well-being.
肝细胞癌(HCC)是最致命的癌症之一。晚期肝细胞癌患者通常会出现肝功能失代偿,导致对化疗和其他积极治疗的耐受性差。因此,开发有效的 HCC 治疗策略仍然至关重要。HCC 的致病因素复杂多样,包括肝炎病毒感染、酒精、药物滥用、慢性代谢异常等。因此,HCC 被归类为 "基因组不稳定 "癌症,其典型表现为染色体断裂和非整倍体,以及 DNA 氧化损伤。近年来,免疫疗法为癌症治疗提供了新的选择,而基因组不稳定的程度与免疫疗法的疗效呈正相关。本文回顾了影响肝细胞基因组稳定性的内源性和外源性原因,并更新了目前基因组不稳定的生物标记物及其检测方法以及在癌症免疫疗法中的相关应用。将基因组不稳定性生物标志物纳入癌症治疗方案的考虑范围,将增加患者的福祉。
{"title":"Genomic instabilities in hepatocellular carcinoma: biomarkers and application in immunotherapies","authors":"Jui-Hsiang Hung , Chiao-Feng Teng , Hsu-chin Hung , Yi-Lin Chen , Pin-Jun Chen , Chung-Liang Ho , Cheng-Hsiang Chuang , Wenya Huang","doi":"10.1016/j.aohep.2024.101546","DOIUrl":"10.1016/j.aohep.2024.101546","url":null,"abstract":"<div><p>Hepatocellular carcinoma (HCC) is one of the deadliest cancers. For patients with advanced HCC, liver function decompensation often occurs, which leads to poor tolerance to chemotherapies and other aggressive treatments. Therefore, it remains critical to develop effective therapeutic strategies for HCC. Etiological factors for HCC are complex and multifaceted, including hepatitis virus infection, alcohol, drug abuse, chronic metabolic abnormalities, and others. Thus, HCC has been categorized as a “genomically unstable” cancer due to the typical manifestation of chromosome breakage and aneuploidy, and oxidative DNA damage. In recent years, immunotherapy has provided a new option for cancer treatments, and the degree of genomic instability positively correlates with immunotherapy efficacies. This article reviews the endogenous and exogenous causes that affect the genomic stability of liver cells; it also updates the current biomarkers and their detection methods for genomic instabilities and relevant applications in cancer immunotherapies. Including genomic instability biomarkers in consideration of cancer treatment options shall increase the patients’ well-being.</p></div>","PeriodicalId":7979,"journal":{"name":"Annals of hepatology","volume":"29 6","pages":"Article 101546"},"PeriodicalIF":3.7,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1665268124003405/pdfft?md5=743982fdcb7f7d0d5fb3cc57442ec238&pid=1-s2.0-S1665268124003405-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-14DOI: 10.1016/j.aohep.2024.101536
Kai Yang , Yanpeng Ding , Jun Han , Rui He
Introduction and Objectives
Radioresistance is a common problem in the treatment of many cancers, including hepatocellular carcinoma (HCC). Previous studies have shown that circROBO1 is highly expressed in HCC tissues and acts as a cancer promoter to accelerate the malignant progression of HCC. However, the role and mechanism of circROBO1 in HCC radioresistance remain unclear.
Materials and Methods
CircROBO1, microRNA (miR)-136-5p and RAD21 expression levels were analyzed by quantitative real-time PCR. Cell function and radioresistance were evaluated by colony formation assay, cell counting kit 8 assay, EdU assay and flow cytometry. Protein expression was determined using western blot analysis. RNA interaction was analyzed by dual-luciferase reporter assay and RNA pull-down assay. In vivo experiments were performed by constructing mice xenograft models.
Results
CircROBO1 was highly expressed in HCC, and its knockdown inhibited HCC cell proliferation and promoted apoptosis to enhance cell radiosensitivity. On the mechanism, circROBO1 could serve as miR-136-5p sponge to positively regulate RAD21. MiR-136-5p inhibitor or RAD21 overexpression reversed the regulation of circROBO1 knockdown on the radiosensitivity of HCC cells. Also, circROBO1 interference improved the radiosensitivity of HCC tumors in vivo.
Conclusions
CircROBO1 might be a promising target for treating HCC radioresistance.
{"title":"CircROBO1 knockdown improves the radiosensitivity of hepatocellular carcinoma by regulating RAD21","authors":"Kai Yang , Yanpeng Ding , Jun Han , Rui He","doi":"10.1016/j.aohep.2024.101536","DOIUrl":"10.1016/j.aohep.2024.101536","url":null,"abstract":"<div><h3>Introduction and Objectives</h3><div>Radioresistance is a common problem in the treatment of many cancers, including hepatocellular carcinoma (HCC). Previous studies have shown that circROBO1 is highly expressed in HCC tissues and acts as a cancer promoter to accelerate the malignant progression of HCC. However, the role and mechanism of circROBO1 in HCC radioresistance remain unclear.</div></div><div><h3>Materials and Methods</h3><div>CircROBO1, microRNA (miR)-136-5p and RAD21 expression levels were analyzed by quantitative real-time PCR. Cell function and radioresistance were evaluated by colony formation assay, cell counting kit 8 assay, EdU assay and flow cytometry. Protein expression was determined using western blot analysis. RNA interaction was analyzed by dual-luciferase reporter assay and RNA pull-down assay. In vivo experiments were performed by constructing mice xenograft models.</div></div><div><h3>Results</h3><div>CircROBO1 was highly expressed in HCC, and its knockdown inhibited HCC cell proliferation and promoted apoptosis to enhance cell radiosensitivity. On the mechanism, circROBO1 could serve as miR-136-5p sponge to positively regulate RAD21. MiR-136-5p inhibitor or RAD21 overexpression reversed the regulation of circROBO1 knockdown on the radiosensitivity of HCC cells. Also, circROBO1 interference improved the radiosensitivity of HCC tumors in vivo.</div></div><div><h3>Conclusions</h3><div>CircROBO1 might be a promising target for treating HCC radioresistance.</div></div>","PeriodicalId":7979,"journal":{"name":"Annals of hepatology","volume":"29 6","pages":"Article 101536"},"PeriodicalIF":3.7,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-13DOI: 10.1016/j.aohep.2024.101538
Junnv Xu , Kun Liu , Zhixun Gong , Jinchen Liu , Haifeng Lin , Bo Lin , Wei Li , Mingyue Zhu , Mengsen Li
Introduction and Objectives
Prostate apoptosis response protein-4 (PAR-4) is considered a tumor suppressor. However, the role of PAR-4 in hepatocellular carcinoma (HCC) has rarely been reported. The study explores the role of PAR-4 in the malignant behaviors of HCC cells.
Materials and Methods
TCGA database was applied to analyze the expression of PAR-4 in HCC. Evaluated PAR-4 relationship with clinical parameters and prognosis by tissue microarray; expression of STAT3, p-STAT3, Src and Ras was detected by Western blotting or laser confocal microscopy. Cell scratch and flow cytometry assays were used to observe IL-6 regulation of the malignant behaviors of HCC cells. The tumorigenic potential of HCC cells in vivo was evaluated in a nude mouse tumor model.
Results
Analysis indicated that the expression of PAR-4 in HCC tissues was significantly higher than that in normal liver tissues; and PAR-4 interacted with STAT3. KEGG analysis showed that PAR-4 plays a role in the Janus kinase (JAK)/STAT signaling pathway. The positive expression rate of PAR-4 in HCC tissues was significantly higher than that in adjacent tissues. Positive correlation between IL-6 and PAR-4 expression in the HCC tissues. Exogenous IL-6 significantly promoted the proliferation and migration of HCC cells and up-regulated the expression of PAR-4 and p-STAT3 in HCC cells. Interference of the expression of PAR-4 could reduce the malignant behaviors of HCC cells and inhibit tumorigenesis in a nude mouse tumor model.
Conclusions
PAR-4 expression is positively correlated with HCC; PAR-4 promotes malignant behavior of HCC cells mediated by the IL-6/STAT3 signaling pathway.
{"title":"IL-6/STAT3 signaling pathway induces prostate apoptosis response protein-4(PAR-4) to stimulate malignant behaviors of hepatocellular carcinoma cells","authors":"Junnv Xu , Kun Liu , Zhixun Gong , Jinchen Liu , Haifeng Lin , Bo Lin , Wei Li , Mingyue Zhu , Mengsen Li","doi":"10.1016/j.aohep.2024.101538","DOIUrl":"10.1016/j.aohep.2024.101538","url":null,"abstract":"<div><h3>Introduction and Objectives</h3><p>Prostate apoptosis response protein-4 (PAR-4) is considered a tumor suppressor. However, the role of PAR-4 in hepatocellular carcinoma (HCC) has rarely been reported. The study explores the role of PAR-4 in the malignant behaviors of HCC cells.</p></div><div><h3>Materials and Methods</h3><p>TCGA database was applied to analyze the expression of PAR-4 in HCC. Evaluated PAR-4 relationship with clinical parameters and prognosis by tissue microarray; expression of STAT3, p-STAT3, Src and Ras was detected by Western blotting or laser confocal microscopy. Cell scratch and flow cytometry assays were used to observe IL-6 regulation of the malignant behaviors of HCC cells. The tumorigenic potential of HCC cells in vivo was evaluated in a nude mouse tumor model.</p></div><div><h3>Results</h3><p>Analysis indicated that the expression of PAR-4 in HCC tissues was significantly higher than that in normal liver tissues; and PAR-4 interacted with STAT3. KEGG analysis showed that PAR-4 plays a role in the Janus kinase (JAK)/STAT signaling pathway. The positive expression rate of PAR-4 in HCC tissues was significantly higher than that in adjacent tissues. Positive correlation between IL-6 and PAR-4 expression in the HCC tissues. Exogenous IL-6 significantly promoted the proliferation and migration of HCC cells and up-regulated the expression of PAR-4 and p-STAT3 in HCC cells. Interference of the expression of PAR-4 could reduce the malignant behaviors of HCC cells and inhibit tumorigenesis in a nude mouse tumor model.</p></div><div><h3>Conclusions</h3><p>PAR-4 expression is positively correlated with HCC; PAR-4 promotes malignant behavior of HCC cells mediated by the IL-6/STAT3 signaling pathway.</p></div>","PeriodicalId":7979,"journal":{"name":"Annals of hepatology","volume":"29 6","pages":"Article 101538"},"PeriodicalIF":3.7,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1665268124003326/pdfft?md5=37afd3d4a443acbf80cb11fd14ebfd92&pid=1-s2.0-S1665268124003326-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chronic hepatitis B virus infection (CHB) remains a global health concern, with currently available antiviral therapies demonstrating limited effectiveness in preventing hepatocellular carcinoma (HCC) development. Two primary challenges in CHB treatment include the persistence of the minichromosome, covalently closed circular DNA (cccDNA) of the hepatitis B virus (HBV), and the failure of the host immune response to eliminate cccDNA. Recent findings indicate several host and HBV proteins involved in the epigenetic regulation of cccDNA, including HBV core protein (HBc) and HBV x protein (HBx). Both proteins might contribute to the stability of the cccDNA minichromosome and interact with viral and host proteins to support transcription. One potential avenue for CHB treatment involves the utilization of therapeutic vaccines. This paper explores HBV antigens suitable for epigenetic manipulation of cccDNA, elucidates their mechanisms of action, and evaluates their potential as key components of epigenetically-driven vaccines for CHB therapy. Molecular targeted agents with therapeutic vaccines offer a promising strategy for addressing CHB by targeting the virus and enhancing the host's immunological response. Despite challenges, the development of these vaccines provides new hope for CHB patients by emphasizing the need for HBV antigens that induce effective immune responses without causing T cell exhaustion.
慢性乙型肝炎病毒感染(CHB)仍然是全球关注的健康问题,目前可用的抗病毒疗法在预防肝细胞癌(HCC)发展方面效果有限。乙型肝炎病毒(HBV)的小染色体、共价闭合环状DNA(cccDNA)的持续存在,以及宿主免疫反应无法消除cccDNA,是乙型肝炎病毒感染治疗面临的两大挑战。最近的研究结果表明,有几种宿主和 HBV 蛋白参与了 cccDNA 的表观遗传调控,其中包括 HBV 核心蛋白(HBc)和 HBV x 蛋白(HBx)。这两种蛋白可能有助于cccDNA小染色体的稳定,并与病毒和宿主蛋白相互作用以支持转录。治疗慢性阻塞性肺病的一个潜在途径是使用治疗性疫苗。本文探讨了适合对cccDNA进行表观遗传操作的HBV抗原,阐明了它们的作用机制,并评估了它们作为表观遗传驱动的CHB治疗疫苗关键成分的潜力。带有治疗性疫苗的分子靶向制剂通过靶向病毒和增强宿主的免疫反应为治疗慢性阻塞性肺病提供了一种前景广阔的策略。尽管存在挑战,但这些疫苗的开发为慢性阻塞性肺病患者带来了新的希望,因为它们强调了对能诱导有效免疫反应而不会导致 T 细胞衰竭的 HBV 抗原的需求。
{"title":"cccDNA epigenetic regulator as target for therapeutical vaccine development against hepatitis B","authors":"Patricia Gita Naully , Marselina Irasonia Tan , Agustiningsih Agustiningsih , Caecilia Sukowati , Ernawati Arifin Giri-Rachman","doi":"10.1016/j.aohep.2024.101533","DOIUrl":"10.1016/j.aohep.2024.101533","url":null,"abstract":"<div><p>Chronic hepatitis B virus infection (CHB) remains a global health concern, with currently available antiviral therapies demonstrating limited effectiveness in preventing hepatocellular carcinoma (HCC) development. Two primary challenges in CHB treatment include the persistence of the minichromosome, covalently closed circular DNA (cccDNA) of the hepatitis B virus (HBV), and the failure of the host immune response to eliminate cccDNA. Recent findings indicate several host and HBV proteins involved in the epigenetic regulation of cccDNA, including HBV core protein (HBc) and HBV x protein (HBx). Both proteins might contribute to the stability of the cccDNA minichromosome and interact with viral and host proteins to support transcription. One potential avenue for CHB treatment involves the utilization of therapeutic vaccines. This paper explores HBV antigens suitable for epigenetic manipulation of cccDNA, elucidates their mechanisms of action, and evaluates their potential as key components of epigenetically-driven vaccines for CHB therapy. Molecular targeted agents with therapeutic vaccines offer a promising strategy for addressing CHB by targeting the virus and enhancing the host's immunological response. Despite challenges, the development of these vaccines provides new hope for CHB patients by emphasizing the need for HBV antigens that induce effective immune responses without causing T cell exhaustion.</p></div>","PeriodicalId":7979,"journal":{"name":"Annals of hepatology","volume":"30 1","pages":"Article 101533"},"PeriodicalIF":3.7,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1665268124003272/pdfft?md5=25de653ac295e8ff5358063ede9c3136&pid=1-s2.0-S1665268124003272-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-13DOI: 10.1016/j.aohep.2024.101535
Mariana M. Ramírez-Mejía , Xingshun Qi , Ludovico Abenavoli , Nahum Méndez-Sánchez
Recent efforts to reclassify non-alcoholic fatty liver disease (NAFLD) as metabolic dysfunction-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) are intended to divert attention to the metabolic basis of the disease rather than to alcohol consumption. This reclassification recognizes the role of obesity, sedentary lifestyles and poor dietary habits in the development of the disease, leading to a better understanding of its etiology. Nevertheless, the transition has posed its own challenges, particularly with regard to communication between patient and healthcare professional. Many healthcare professionals report difficulty in explaining the nuanced concepts, especially the term "steatosis". In addition, the change in terminology has not yet removed the stigma, with ongoing debates about the appropriateness of the terms "fatty" and "steatotic". Surveys suggest that while "obesity" may be perceived as more stigmatizing, the medical term "steatotic liver disease" is not considered as stigmatizing, indicating a disconnect in perceptions between healthcare professionals and patients.
{"title":"The myth of the stigma of fatty liver: What does the evidence show?","authors":"Mariana M. Ramírez-Mejía , Xingshun Qi , Ludovico Abenavoli , Nahum Méndez-Sánchez","doi":"10.1016/j.aohep.2024.101535","DOIUrl":"10.1016/j.aohep.2024.101535","url":null,"abstract":"<div><p>Recent efforts to reclassify non-alcoholic fatty liver disease (NAFLD) as metabolic dysfunction-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) are intended to divert attention to the metabolic basis of the disease rather than to alcohol consumption. This reclassification recognizes the role of obesity, sedentary lifestyles and poor dietary habits in the development of the disease, leading to a better understanding of its etiology. Nevertheless, the transition has posed its own challenges, particularly with regard to communication between patient and healthcare professional. Many healthcare professionals report difficulty in explaining the nuanced concepts, especially the term \"steatosis\". In addition, the change in terminology has not yet removed the stigma, with ongoing debates about the appropriateness of the terms \"fatty\" and \"steatotic\". Surveys suggest that while \"obesity\" may be perceived as more stigmatizing, the medical term \"steatotic liver disease\" is not considered as stigmatizing, indicating a disconnect in perceptions between healthcare professionals and patients.</p></div>","PeriodicalId":7979,"journal":{"name":"Annals of hepatology","volume":"29 6","pages":"Article 101535"},"PeriodicalIF":3.7,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1665268124003296/pdfft?md5=7ee64d135d5dc70959f6131b8c271544&pid=1-s2.0-S1665268124003296-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}