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Hepatitis B virus X protein differentially regulates the angiogenesis of Hepatocellular Carcinoma through p53-VEGF axis according to glucose levels 乙型肝炎病毒X蛋白通过p53-VEGF轴对肝细胞癌血管生成的调节随葡萄糖水平而异
IF 3.7 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-08-30 DOI: 10.1016/j.aohep.2024.101543

Introduction and Objectives

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.

引言和目的:在糖尿病(DM)和肿瘤微环境中,血糖会发生剧烈波动。我们之前的研究发现,乙型肝炎病毒 X 蛋白(HBx)可随葡萄糖浓度的不同而对肝癌细胞的转移和凋亡进行不同程度的调控。我们在此旨在探讨 HBx 是否在不同葡萄糖浓度下对肝细胞癌的血管生成起双重作用:我们收集了用两种葡萄糖溶度培养的 HBx 表达细胞的条件培养基,然后将其应用于 EA.hy926 细胞。另外,我们还建立了肝癌细胞和 EA.hy926 细胞的共培养细胞系统。我们用 CCK8、伤口愈合、跨孔迁移和管形成实验分析了 EA.hy926 细胞的血管生成情况。使用 siRNAs 检测 P53-VEGF 轴:结果:肝癌细胞中表达的 HBx 可抑制血管内皮生长因子的分泌,进而抑制 EA.hy926 细胞在高糖条件下的增殖、迁移和管形成,而在低糖条件下则减弱这些作用。此外,HBx 在血管生成中的双重作用需要 p53-VEGF 轴。此外,HBx 主要调节核 p53:这些数据表明,HBx 的双重作用使肝癌细胞能够保持在葡萄糖丰富的环境中,并通过肿瘤血管逃离葡萄糖低的环境,从而促进肝脏肿瘤的整体进展。我们独家揭示了HBx在肝脏肿瘤血管生成中的双重作用,这可能为HBV和DM相关肝细胞癌的发病机制和治疗策略提供新的启示。
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引用次数: 0
Relationship between sarcopenia and metabolic dysfunction-associated steatotic liver disease (MASLD): A systematic review and meta-analysis 肌肉疏松症与代谢功能障碍相关性脂肪性肝病(MASLD)之间的关系:系统回顾与荟萃分析。
IF 3.7 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-08-29 DOI: 10.1016/j.aohep.2024.101544

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.

导言和目标:代谢功能障碍相关性脂肪性肝病(MASLD)前身为非酒精性脂肪肝(NAFLD),是一种常见的慢性疾病。识别代谢功能障碍相关性脂肪肝的风险因素有助于早期干预并减轻疾病负担。以往的研究调查了肌肉疏松症与非酒精性脂肪肝之间的关系。在上一次荟萃分析之后,又发表了几项试验,但结果并不确定。这是一项最新的荟萃分析,旨在评估肌肉疏松症、MASLD和MASLD相关纤维化之间的关联:方法:纳入截至 2022 年 10 月在 PubMed、Web of Science、Scopus 和 Cochrane Library 数据库上发表的相关试验。我们纳入了比较非酒精性脂肪肝和非酒精性脂肪肝患者的骨骼质量指数(SMI)或肌肉疏松症的研究。此外,我们还纳入了对患有和不患有肌肉疏松症的 MASLD 患者的纤维化情况进行比较的研究。使用Review Manager软件以几率比(ORs)和95%置信区间(CIs)对数据进行汇总:结果:共纳入 25 项研究。MASLD的肌少症发病率明显高于对照组(OR,1.25;95% CI,1.08-1.44;P = 0.003)。非酒精性脂肪肝患者与对照组的 SMI 发生率无明显差异(OR,1.02;95% CI,0.91-1.15;P = 0.7)。与无肌肉疏松症的非酒精性脂肪肝患者相比,患有肌肉疏松症的非酒精性脂肪肝患者发生纤维化的几率更高(OR,1.49;95% CI,1.03-2.14;P = 0.03):肌肉疏松症增加了非酒精性脂肪肝的概率,并与非酒精性脂肪肝患者肝纤维化的概率升高有关。然而,SMI对MASLD的发生没有预测价值。
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引用次数: 0
Helicobacter pylori cagA/vacAs1-m1 strain is associated with high risk of fibrosis in metabolic-dysfunction-associated steatotic liver disease 幽门螺杆菌 cagA/vacAs1-m1 株与代谢功能障碍相关性脂肪肝的高纤维化风险有关。
IF 3.7 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-08-29 DOI: 10.1016/j.aohep.2024.101541

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.

引言和目的:最近的研究表明,幽门螺杆菌与代谢功能障碍相关性脂肪性肝病(MASLD)之间存在关联。我们旨在评估幽门螺杆菌毒力基因与MASLD受试者肝损伤和肝纤维化的非侵入性标记物之间的关联:患者和方法:共选取了 362 名接受胃镜检查的消化不良患者。对生化指标、临床参数、超声波、FIB-4评分、振动控制瞬态弹性成像(VCTE)肝脏硬度测量(LSM)、胃活检和幽门螺杆菌毒力基因(cagA、vacA)进行了评估:61%的患者为女性,39%为男性,中位年龄为52(40-60)岁。42%的人患有MASLD,45%的人幽门螺杆菌阳性。在幽门螺杆菌状态和合并代谢性疾病方面没有发现差异。在 MASLD 群体中,幽门螺杆菌阳性与较高的 AST、ALT、FIB-4 和 LSM 相关。事实上,cagA/vacA-s1/m1等位基因组合阳性的携带者与较高的谷草转氨酶、谷丙转氨酶、FIB-4和LSM相关,而cagA/vacA-s1/m1阴性的携带者与较高的谷草转氨酶、谷丙转氨酶、FIB-4和LSM无关。幽门螺杆菌阳性者的 VCTE(≥8kPa)显着/晚期纤维化高风险 OR 为 2.56(95% CI,1.2-5.75),cagA/vacA-s1/-m1 阳性等位基因携带者的 OR 为 4.01(95% CI,1.38-11.56),但与 cagA/vacA-s1/-m1 阴性者无显著相关性。在对年龄、性别、糖尿病、体重指数和高血压进行调整后,幽门螺杆菌阳性者VCTE≥8kPa的OR值为2.43(95% CI,1.88-12.44),cagA/vacA-s1/m1阳性等位基因携带者的OR值为4.06(95% CI,1.22-14.49):在我们的MASLD FD患者队列中,幽门螺杆菌与肝损伤和肝纤维化的非侵入性标志物有关。cagA/vacA-s1/m1等位基因组合阳性携带者在VCTE中显示出明显/晚期肝纤维化的独立风险。
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引用次数: 0
Prognostic factors influencing outcomes in hepatocellular carcinoma patients undergoing selective internal radiation therapy 影响接受选择性内放射治疗的肝细胞癌患者预后的因素。
IF 3.7 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-08-22 DOI: 10.1016/j.aohep.2024.101539

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.

选择性内放射治疗(SIRT)已成为一种可行的肝细胞癌(HCC)血管内治疗策略。根据巴塞罗那肝癌诊所(BCLC)的分类,SIRT 目前被推荐用于不适合采用其他局部疗法的早期和中期 HCC。此外,对于晚期 HCC 和门静脉血栓形成(PVT)但无肝外转移的患者,SIRT 仍是推荐的治疗方法。多项研究表明,SIRT 是一种具有广泛应用前景的多功能治疗方法。因此,鉴于其在各种情况下的有利特性,SIRT 对 BCLC 不同分期的 HCC 患者来说可能是一种令人鼓舞的治疗选择。在过去的十年中,越来越多的研究侧重于更好地了解与 SIRT 相关的预后因素,以确定从这种治疗中获益最多的患者,或完善 SIRT 的最佳技术程序。有几个变量会影响治疗决策,个性化治疗方法日益受到重视。本综述以文献为基础,重点探讨与放射栓塞疗效和相关并发症有关的预后因素。通过全面分析这些因素,我们旨在更清楚地了解如何在管理 HCC 患者时优化 SIRT 的使用,从而提高各种临床情况下的治疗效果。
{"title":"Prognostic factors influencing outcomes in hepatocellular carcinoma patients undergoing selective internal radiation therapy","authors":"","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":null,"pages":null},"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}
引用次数: 0
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 开发基于机器学习的个性化预测模型,用于评估血清甲胎蛋白水平较低的乙肝病毒相关肝硬化患者患肝细胞癌的风险。
IF 3.7 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-08-15 DOI: 10.1016/j.aohep.2024.101540

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.

引言和目的:肝细胞癌(HCC)在中国的发病率不断上升,需要早期诊断和治疗,这是一个紧迫的问题。本研究旨在通过将机器学习(ML)技术与人口统计学、病史和无创生物标志物数据相结合,开发个性化预测模型。这些模型可提高医生对血清甲胎蛋白(AFP)水平较低的乙型肝炎病毒(HBV)相关肝硬化患者的 HCC 的决策能力:共纳入2012年1月至2018年12月期间接受治疗的6980名患者。获得了治疗前的实验室检查和临床数据。确定了HCC的重要风险因素,并使用ML和单变量回归分析计算了每个变量影响其诊断的相对风险。然后将数据集随机分为验证集(20%)和训练集(80%),以建立 ML 模型:结果:利用高斯天真贝叶斯、极梯度提升(XGBoost)、随机森林、最小绝对收缩和选择操作回归模型,确定了12个独立的HCC风险因素。多变量分析显示,男性、年龄大于 60 岁、碱性磷酸酶大于 150 U/L、甲胎蛋白大于 25 ng/mL、癌胚抗原大于 5 ng/mL、纤维蛋白原大于 4 g/L 是 HCC 患者的危险因素,而高血压、血钙 6.8 μmol/L、血红蛋白 40 U/L是 HCC 患者的保护因素。根据这些因素构建的提名图显示曲线下面积(AUC)为 0.746(灵敏度=0.710,特异性=0.646),明显高于 AFP 的 AUC 0.658(灵敏度=0.462,特异性=0.766)。与几种 ML 算法相比,XGBoost 模型的 AUC 为 0.832(灵敏度=0.745,特异度=0.766),独立验证 AUC 为 0.829(灵敏度=0.766,特异度=0.737),是两组模型中表现最好的。外部验证结果证明了 XGBoost 模型的准确性:结论:所提出的 XGBoost 模型在对 AFP 水平较低的 HBV 相关肝硬化患者的 HCC 进行个体化预测方面表现出了良好的能力。
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引用次数: 0
Genomic instabilities in hepatocellular carcinoma: biomarkers and application in immunotherapies 肝细胞癌的基因组不稳定性:生物标记物和在免疫疗法中的应用。
IF 3.7 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-08-14 DOI: 10.1016/j.aohep.2024.101546

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。
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引用次数: 0
CircROBO1 knockdown improves the radiosensitivity of hepatocellular carcinoma by regulating RAD21 CircROBO1基因敲除通过调节RAD21提高肝细胞癌的放射敏感性
IF 3.7 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-08-14 DOI: 10.1016/j.aohep.2024.101536

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.
引言和目的:放射耐药性是包括肝细胞癌(HCC)在内的许多癌症治疗中的常见问题。先前的研究表明,circROBO1 在 HCC 组织中高表达,并作为癌症启动子加速 HCC 的恶性进展。然而,circROBO1在HCC放射抗性中的作用和机制仍不清楚:通过实时定量 PCR 分析 CircROBO1、microRNA (miR)-136-5p 和 RAD21 的表达水平。通过集落形成试验、细胞计数试剂盒 8 试验、EdU 试验和流式细胞术评估细胞功能和放射抗性。蛋白质表达采用 Western 印迹分析法测定。通过双荧光素酶报告实验和 RNA 下拉实验分析 RNA 相互作用。通过构建小鼠异种移植模型进行体内实验:结果:CircROBO1在HCC中高表达,敲除CircROBO1可抑制HCC细胞增殖,促进细胞凋亡,增强细胞的放射敏感性。在机制上,circROBO1可作为miR-136-5p海绵对RAD21进行正向调节。MiR-136-5p抑制剂或RAD21过表达可逆转circROBO1敲除对HCC细胞辐射敏感性的调控。同时,circROBO1干扰也改善了HCC肿瘤在体内的放射敏感性:CircROBO1可能是治疗HCC放射抗性的一个有前景的靶点。
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引用次数: 0
IL-6/STAT3 signaling pathway induces prostate apoptosis response protein-4(PAR-4) to stimulate malignant behaviors of hepatocellular carcinoma cells IL-6/STAT3信号通路诱导前列腺凋亡应答蛋白-4(PAR-4)刺激肝癌细胞的恶性行为
IF 3.7 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-08-13 DOI: 10.1016/j.aohep.2024.101538

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.

引言和目的:前列腺凋亡应答蛋白-4(PAR-4)被认为是一种肿瘤抑制因子。然而,PAR-4在肝细胞癌(HCC)中的作用却鲜有报道。本研究探讨了 PAR-4 在 HCC 细胞恶性行为中的作用:应用TCGA数据库分析PAR-4在HCC中的表达。通过组织芯片评估 PAR-4 与临床参数和预后的关系;通过 Western 印迹或激光共聚焦显微镜检测 STAT3、p-STAT3、Src 和 Ras 的表达。通过细胞划痕和流式细胞术观察IL-6对HCC细胞恶性行为的调控。在裸鼠肿瘤模型中评估了HCC细胞的体内致瘤潜能:结果:分析表明,PAR-4在HCC组织中的表达明显高于正常肝组织;PAR-4与STAT3相互作用。KEGG分析显示,PAR-4在Janus激酶(JAK)/STAT信号通路中发挥作用。PAR-4在HCC组织中的阳性表达率明显高于邻近组织。IL-6和PAR-4在HCC组织中的表达呈正相关。外源性IL-6能明显促进HCC细胞的增殖和迁移,并上调HCC细胞中PAR-4和p-STAT3的表达。在裸鼠肿瘤模型中,干扰 PAR-4 的表达可减少 HCC 细胞的恶性行为并抑制肿瘤发生:结论:PAR-4的表达与HCC呈正相关;PAR-4通过IL-6/STAT3信号通路促进HCC细胞的恶性行为。
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引用次数: 0
cccDNA epigenetic regulator as target for therapeutical vaccine development against hepatitis B cccDNA表观遗传调节因子是开发乙型肝炎治疗疫苗的靶标。
IF 3.7 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-08-13 DOI: 10.1016/j.aohep.2024.101533

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。
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引用次数: 0
The myth of the stigma of fatty liver: What does the evidence show? 脂肪肝耻辱的神话:证据显示了什么?
IF 3.7 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-08-13 DOI: 10.1016/j.aohep.2024.101535

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.

最近,非酒精性脂肪肝(NAFLD)被重新分类为代谢功能障碍相关性脂肪肝(MAFLD)和代谢功能障碍相关性脂肪肝(MASLD),目的是将人们的注意力转移到该疾病的代谢基础上,而不是酒精消费上。这一重新分类承认了肥胖、久坐不动的生活方式和不良饮食习惯在疾病发生中的作用,从而使人们对其病因有了更好的了解。然而,这一转变也带来了挑战,尤其是在患者与医护人员的沟通方面。许多医护人员表示很难解释其中的微妙概念,尤其是 "脂肪变性 "一词。此外,术语的变化尚未消除耻辱感,关于 "脂肪 "和 "脂肪变性 "这两个术语是否恰当的争论仍在继续。调查显示,虽然 "肥胖 "可能被认为更具有污名化,但医学术语 "脂肪肝 "却不被认为具有污名化,这表明医护人员和患者之间的认知存在脱节。
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引用次数: 0
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Annals of hepatology
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