Clinical features of hepatitis B virus-related hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a major cause of cancer death,and chronic hepatitis B is a serious worldwide problem.The epidemiology of HCC is distinctive.Hepatitis B virus (HBV) plays a major role in hepatocarcinogenesis.Prevention of HBV-related HCC is a key issue in current hepatology.This paper describes the prevention and clinical features of HBVrelated HCC,along with a short review of the disease.     

Molecular mechanism of hepatitis B virus X protein function in hepatocarcinogenesis

Many factors are considered to contribute to hepatitis B virus(HBV)-associated hepatocellular carcinoma(HCC),including products of HBV,HBV integration and mutation,and host susceptibility. HBV X protein(HBx) can interfere with several signaling pathways associated with cell proliferation and invasion,and HBx C-terminal truncation has been suggested to impact the development of HCC. This review focuses on the pathological functions of HBx in HBV-induced hepatocarcinogenesis. As a transactivator,HBx can affect regulatory non-coding RNAs(nc RNAs),including micro RNAs and long nc RNAs. HBx is also involved in epigenetic modification and DNA repair. HBx interacts with various signal-transduction pathways,such as the p53,Wnt,and nuclear factor-κB pathways. We conclude that HBx hastens the development of hepatoma.     

原发性肝癌患者血清HBV标志物和HBV DNA测定的临床意义

目的观察原发性肝癌患者血清HBV标志物模式及HBV DNA水平。方法采用化学发光法检测151例PHC、132例慢性乙型肝炎和140例乙型肝炎肝硬化患者血清乙型肝炎病毒标记物;采用聚合酶链反应检测血清HBV DNA水平。结果在151例原发性肝癌患者中,HBV感染率达97.4%（147/151）,HBV DNA阳性率为74.8%（113/151）,平均水平为5.6±1.1 lgcopies/ml;HBsAg（＋）、HBeAb（＋）、HBcAb（＋）90例（59.6%）,其血清HBVDNA检出率为76.7%,平均水平为5.1±0.9lgcopies/ml;HBsAg（＋）、HBeAg（＋）、HBcAb（＋）38例（25.2%）,血清HBVDNA检出率100.0%,平均水平为6.4±0.9 lgcopies/ml。结论 PHC患者HBV感染率高,HBV与PHC发生有十分密切的关系。随着慢性乙型肝炎和乙型肝炎肝硬化病情的进展,血清HBeAg自发性发生血清学转换和HBV DNA载量下降,要警防原发性肝癌的发生。     

Pin1 interacts with a specific serine-proline motif of hepatitis B virus X-protein to enhance hepatocarcinogenesis

BACKGROUND AND AIMS: The peptidyl prolyl isomerase Pin1 frequently is overexpressed in hepatocellular carcinoma (HCC). Hepatitis B virus (HBV) is the most common etiologic agent in HCC, and its encoded X-protein (HBx) is oncogenic and possesses a serine-proline motif that may bind Pin1. The role of Pin1 in hepatocarcinogenesis, particularly in HBV-related HCC, was investigated. METHODS: Immunohistochemical staining was performed to evaluate the prevalence of Pin1 overexpression in HCCs of different etiologies. Glutathione S-transferase pull-down and co-immunoprecipitation experiments were used to validate the physical interaction between Pin1 and HBx. Reporter assay, cell proliferation assay, and xenotransplantation experiments were used to show the functional consequence and importance of Pin1-HBx interaction in hepatocarcinogenesis. RESULTS: We showed preferential Pin1 overexpression in HBV-related tumors and confirmed the interaction between Pin1 and HBx at the specific serine-proline motif. Pin1 overexpression increased the protein stability of HBx. Furthermore, HBx-mediated transactivation was enhanced by co-expression of Pin1. HepG2 expressing Pin1 and HBx showed a synergistic increase in cellular proliferation, as compared with cells expressing Pin1 or HBx alone. Furthermore, concomitant expression of Pin1 and HBx in the nontumorigenic human hepatocyte cell line MIHA led to a synergistic increase in tumor growth. Finally, in Hep3B cells with suppressed Pin1 expression, HBx-enhanced tumor growth in nude mice was abrogated. CONCLUSIONS: Pin1 binds HBx to enhance hepatocarcinogenesis in HBV-infected hepatocytes. The discovery of an interaction between Pin1 and HBx will further our understanding of the molecular pathogenic mechanism of HBV-related HCC in human beings.     

THE ROLE OF HEPATITIS B VIRUS IN THE ETIOLOGY OF HEPATOCELLULAR CARCINOMA IN AUSTRALIA

:Fifty-three patients with Hepatocellular Carcinoma (HCC) from three Sydney teaching hospitals were examined for possible evidence of Hepatitis B virus (HBV) infection. Hepatitis Surface Antigen (HB_sAg) was positive in 38% of those in whom it was sought, a higher incidence than previously reported in an Australian series. A further 13 patients had antibody to Hepatitis B core (Anti-HB_C), but negative HB_sAg, confirming past exposure to HBV. Where serum was available evidence of HBV infection was obtained in 62% of patients. It is argued that the incidence of HBV infection may be shown to be higher still with the advent of new technology as applied to HBV assays and tissue stains. The need to be aware of the growing evidence of a strong association between Hepatitis B virus and the development of HCC is stressed and the clinical implications are discussed. (Aust NZ J Med 1983; 13: 605–607.)     

孕期干预阻断乙肝病毒母婴垂直传播效果评价

目的　探讨孕期干预治疗阻断乙型肝炎病毒母婴垂直传播的效果。方法　将 6 0例 HBs Ag/ HBe Ag阳性孕妇分成治疗组 31例 ,对照组 2 9例。治疗组均在孕 2 6周起开始注射乙肝免疫球蛋白 (HBIG)及外用左旋咪唑涂布剂 ,采用 EL ISA法检测孕妇和新生儿血清 HBs Ag、HBAb、Hbe Ag、HBe Ab、HBc Ab,用 PCR电泳和 RT-PCR法测定 HBV- DNA及全长型和顿挫性转录体。分析母婴之间乙肝病毒分子水平上的关系。结果　新生儿外周血中 HBs Ag阳性者 2例 ,宫内感染率为 6 .4 5 %。对照组 4例 ,宫内感染率 13.7%。与对照组比较差异有显著性。 (P<0 .0 1) ,两组都有超过一半的患儿携带顿挫型病毒转录体。结论　携带 HBV孕妇于孕晚期给 HBIG和左旋咪唑涂布剂联合治疗后 ,可有效降低婴儿 HBs Ag和 HBV- DNA携带率     

Surgical treatment of HCC in a patient with lamivudine-resistant hepatitis B cirrhosis with adefovir dipivoxil

We describe a 77-year-old woman with chronic hepatitis B who became resistant to lamivudine. She was started on adefovir (10 mg daily) while still continuing lamivudine therapy. Four mo later her liver function improved and serum Hepatitis B virus (HBV)-DNA level became undetectable. Three years after the start of additional adefovir treatment, hepatocellular carcinoma (HCC) was detected and the patient underwent a successful hepatectomy. Our findings suggest that the addition of adefovir to ongoing lamivudine therapy cannot completely suppress hepatocarcinogenesis, but is useful for improving liver function in patients with lamivudine-resistant HBV-related cirrhosis, allowing HCC surgery.     

Hepatitis B virus and hepatocellular carcinoma at the miRNA level

AIM: To study Hepatitis B virus (HBV) infection and its association with hepatocellular carcinoma (HCC) at the miRNA level.METHODS: Three cellular models were used to investigate miRNA expression changes during HBV infection: human HepG2 hepatoblastoma cell line as a model without HBV infection;HepG2 cell line transfected with a 1.3-fold full-length HBV genome as an acute infection model;and HepG2.2.15 cell line,which is derived from HepG2 and stably transfected with a complete HBV genome,as a chronic infec...     

Significance of viral status on occurrence of hepatitis B-related hepatocellular carcinoma

Hepatitis B virus (HBV) infection remains a challenging global health problem, with more than 350 million people chronically infected and at risk of developing hepatocellular carcinoma (HCC). Interactions that occur among host, environmental, and viral factors determine the natural course and predict the prognosis of patients with chronic HBV infection. In the past decades, several important viral factors of predictive of HCC have been identified, such as high hepatitis B surface antigen level, seropositivity of hepatitis B e antigen, high viral load, viral genotype, and specific viral sequence mutations. Identification of certain viral risk factors for HCC development and stratification of patient risk are very important to perform future surveillance programs. In this article, we thus reviewed the risk of viral factors involved in hepatocarcinogenesis.     

23株HBeAg阳性慢性乙型肝炎患者病毒的全基因组分析

目的研究HBeAg阳性慢性乙型肝炎患者HBV变异特点。方法PCR扩增并克隆HBeAg阳性慢性乙型肝炎患者血清中HBV全基因组DNA,测序并进行基因结构分析。结果获得23株HBV全基因组DNA,它们均属于c或B基因型。与中国HBVB、C基因型参照序列相比,HBeAg阳性慢性乙型肝炎患者来源的HBV在表面抗原、P蛋白、X蛋白的反式激活区及增强子II／核心启动子区发生了一些有意义的共有变异。结论HBV变异可能与HBeAg阳性慢性乙型肝炎的发生、发展有关。     

HBV/HCV重叠感染的抗病毒治疗

从全球范围看,乙型肝炎病毒(hepatitis B virus,HBV)和丙型肝炎病毒(hepatitis C virus,HCV)重叠感染估计约有700-2000万人口感染.重叠感染和单一HBV或HCV感染比较,更易发展为肝硬化、肝细胞癌甚至肝衰竭的比例也高,HBV和HCV重叠感染可有四种不同的临床模式,即HCV活动...     

How did hepatitis B virus effect the host genome in the last decade?

The principal reason of chronic liver disease, cirrhosis and hepatocellular carcinoma is chronic viral hepatitis all over the world. Hepatitis B virus (HBV) has some mutagenic effects on the host genome. HBV may be exhibiting these mutagenic effects through integrating into the host genome, through its viral proteins or through some epigenetic mechanisms related with HBV proteins. This review aims to summarize the molecular mechanisms used by HBV for effecting host genome determined in the last decade. The focus will be on the effects of integration, HBV proteins, especially HBV X protein and epigenetic mechanisms on the host genome. These interactions between HBV and the host genome also forms the underlying mechanisms of the evolution of hepatocellular carcinoma.     

HBV基因分型的研究进展

乙型肝炎病毒(HBV)感染是一个影响全球的健康问题.HBV有8种基因型,呈地域性分布.研究表明HBV基因型对慢性HBV感染的自然病程、临床结局、抗病毒治疗等具有影响.A基因型与C基因型与严重的肝损害相关;A基因型与B基因型对干扰素的应答率分别较D基因型与C基因型均更高;有研究发现HBV的基因型可能影响HBV的传播途径.然而,目前大多数临床资料来自亚洲及对B、C基因型的相关研究,基于基因型的地域性分布,对HBV基因型的全面认识,还有待进一步的国际化合作.     

Occult Hepatitis B Virus Infection in Hemodialysis Patients: A Concept for Consideration

Hemodialysis patients potentially have an increased risk of infection with parenterally transmitted viral agents due to an impaired host immune response and multiple transfusion requirements. Viral hepatitis is considered as a problem for hemodialysis patients because 1.9% of all deaths among this population are related to the consequence of viral hepatitis. Hepatitis B virus (HBV) is one of the most important causes of transmitted infections by the parenteral route in hemodialysis patients. Occult HBV infection is characterized by presence of HBV infection without detectable hepatitis B surface antigen (HBsAg), which harbors potential risk of HBV transmission through hemodialysis. There are conflicting reports on the prevalence of occult HBV infection (OBI) in hemodialysis patients. Considering the importance of occult HBV infection in hemodialysis patients and the growing evidence on this subject, the purpose of this review is to provide comprehensive information on OBI prevalence in hemodialysis patients and highlight the most important points in this issue.     

乙型肝炎病毒致肝细胞癌发生机制研究进展

肝细胞癌（HCC）的发生与乙型肝炎病毒（HBV）感染密切相关。HBV感染所致的炎症反应、HBV X基因及其产物X蛋白、核心启动子突变、前S2区突变、剪接特异性蛋白等均可能参与HCC的发生发展。     

Interaction of Hepatitis B Virus X Protein with the Pregnane X Receptor Enhances the Synergistic Effects of Aflatoxin B1 and Hepatitis B Virus on Promoting Hepatocarcinogenesis

Background and AimsHepatitis B virus (HBV) infection has been found to increase hepatocellular sensitivity to carcinogenic xenobiotics, by unknown mechanisms, in the generation of hepatocellular carcinoma. The pregnane X receptor (PXR) is a key regulator of the body’s defense against xenobiotics, including xenobiotic carcinogens and clinical drugs. In this study, we aimed to investigate the molecular mechanisms of HBV X protein (HBx)-PXR signaling in the synergistic effects of chemical carcinogens in HBV-associated hepatocarcinogenesis.MethodsThe expression profile of PXR-cytochrome p450 3A4 (CYP3A4) signaling was determined by PCR, western blotting, and tissue microarray. Cell viability and aflatoxin B1 (AFB1) cytotoxicity were measured using the cell counting kit-8 assay. Target gene expression was evaluated using transient transfection and real time-PCR. The genotoxicity of AFB1 was assessed in newborn mice with a single dose of AFB1.ResultsHBx enhanced the hepatotoxicity of AFB1 by activating CYP3A4 and reducing glutathione S-transferase Mu 1 (GSTM1) in cell lines. Activation of PXR by pregnenolone 16α-carbonitrile increased AFB1-induced liver tumor incidence by up-regulating oncogenic KRAS to enhance interleukin (IL)-11:IL-11 receptor subunit alpha-1 (IL11RA-1)-mediated inflammation in an HBx transgenic model.ConclusionsOur finding regarding AFB1 toxicity enhancement by an HBx-PXR-CYP3A4/ GSTM1-KRAS-IL11:IL11RA signaling axis provides a rational explanation for the synergistic effects of chemical carcinogens in HBV infection-associated hepatocarcinogenesis.     

乙型病毒性肝炎的预后研究进展

乙型病毒性肝炎是由乙型肝炎病毒(HBV)引起的、以肝脏炎性病变为主、并可引起多器官损害的一种疾病。我国是HBV高流行区,HBV感染是发生慢性肝炎、肝硬化及肝癌的主要原因。乙型病毒性肝炎已成为严重危害我国人民健康的公共问题。本综述简要描述了慢性HBV感染自然史的五个分期,并详细地归纳总结了乙型病毒性肝炎预后的影响因素,为减缓乙型病毒性肝炎引起的肝功能损伤及减少不良预后的发生提供借鉴。     

Hepatitis B viral load affects prognosis of hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is a complex disease that is dually challenging to treat due to underlying chronic liver disease in addition to the cancer itself.The prognosis of patients with HCC is determined by intrahepatic tumor status and reserved hepatic function.Hepatitis B virus(HBV)is an established major risk factor of HCC development,and HBV viral load is being increasingly recognized as a prognostic factor in the presence of established HCC.High HBV viral load may affect the prognosis of HBV-related HCC patients in several ways.First,it is associated with more frequent recurrence of HBV-related HCC after treatment.Second,it is associated with more occurrence and severity of potentially life-threatening HBV reactivation.Last,it is associated with more worsened liver function,which limits the therapeutic options for HBV-related HCC.HBV,directly or indirectly,can induce hepatocarcinogenesis.In patients with a high HBV DNA level and subsequent active hepatitis,adhesion molecules expressed on the sinusoidal cells are up-regulated and may increase intrahepatic metastasis.HCC progression after treatment can lead to a poor prognosis by reducing number of normal functioning hepatocytes.Thus,high HBV viral load can affect the prognosis of patientswith HCC by frequent recurrence after treatment for HCC and deterioration of hepatic function associated with HCC progression.Recent meta-analysis showed that antiviral treatment reduces HCC recurrence and liver-related mortality after curative therapy of HCC.Given the strong relationship between high HBV DNA load and poor survival outcome of HCC patients due to cancer progression,it is expected that long-term antiviral therapy results in the sustained HBV suppression,control of inflammation,reduction in HCC progression,and eventually in improved overall survival.