乙肝病毒X蛋白在肝癌转移中的作用

乙肝病毒X蛋白(HBx)是乙肝病毒感染相关性肝癌的重要致病因子,与原发性肝细胞癌(HCC)的发生与发展密切相关.研究表明,HBx也参与血管生成、HGW/c-met信号通路、基质金属蛋白酶(MMP)等相关因素而促进肝癌转移.加强HBx参与肝癌侵袭转移分子机制的研究,有助于完善HCC侵袭转移机制,以进一步提高肝癌的疗效.     

Hedgehog信号通路相关蛋白Gli1在乳腺癌中的表达及其意义

目的 探讨Hedgehog信号通路转录因子Gli1在乳腺癌组织中的表达及其临床意义。方法 应用免疫组织化学染色检测Hedgehog信号通路相关蛋白Gli1在102例乳腺浸润性导管癌及30例癌旁正常组织中的表达,并分析其表达与临床病理特征的关系。结果 Gli1蛋白在乳腺癌组织中的阳性表达率为75.5％（77／102）,高于癌旁正常组织的26.7％（8／30）,两者差异有统计学意义（P＜0.05）。Gli1蛋白的表达与腋窝淋巴结转移、雌激素受体（ER）表达有关（P＜0.05）,而与患者的年龄、绝经状况、肿瘤直径、病理分期、组织学分级、孕激素受体（PR）及人表皮生长因子受体-2（HER-2）表达状况均无关（P＞0.05）。结论 Hedgehog信号通路相关蛋白Gli1在乳腺癌组织中存在高表达,其一定程度上对ER表达起到负向调节作用。     

The Biological Function of Hepatitis B Virus X Protein in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the major malignant tumors that lead to death. Chronic hepatitis B virus infection is an important risk factor for HCC initiation. HBx protein, encoded by the HBV X gene, is a significant factor that promotes HBV-related HCC, although the exact molecular mechanism remains unclear. This article summarizes the pathological roles and related mechanisms of HBx in HCC. HBx plays a carcinogenic role by promoting cell proliferation, metastasis, and angiogenesis and inhibiting apoptosis in HCC. A detailed study of the biological functions of HBx will help to elucidate the mechanism of hepatocarcinogenesis and lead to the development of novel therapeutic targets for the treatment of HBV-related HCC.     

Gli1蛋白在乳腺癌组织中的表达及其与血管生成的关系

目的研究Hedgehog/Gli1信号通路中Gli1蛋白在人乳腺癌组织中的表达,初步探讨Gli1与乳腺癌血管生成的关系。方法  采用免疫组织化学SP法测定79例乳腺癌标本、68例癌旁组织及42例乳腺纤维腺瘤组织中Gli1蛋白的表达;同时用CD34单克隆抗体标记乳腺癌组织中新生血管,计算肿瘤MVD并分析Gli1蛋白的表达与MVD的关系。结果  乳腺癌组织中Gli1阳性率显著高于乳腺纤维腺瘤和癌旁正常组织;Gli1在Ⅲ期乳腺癌中的阳性表达率要高于Ⅰ～Ⅱ期乳腺癌(P<0.05)。Gli1在有腋窝淋巴结转移组中的阳性表达率高于无淋巴结转移组(P<0.05);相关性分析显示乳腺癌组织中Gli1与MVD表达呈正相关(r=0.325,P<0.05)。结论 Gli1蛋白在乳腺癌中活化,并参与了乳腺癌的发生发展,促进新生血管的生成是其可能的机制之一。     

乙肝病毒X蛋白对肝细胞生物钟基因的影响及其意义

Objective:The aim of this study was to investigate the influence of hepatitis B virus X protein (HBx) on the clock genes in LO2 cells and its significance.Methods:A cell line LO2-HBx,Stably transfected with HBx gene,was established.The levels of mRNA and protein expression of CLOCK and BMAL1 were detected by real-time PCR and western blot.Results:The expression of CLOCK mRNA and protein were increased in cell line LO2-HBx (P<0.05),while the expression of BMAL1 mRNA and protein were decreased in cell line LO...     

Gli1蛋白及E-cadherin蛋白在宫颈癌中的表达及临床意义

目的:探讨Gli1蛋白及E-cadherin蛋白在宫颈癌中的表达及临床意义.方法:应用免疫组化SP法检测50例宫颈癌组织、30例宫颈上皮内瘤变(CIN)组织、40例正常组织中Gli1蛋白及E-cadherin蛋白的表达.结果:Gli1蛋白在宫颈癌组织中明显高于正常宫颈组织(P＜0.05),E-cadherin蛋白在宫颈癌组织中明显低于正常宫颈组织(P＜0.05).结论:Gli1蛋白的高表达及E-cadherin蛋白的低表达与宫颈癌的病理分级、临床分期、淋巴转移等密切相关,且两者在宫颈癌的表达呈负相关.     

Adenovirus vector-mediated Gli1 siRNA induces growth inhibition and apoptosis in human pancreatic cancer with Smo-dependent or Smo-independent Hh pathway activation in vitro and in vivo

Activation of Hedgehog (Hh) signaling pathway is a core molecular mechanism in pancreatic carcinogenesis. However, the inhibition of upstream Hh signals does not inhibit the growth of a subset of pancreatic cancer (PC). This study was to examine the effect of siRNA targeting Gli1, the downstream component of Hh pathway, on PC cells and to provide some insight into the underlying mechanisms. A Gli1siRNA-expressing adenovirus (Ad-U6-Gli1siRNA) was constructed, and its effect on PC cells was investigated in vitro and in vivo. Gli1 was expressed in 83.3% (20/24) PC tissues, whereas no expression was found in normal pancreatic ductal epithelium. Gli1 was expressed in SW1990 and CFPAC cells in which Smo was completely absent, as well as in PaTu8988, Panc-1 and BxPC-3 cells in which Smo was concomitantly present. Ad-U6-Gli1siRNA induced cell growth inhibition, strong G0/G1 cell cycle arrest and apoptosis in all five human PC cell lines. Meanwhile, Ad-U6-Gli1siRNA significantly suppressed the expression of Gli1, Ptch1 and two target genes, Cyclin D2 and Bcl-2, in all five lines. Furthermore, two tumor xenograft nude mice models were established by subcutaneously injecting Smo-positive Panc-1 cells or Smo-negative SW1990 cells. The in vivo experimental results demonstrated that Ad-U6-Gli1siRNA inhibited the growth of both Panc1-derived and SW1990-derived tumors and induced cell apoptosis. Our study indicates that Gli1-targeting siRNA could induce growth inhibition and apoptosis in PC through knockdown of Gli1 and its target genes; and this method may represent a more effective therapeutic strategy for PC with Smo-dependent or Smo-independent Hh pathway activation.     

Incidence of Hepatocellular Carcinoma in Children in Khon Kaen before and after National Hepatitis B Vaccine Pogram

Background: Hepatitis B virus infection is one of the most important risk factors for hepatocellular carcinoma.Hepatitis B vaccination has been obligatory in the Expanded Program on Immunization (EPI) in Khon Kaensince 1990. Objective: To compare the incidence of hepatocellular carcinoma in children in Khon Kaen provincebefore and after the introduction of national hepatitis B vaccination program. Methods: Cases of liver tumors inchildren under 18, diagnosed during 1985-2007, were retrieved from the population-based cancer registry ofKhon Kaen. Patients were divided into 2 groups, vaccinated and non-vaccinated with hepatitis B vaccine regardingthe year of birth before or after 1990. Patients with diagnosis of liver cancer from any basis of diagnosis inpopulation-based registration, except hepatoblastoma, were included. Patients without verified histology wereassumed as having hepatocellular carcinoma if the age at diagnosis was over 10. Age-standardized incidencerates (ASRs) were analyzed and expressed as numbers per 1,000,000 population. Results: Fifteen patients aged13 to 18 years were included to this study. The mean and median ages at diagnosis were 15.7 and 15 yearsrespectively. Four children had a verified histology (age 14 to 18 years, median and mean = 16). The remaining11 patients were diagnosed based on history & physical examination, radiology and death certificate, at theaged of 13 to 18 years. The ASRs for liver cancer in children over 10 years of age of non-vaccinated and vaccinatedchildren were 0.88 and 0.07 per million respectively (p = 0.039). When calculated by including children at orolder the 5 years of age, the ASRs for non-vaccinated and vaccinated cases were 0.97 and 0.24 per millionrespectively (p = 0.007). Conclusions: The incidence of hepatocellular carcinoma is significantly lower in Thaichildren who receive hepatitis B vaccine at birth.     

肝细胞癌患者B和C基因型乙型肝炎病毒X蛋白的变异特点

背景与目的：X蛋白是乙型肝炎病毒(hepatitis B virus,HBV)最重要的致病因子之一,它在HBV相关性肝细胞癌(hepatocellular carcinoma,HCC)的发生发展中起着重要作用。目前已知B、C基因型HBV相关性HCC的临床及病理表现不尽相同,但目前尚不清楚这种差别是否与B、C基因型HBV X基因之间的差别有关。因此本实验拟研究B、C基因型间HBV X蛋白氨基酸差异及其在HCC患者中的变异及特点,初步探讨其与HCC发生、发展的关系。方法：PCR扩增22份乙型肝炎病毒表面抗原(HBsAg)阳性HCC患者血清HBV X基因,克隆、测序并以Vector NTI6．0软件分析其基因型。以DNAMAN软件对标准HBV及HCC来源的HBV X蛋白进行氨基酸同源分析。结果：检测的22个HBV X基因片段均属于B或C基因型。B、C基因型HBV X蛋白之间存在14个氨基酸的差异,HCC患者来源的B、C型HBV X蛋白存在4个氨基酸的共有变异,C型HBV X蛋白尚有6个型特异性变异。这些差异或变异氨基酸均位于X蛋白B、T细胞表位或反式激活区及调节区内。结论：B、C基因型HBV X蛋白之间存在氨基酸差异,且在HCC中发生基因型特异性变异,这些差异或变异氨基酸可能导致X蛋白免疫学功能及反式激活功能的不同。     

乙肝病毒/黄曲霉毒素B1双暴露相关性肝细胞癌的p53基因249位点突变与p53蛋白表达的关系

目的研究乙肝病毒/黄曲霉毒素B1双暴露相关性肝细胞癌的p53基因249位点突变与p53蛋白表达关系。方法通过IHG特殊免疫组织化学法检测55例手术切除经病理证实为原发性肝癌的HCC组织及10例正常肝组织中AFB1-DNA加合物的暴露情况,并根据是否同时存在HBV暴露加以分组,通过免疫组化S-P法检测并比较各组间p53蛋白的表达情况。同时,通过PCR结合直接测序的方法检测其p53基因第7外显子249密码子的突变情况。结果 p53基因第7外显子249位点的突变在实验组A与对照组C中均具有较高阳性突变率,其突变率分别为68.75%（22/32）、63.64%（7/11）,在对照组B中的突变率较低,为16.67%（2/12）,在正常对照组中无1例出现有突变。其中实验组A与对照组B及正常对照组D的比较差异具有统计学意义（P〈0.05）,而与对照组C比较差异无统计学意义（P〉0.05）;p53蛋白在其基因249位点突变阳性组与阴性组中的表达阳性率分别为92.86%（26/28）、60.87%（16/27）,差异具有统计学意义（P〈0.05）。结论 HCC的发生过程中,AFB1暴露与p53第7外显子249位点的突变密切关系相关,当同时存在乙肝病毒暴露的协同作用的情况下突变率更高;p53基因的突变可能是造成HCC中p53蛋白高表达的重要因素之一。     

Control of hepatocellular carcinoma through Hepatitis B vaccination in areas of high endemicity: Perspectives for global liver cancer prevention

There are approximately 360 millions chronic carriers of Hepatitis B virus worldwide. Patterns of HB carriage are variable from one region to the other. Regions with rates of carriage over 8% are commonly considered as “high endemicity” regions. HB carriers have a very significant lifetime risk of developing chronic liver diseases such as cirrhosis and/or liver cancer (hepatocellular carcinoma, HCC). An efficient HB vaccine is available since the early eighties and has been used since for universal infant vaccination in regions of high endemicity. Observations from Taiwan, where universal infant vaccination was introduced from 1984, show a remarkable, long-lasting protection against carriage and reduction of HCC rates in adolescent and young adults born after the initiation of the programme. Two population-based trials have been set up in the mid-eighties to evaluate lifelong protective effects of infant HB vaccine against liver cancer, in The Gambia (West Africa) and in the area of Qidong, China. In other high-endemicity regions of Asia and Africa, universal infants vaccination has consistently showed a long-lasting high protection against chronic carriage and this is expected to lead to a dramatic decrease of chronic liver disease and liver cancer within the next decades. Here we briefly review the lessons of vaccination programmes and trials in high-endemicity regions, based on data gathered during 15–20 years of implementation.     

Hepatitis B Virus X Protein Up-regulates TNF-α and IL-1β Secretion of Macrophages

Objective: To provide the experimental basis for further studying the molecular transformation mechanism of Hepatitis B virus (HBV) X protein (HBx) on hepatocellular carcinoma. Methods: Reconstructed plasmid pcDNA3.1( )-HBx was transfected into THP-1 macrophages. Expression of HBx was assayed in macrophages lysate by Western-blotting, and TNF-α and IL-1β contents were detected respectively by ELISA. All the data were analyzed by SPSS13.0. Results: In THP-1macrophages, the pcDNA3.1( )-HBx plasmid expressed HBx with a molecular weight of about 17 KDa demonstrated by Western-blotting. The secreted TNF-α and IL-1β from macrophages were determined by ELISA, the results from analysis of all groups showed as following: control group was different from LPS group and pcDNA3.1( ) group (P<0.01), and so was pcDNA3.1( )-HBx group; but there was no obvious difference between pcDNA3.1( ) group and LPS group (P>0.05), all of which indicated that transient overexpression of HBx enhanced LPS-induced production of TNF-α and IL-1β by macrophages. Conclusion: Transient overexpression of HBx up-regulates LPS-induced TNF-α and IL-1β secretion of macrophages.     

广西贵港地区乙型肝炎病毒感染及肝细胞性肝癌家族史与肝细胞性肝癌患者住院年龄的相关性分析

目的通过对肝细胞性肝癌（hepatocellularcarcinoma,HCC）住院病例的调查,探讨广西贵港地区乙型肝炎病毒（简称乙肝）感染及HCC家族史与HCC患者住院年龄的关系。方法应用临床流行病学横断面的研究方法,以2004~2008年贵港市人民医院首次住院的HCC患者1365例为研究对象。回顾性构建调查表的数据库,对贵港地区乙肝感染及HCC家族史与HCC患者住院年龄进行相关性分析。结果HCC家族史（＋）者住院年龄较HCC家族史（-）者小（P〈O．05）;HCC病例中乙肝（-）者住院年龄与乙肝（＋）者的差异无统计学意义（P=0．738）;以乙肝（-）且HCC家族史（-）者作为参照组,乙肝（＋）且HCC家族史（-）组与之比较,患者住院年龄的差异无统计学意义（聘0．443）,乙肝（-）且HCC家族史（＋）者及乙肝（＋）且HCC家族史（＋）者的住院年龄均偏小（尸均〈0．05）。结论①无论是否有乙肝感染,HCC家族史（＋）的肝癌患者住院年龄均较HCC家族史（-）者小;@HCC家族史及乙肝感染史与贵港地区HCC患者的住院年龄有关系。