肝细胞癌相关胆汁酸代谢失衡及调控机制的研究进展

胆汁酸代谢、肠道菌群及胆汁酸受体调控通路均参与了肝细胞癌(HCC)发生发展的全过程。HCC小鼠模型的肝脏组织、HCC患者的血浆和粪便中某些胆汁酸如甘氨胆酸、牛磺胆酸、牛磺鹅去氧胆酸等水平均显著升高;肠道产胆盐水解酶细菌及梭状芽胞杆菌丰度失衡导致的胆汁酸代谢及机体免疫微环境的改变等也会促进HCC发生;此外,胆汁酸受体如法尼醇X受体、G蛋白偶联受体1、孕烷X受体、本构雄烷受体及鞘氨醇-1-磷酸受体2等多种受体亦被证实可以通过多种途径参与调控HCC的发生发展。胆汁酸代谢的各个环节在HCC的进程中发挥着不同的作用,系统诠释它们之间的相互作用有助于加深对HCC发病机制的认识,开发早期诊断、预后预测及精准治疗的生物靶标。     

胆汁酸代谢对肝细胞功能的影响

胆汁酸是胆固醇代谢过程中的主要代谢产物,对胆固醇代谢的调控、排泌以及胆汁胆固醇的溶解和食物脂类的消化、吸收具有重要意义.然而,由于肝内外胆管狭窄、阻塞,胆汁酸分泌模式改变及长期胃肠外营养等多种原因导致胆汁的排泌障碍将对肝细胞产生不可逆的危害.     

胆汁酸代谢途径的研究进展

肝脏的胆汁酸代谢在维持机体的胆固醇稳态中起了重要的作用。本文对胆汁酸代谢的两条途径和它们在整个胆汁酸代谢中的相应地位及与胆汁酸代谢紊乱相关的两种疾病作一综述。     

AEG1促进肝癌细胞HepG2分泌细胞因子IL-6、IL-1β的实验研究

目的研究AEG1能否促进肝癌细胞HepG2分泌细胞因子IL-6、IL-1β,探讨AEG1是否参与改变肿瘤微环境。方法用脂质体稳定转染法分别转染pcDNA3.1(-)-AEG1(AEG1全长质粒)、psilencer 2.0-shAEG1(AEG1干扰质粒)至HepG2细胞,相对应以转染空质粒pcDNA3.1(-)、psilencer 2.0的HepG2细胞为对照组;采用实时荧光定量RT-PCR(qRT-PCR)、Western blotting检测AEG1 mRNA和蛋白表达变化;采用实时荧光定量RT-PCR和酶联免疫吸附实验(ELISA)检测细胞因子IL-6、IL-1β的表达和分泌。结果与转染相应空载体的阴性对照组和未转染的空白对照组相比,分别转染AEG1全长质粒/AEG1干扰质粒后,HepG2细胞中AEG1的蛋白表达明显增高/降低。转染AEG1全长质粒的HepG2细胞中IL-6、IL-1βmRNA均较对照组和空白组明显增强(P均<0.05),细胞培养介质中IL-6、IL-1β蛋白浓度也显著高于对照组(P均<0.05);转染AEG1 shRNA的HepG2细胞中IL-6、IL-1βmRNA均较对照组和空白组降低(P均<0.05),细胞培养介质中IL-6、IL-1β蛋白浓度也低于对照组(P均<0.05)。结论成功构建稳定过表达和沉默AEG1的HepG2细胞,AEG1能调控IL-6、IL-1β的表达和分泌。     

道路交通噪音对大鼠血压的影响及粪便代谢组学分析

[目的]研究道路交通噪音对大鼠血压的影响,并通过分析其粪便代谢物水平的变化探究其可能的作用机制。[方法]将12只Wistar大鼠(雌雄各半)按性别随机分为噪音组和对照组。噪音组每日23:00至次日7:00暴露于平均75 dB的道路交通噪音,持续2.5个月。实验结束后测量两组血压,并收集大鼠粪便进行液相色谱-质谱联用(LC-MS)非靶向代谢组学分析。[结果]噪音组的收缩压和舒张压均高于对照组(P<0.001),其中噪音组的收缩压和舒张压分别为(176.67±27.07) mmHg及(93.93±21.54) mmHg,对照组的收缩压和舒张压分别为(150.38±17.98) mmHg和(67.72±24.67) mmHg。代谢组学分析发现41种差异代谢物,包括2-羟基苯乙酸、N-甲酰蛋氨酸、3-羟基苯丙氨酸等代谢物等。京都基因和基因百科全书(KEGG)通路富集发现氨基酸代谢通路可能参与了道路交通噪音对血压的作用过程。[结论]道路交通噪音暴露与大鼠血压的增加之间存在关联,而2-羟基苯乙酸和N-甲酰甲硫氨酸等可能在其中发挥了作用。     

孕烷X受体调控胆汁酸与脂质代谢机制的研究进展

孕烷X受体(pregnane X receptor, PXR)是一种配体依赖型受体,属于核受体超家族成员.通过调控相关基因的转录水平,PXR在胆汁酸、脂质代谢起到重要作用.     

乙型肝炎病毒导致的肝硬化伴肝癌患者血清中N糖组学改变

肝细胞癌（HCC）是最常见的肿瘤和最主要的死因之一，多发生于HBV和HCV感染导致的肝硬化患者，筛查肝硬化人群，早期诊断HCC可降低肿瘤的病死率。甲胎蛋白（AFP）是目前广泛应用的辅助诊断HCC的血清学指标，是对B超、CT等影像学诊断的有效补充。最近的荟萃分析表明，不同研究论文报道的AFP的灵敏度和特异度有很大的不同，这种现象不能完全用AFP的临界值不同解释。血清中的N糖蛋白主要由肝脏和B淋巴细胞合成，N糖成分的改变可反应肝脏或B淋巴细胞功能的改变，糖链的改变常常反应出机体的异常改变。糖组学在诊断领域的应用曾经因为缺少合适的分析技术而受限制，血清中N糖组学分析技术克服了这一屏障。本研究的目的是评价血清中N糖指纹图谱应用于乙型肝炎后肝硬化伴肝癌辅助诊断的意义。     

基因突变致胆汁酸代谢异常相关发生机制的研究进展

胆汁酸由肝脏合成并分解代谢,诸多原因均可导致其生成、分泌及重吸收障碍,进而引起体内胆汁酸代谢异常。常见诱因包括肝炎、病毒、酒精、药物、胆道梗阻及遗传等。目前已有研究报道胆汁酸代谢异常与转运蛋白基因突变存在联系,国内外对此均进行了深入研究。本文主要对基因突变所致胆汁酸代谢异常的发生机制及相关研究进展作一综述,为阐明此类疾病的诊断和治疗提供新依据及新思路。     

The molecular pathogenesis of hepatocellular carcinoma

SUMMARY. Some of the multiple factors involved in the molecular pathogenesis of hepatocellular carcinoma have been elucidated in recent years but no clear picture of how and in what sequence these factors interact at the molecular level has emerged yet. Transformation of hepatocytes to the malignant phenotype may occur irrespective of the aetiological agent through a pathway of chronic liver injury, regeneration and cirrhosis. The activation of cellular oncogenes, the inactivation of tumour suppressor genes and overexpression of certain growth factors contribute to the development of HCC. There is increasing evidence that the hepatitis B virus may play a direct role in the molecular pathogenesis of HCC. Aflatoxins have been shown to induce specific mutations of the p53 tumour suppressor gene thus providing a clue to how an environmental factor may contribute to tumour development at the molecular level.     

Lower serum viral loads in young patients with hepatitis-B-virus-related hepatocellular carcinoma

Advanced age and high hepatitis B virus (HBV) DNA level are risk factors associated with the development of HBV-related hepatocellular carcinoma (HCC). However, little is known about the role of viral load in the carcinogenesis of HCC in young people. A total of 183 HBV-related HCC patients and 202 HBV carriers were therefore enrolled to compare serum viral loads in young (40 years of age) age groups. Other factors associated with the development of HCC were also analysed. The results showed that serum alanine aminotransferase (38.7 +/- 24.1 vs 58.4 +/- 65.4 IU/L, P = 0.006) and HBV DNA levels (log(10) titre: 4.20 +/- 1.33 vs 4.80 +/- 1.39, P = 0.053) were lower in young HCC patients than in old HCC patients. There was a positive correlation between age and serum HBV DNA level in HCC patients but a negative correlation in HBV carriers. Young HCC patients with HBV genotype B infection had higher viral loads than those with genotype C infection (log(10) titre: 4.79 +/- 1.34 vs 3.27 +/- 0.60, P = 0.001). By multivariate logistic regression analyses, high serum HBV DNA level was associated with the development of HCC in old patients [odds ratio (OR) 1.584, 95% confidence interval (CI) 1.075-2.333] rather than in young patients (OR 0.848, 95% CI 0.645-1.116). In conclusion, viral factors in association with the development of HBV-related HCC in young patients may be different from their old counterparts. The complicated interplay between host and virus could be responsible for the emergence and aggressive outcome of early-onset HCC.     

HBV相关肝癌的治疗方案对HBV再激活的影响

[摘要]　HBV是肝细胞癌（hepatocellular carcinoma, HCC）最重要的危险因素,而HBV再激活很可能加快HCC的发生发展。了解HBV再激活的影响因素对HCC的治疗和预后有重要意义。本文对HCC不同治疗方案对HBV再激活的影响展开综述。     

HBV感染对原发性肝细胞癌生物学行为及p53蛋白的表达影响

探讨在原发性肝细胞癌(HCC)中乙型肝炎病毒(HBV)的感染对肿瘤生物学行为以及突变型p53蛋白的表达影响。利用血清学指标检测60例HCC的HBV感染情况,采用抗生蛋白链霉素-过氧化酶法(S-P)检测癌组织中突变p53蛋白的表达。38例HBV感染HCC中突变p53蛋白的表达率为73.68%(28/38),22例非HBV感染表达率为45.45%(10/22),两者有显著差异(P<0.05)。在HCC中,HBV感染与肿瘤的Edmondson分级、AFP值增高、门静脉癌栓形成、肝内转移以及转氨酶增高相关(P<0.05)。HBV的感染可能与p53基因的突变共同作用导致HCC的发生及发展。同时检测以上二种指标可以为认识HCC的生物学特性,制定合理的综合治疗方案提供依据。     

Hepatitis C and hepatocellular carcinoma

Abstract Hepatitis C virus (HCV) infection is aetiologically very closely associated with hepatocellular carcinoma (HCC). World-wide, hepatitis B virus infection is the predominant aetiological factor in developing countries, whereas in industrialized countries, HCV has a far more important role in hepatocarcinogenesis. The varying weights of the aetiological role of HCV infection are compared among countries. The speed of progression of chronic hepatitis C to cirrhosis, thenceforth to HCC, and certain discrepancies between an American study and the Japanese experience are described. The reason for the recent surge of HCV infection and subsequent increase in the incidence of HCC is also discussed. The genetic mechanism of HCV-induced hepatocarcinogenesis is still poorly understood.     

Risk factors analysis for hepatocellular carcinoma in patients with and without cirrhosis: a case-control study of 213 hepatocellular carcinoma patients from India

AIM: To assess the role of hepatitis B virus (HBV), hepatitis C virus (HCV) and alcohol intake as risk factors for hepatocellular carcinoma (HCC) in the presence or absence of cirrhosis in Indian population. METHODS: A total of 213 patients with HCC and 254 control subjects not affected with hepatic diseases or neoplasm were recruited. Odds ratios (ORs) were estimated for each risk factor and synergism among various risk factors was also studied. RESULTS: The ORs and 95% confidence intervals (CI) of HCC were 48.02 (25.06-91.98) for any HBV marker, 38.98 (19.55-77.71) for HBsAg positivity, 12.34 (2.84-53.61) for HBsAg negative and antibody positive (either of anti-HBe or total anti-HBc), 5.45 (2.02-14.71) for anti-HCV positive and HCV RNA positive, and 2.83 (1.51-5.28) for heavy alcohol use. No significant risk increase was evident for subjects who were anti-HCV positive and HCV RNA negative. Synergism between alcohol and HCV infection in causing HCC was found, but not between alcohol and HBV. Overall, conclusive evidence of the presence or absence of cirrhosis was reached in 189 (88.73%) HCC patients; cirrhosis was present in 137 (72.48%) of them. ORs with 95% CI of HCC in the presence and absence of cirrhosis, respectively, for HBV were as follows: (i) 48.90 (24.61-97.19) and 35.03 (15.59-78.66) for any HBV marker; (ii) 39.88 (19.41-81.97) and 24.40 (10.60-56.18) for HBsAg positivity; and (iii) 12.10 (2.67-54.88) and 19.60 (3.94-97.39) for HBsAg negativity and antibody positivity. Significantly increased risk was found among cirrhotic patients for anti-HCV positivity and HCV RNA positivity [OR = 7.53 (2.73-20.78)] and for heavy alcohol use [OR = 3.32 (1.70-6.47)]; however, in the absence of cirrhosis, no significant risk increase was evident for subjects who were anti-HCV positive and HCV RNA positive [OR = 0.97 (0.11-8.54)], or who had history of heavy alcohol use [OR = 1.58 (0.55-4.53)]. CONCLUSIONS: Infection with HBV and HCV are the major risk factors for the development of HCC in Indian patients. Presence of HBV antibodies even in the absence of HBsAg conferred increased risk for HCC in the presence or absence of cirrhosis. Anti-HCV positivity in the absence of HCV RNA conferred no increased risk. HCV RNA positivity and heavy alcohol use significantly increased the risk of HCC among cirrhotic patients, but not non-cirrhotic patients.     

SEN virus infection in patients with hepatocellular carcinoma

Although most cases of hepatocellular carcinoma (HCC) are associated with either the hepatitis B or C viruses (HBV, HCV), about 10-20% of HCCs occur in patients with chronic hepatitis that is aetiologically undefined. The aim of the present study was to determine the prevalence of the transfusion-transmitted SEN virus (SEN-V) in patients with HCC, including those patients who do not otherwise appear to be infected with HBV or HCV. Fragments of SEN-V subtypes D and H were amplified separately by PCR from the sera of 50 patients with HCC (31 from Canada and 19 from Japan) as well as from HCC and adjacent nontumourous liver tissues from eight of the Canadian patients. SEN-V DNA was found in the serum of 10 of 31 (32%) Canadian patients and eight of 19 (42%) Japanese patients [overall, 18 of 50 (36%) HCC patients]. SEN-V DNA was detected in the serum of 10 of 23 (43%) HCC patients with antibody to HCV (anti-HCV), six of 11 (55%) with hepatitis B surface antigen (HBsAg), and two of 16 (12%) without detectable anti-HCV or HBsAg. Twenty-three HCC patients in this study had 'silent HBV,' characterized by the detection of HBV DNA in the absence of HBsAg; eight of these (35%) also had SEN-V infections. SEN-V DNA was detected in HCC patients most typically in those with coexistent HBV or HCV infection. SEN-V was found in only one of seven HCC patients without HBV (without HBsAg or HBV DNA) or HCV and thus does not appear to be an important cause of 'cryptogenic' HCC.     

乙型/丙型肝炎病毒相关性肝细胞癌450例分析

目的比较乙型/丙型肝炎病毒(HBV/HCV)相关性肝细胞癌(HCC)的特点,探讨HCC发生的相关因素。方法收集2005年1月～2009年7月济南市传染病医院450例确诊的HCC住院患者病史及血清学资料,建立数据库,应用SPSS16.0软件进行统计分析。结果450例HCC患者HBV、HCV、HBV合并HCV感染分别为422、17例和11例。422例HBV感染者平均年龄(53.85±10.00)岁,高发年龄为50～59岁,男女比例为7.79∶1;17例HCV感染者平均年龄(60.18±5.47)岁,高发年龄为60～69岁,男女比例为2.40∶1。HCV相关性HCC(C-HCC)患者的发病年龄高于HBV相关性HCC(B-HCC)患者;B-HCC男性患者比例高于C-HCC;高病毒载量及长期肝炎发作是HCC形成的相关因素;C-HCC患者中2型糖尿病比例高于B-HCC患者。结论HBV感染所致的肝炎较HCV所致的肝炎更容易发生HCC。年龄大、男性、肝炎史长、肝硬化是HBV/HCV相关性HCC的主要相关因素。