甲胎蛋白在肝癌的诊断和治疗中的研究进展

肝细胞癌(Hepatocellular carcinoma,HCC)是致死率第3的恶性肿瘤,也是全球第5大常见癌症。肝癌在临床上的治疗手段非常有限,患者的总生存率也很低。因此,肝癌的早期诊断和治疗对于患者总生存率有着重要的影响。甲胎蛋白(Alpha-fetoprotein,AFP)是最早发现也是目前应用最广泛的肝癌标志物之一。目前,多项研究表明,作为一个特异性的癌基因,AFP在肝癌的发生、发展、诊断和治疗中有巨大的研究价值。文中简述了AFP在肝癌发生发展中的分子调控机制以及在肝癌细胞逃避免疫监视中的作用,着重阐述AFP作为重要的肝癌靶标分子在肝癌的临床诊断和治疗研究中的应用。     

高尔基体蛋白73与肝癌诊断

肝癌是我国最常见的恶性肿瘤之一,血清甲胎蛋白(α-fetoprotein,AFP)检查是目前肝癌诊断最常采用的手段,但血清AFP对肝癌诊断的灵敏度和特异性均不理想,因此,临床上迫切需要更理想的肝癌标志物。高尔基体蛋白73(Golgi protein 73,GP73)是一种II型高尔基体跨膜糖蛋白,与肝炎、肝硬化和肝癌等肝病的发生、发展密切相关,GP73对肝癌诊断的灵敏度和特异性为65%和90%,而核心岩藻糖化GP73对肝癌诊断的灵敏度和特异性则高达90%和100%。GP73有可能成为一种更理想的肝癌临床诊断标志物,而核心岩藻糖化的GP73在肝癌的早期诊断中可能具有更重要的意义。     

常用实验动物肝癌模型研究进展

肝癌动物模型是研究肝癌发病病因和机理的重要平台和手段,在肝癌研究过程中,肝癌动物模型的建立起着非常重要的作用,建立和提供良好的肝癌动物模型为今后进一步研究肝癌的致病机理,指导临床肝癌的诊断和治疗提供理论参考。     

肝癌血清标志物研究进展

肝癌是全球最常见的恶性肿瘤之一,多数患者确诊时已属中晚期。5年以上长期生存率仅为10%左右。肝癌的早期诊断成为提高患者长期生存率的最佳有效途径。近年来,血清肿瘤分子标志物已经成为肝癌早期诊断研究领域的研究热点之一血清甲胎蛋白(AFP)检测是当前诊断肝癌常用而又重要的方法。对肝癌的确诊、预后推测、疗效判断及复发转移的监测具有良好的临床价值。甲胎蛋白异质体(AFP-L3)和脱α-羧基凝血酶原(DCP)在预测肝癌预后方面可能优于AFP。磷脂酰基醇蛋白聚糖3(GPC-3)和α-L岩藻糖苷酶(AFU)作为AFP的补充,能够大幅提高肝癌诊断的正确率。血管内皮生长因子(VEGF)、胰岛素样生长因子Ⅱ(IGF-Ⅱ)和高尔基Ⅱ型跨膜蛋白(GP-73)过表达发生在肝癌早期,有可能成为肝癌早期诊断指标。凋亡早期蛋白(M30)可以作为监测癌细胞凋亡的重要生物标记。细胞质胸苷激酶(TK1)、肝细胞生长因子(HGF)和CD147抗原分子在多种癌组织包括肝癌中显著高表达。本文对国外近几十年来肝癌血清标志物研究的一些成果进行了总结和评价,以期为国内学者进行此类研究提供一定的借鉴。     

PEG10基因在肝癌中的表达及研究意义

PEG10基因是由反转座子衍生而来的遗传印记基因,研究表明,PEG10是肝细胞癌(HCC)发生的重要促进作用之一,在绝大多数肝癌中特异性高表达,具有作为更有效的肝癌诊断标志物和基因治疗新靶点的潜力。本文概述PEG10基因与肝癌发生、发展和转移的关系及其作用与肝癌的机制,并对其前景进行展望,以期为肝癌的标志物诊断和基因靶向治疗的研究提供理论参考依据。     

用于肝癌检测的酶底物——5′-(5-碘吲哚酚-[3])胸腺嘧啶核苷酸的制备

检测人血清中5′-核苷酸磷酸二酯酶同工酶谱的变化,是诊断人类原发性肝癌的一个有效的血清酶学方法。和甲胎蛋白诊断法协同,可使肝癌的诊断符合率自80％提高到约94％。减少了甲胎蛋白诊断肝癌存在的假阴性问题,具有重要的临床诊断意义。 检测5′-核苷酸磷酸二酯酶(5′-NPDase)同工酶的底物,5′-(5-碘吲哚酚-[3])胸腺嘧啶核苷酸,我所潘禄兴等已有直接合成法报道。本文在潘禄兴等工作基础上对工艺作了改进,使产率有了明显提高。     

大鼠肝癌细胞(CBRH-7919)的建株及其生物学特性研究

近年来由于甲胎蛋白的发现及其在肝癌诊断方面的应用,甲胎蛋白与肝癌的关系日益受到人们的重视。因而建立甲胎蛋白阳性的动物肝癌体外细胞株,对于肝癌体内外互相配合互相引证的实验研究是极     

肠道菌群与肝癌

肝癌是世界上最恶性的疾病之一,发病率居世界第六位,病死率居世界第四位。尽管近年来在肝癌的诊断和治疗方面取得了进展,但患者生存率和术后复发率仍然不尽人意。肠道菌群栖息于人类的消化道,介导人体内多种代谢反应,协助机体完成正常生命活动。目前大量的研究证实,慢性肝病患者（如酒精性肝炎、非酒精性脂肪性肝病和病毒性肝炎等）体内均存在一定程度的肠道菌群紊乱且与疾病的发生发展相关,可能是慢性肝病向肝癌进展的主要因素,因此靶向肠道菌群的诊疗手段可能为肝癌患者的治疗提供新的思路。在此基础上,本文总结大量相关文献,从肠道菌群促进肝癌的机制及其对肝癌的预防、诊断以及治疗等方面进行综述。     

肝癌转基因小鼠模型的应用研究进展北大核心CSCD

肝细胞癌是全球范围内的恶性肿瘤,由于其进展迅速、易于复发转移,早期诊断和有效治疗一直是临床难题,对于肝癌的发病机制也亟待进一步阐明。利用基因工程手段构建的肝癌转基因小鼠模型,为肝癌发病机制研究和药物筛选提供了宝贵的研究材料。结合经典研究与近年进展,对常用肝癌转基因小鼠模型的构建方法、模型特点、特别是应用研究状况进行了分类介绍,并展望了未来发展的方向。     

miR-200a 及AFP 在肝癌、肝硬化患者血清中表达比较分析*

目的:分析miR-200a及AFP在肝癌、肝硬化患者血清中的表达水平并进行比较,探索其成为肝癌早期诊断血清标志物的可能性。方法:临床收集肝正常、肝硬化、肝癌患者血液标本。运用实时定量PCR技术检测血清miR-200a的相对表达情况,血清AFP水平从临床资料中提取。结果:临床标本分析结果显示,miR-200a在肝硬化及肝癌患者中均显著下调(P<0.05),AFP仅在肝癌患者中出现异常表达。结论:血清miR-200a极大程度地参与了肝癌发生,对肝硬化及肝癌具有一定的诊断价值。     

Hepatocellular carcinoma: epidemiology and clinical aspects

Liver cancer is one of the most frequent solid cancers that kills more than 650,000 people around the world each year. Though great improvements have been done in last 10 years on the understanding the molecular mechanisms involved in liver oncogenesis, the prognosis of patients affected by liver cancer is still poor for most of them. Even in those where a relatively early diagnosis is done, the course of the disease is often fatal due to the underlying liver cirrhosis. In this review authors report the most recent findings on the pathogenesis of liver cancer and on therapeutic approaches, included those emerging from the most recent literature.     

DKK-1 与肝脏恶性肿瘤的相关研究进展

肝脏恶性肿瘤包括原发性肝癌、继发性肝癌、肝母细胞瘤、肝脏淋巴瘤、肝脏血管内皮细胞肉瘤、纤维板层肝细胞癌、肝脏未分化胚胎肉瘤等发生在肝脏的恶性病变。其中原发性肝癌(primary liver cancer,PLC)是临床上最常见的恶性肿瘤之一。PLC在我国的发病人数占全球的55%,是我国第二个最常见的癌症死亡原因。由于肝脏恶性肿瘤具有隐匿性强、恶性程度高,病情进展快的特点,很多患者就诊时已到疾病中晚期,即使采取多学科综合治疗,预后也很不理想。因此,美国肝病研究学会(AASLD)和卫生部制定的《原发性肝癌诊疗规范(2011年版)》特别强调了早期筛查和早期监测对提高患者生存时间和生存质量的作用。甲胎蛋白(AFP)联合影像学检查是目前筛查肝脏恶性肿瘤的主要方法,但是AFP和影像学检查尚缺乏足够的敏感性和特异性,尤其对于早期癌症的诊断而言。DKK-1(dickkopf-1)是近年来由德国科学家新发现的一种分泌型糖蛋白。DKK-1与肝脏恶性肿瘤,尤其与原发性肝癌的早期诊断和预后判断关系密切,是最值得期待的肿瘤诊断标志物之一。本文谨对DKK-1的分子生物学特点、在恶性肿瘤中的表达以及与肝脏恶性肿瘤的关系进行综述,探讨其作为肝癌诊断蛋白标志物的研究现状及临床应用前景。     

原发性肝癌临床分期的对比探讨

原发性肝癌严重威胁着人类的健康,全球每年新增的病例数约为50万,其中54％发生在我国,且患者在3年内复发率高于60％,可见诊治形势十分严峻。肝癌的临床分期系统对于患者的预后评估以及选择何种治疗方案有着极其重要的意义。国内外虽有此类研究的相关内容,但将各种分期的评价及适用范围、发展趋势相结合进行分析的较少。本文对国际上多种常用的分期方案（TNM分期、Child-Pu曲分期、Okuda分期、CLIP评分、JIS分期、CUPI指标、CIS记分）进行探讨,论述各种方案间的差异及相互关系,并对未来可能发展方向进行展望。经本文分析多项研究发现：TNM分期更适用于外科病人,Child—Pugh对肝功能受损的患者具有较好的预后价值,而Okuda、CLIP、JIs分期适用于不适合手术治疗的进展期病人,CUPI指数则对慢性乙肝患者有疗效,CIS适用于非手术治疗的患者。随着肿瘤分子生物学技术的进步,肝癌分期有可能上升到分子病理学的水平,肝癌切除的根治程度将划分得更为细致,以反映患者肝癌切除后所处状态的多种可能性,分子指标也将更加客观、敏感,有利于患者早期的诊断与治疗。     

Does Microhistology Improve the Cytological Diagnosis of Liver and Pancreatic Tumours?

Guided percutaneous fine needle aspiration cytodiagnosis of the liver, retroperitoneum and pancreas was performed in 197 patients. In 42 cases, material left after the smears were prepared was embedded in paraffin wax for histological examination. Six liver tumours and seven pancreatic tumours were identified in this material. In two cases the diagnosis of liver cell carcinoma was made only after microhistological examination. Re-examination of the cytological material in both cases disclosed features of liver cell carcinoma which were underestimated in the first examination and diagnosed only broadly as cancer cells. On the other hand, in another case cancer cells were present only in the smear and absent in the microhistological preparation. Diagnosis of pancreatic tumours was generally not improved by microhistological examination. In one case cancer cells were present only in the cytological material. In another case a cytological diagnosis of suspected cancer was confirmed as adenocarcinoma by microhistology. The diagnosis of non-neoplastic material in the remaining 29 cases were identical by cytopathology and microhistology. It is concluded that the microhistology of needle aspirate material complements cytological examination and can refine diagnosis although it increases cost.     

Anti-Proliferative Activities of Sinigrin on Carcinogen-Induced Hepatotoxicity in Rats

Liver cancer is one of the leading causes of cancer death worldwide. A very high incidence of new liver cancer cases is diagnosed every year, and metastasis has been found to correlate to poor prognoses in humans. Better treatments for liver cancer are thus clearly needed. Sinigrin is one of the major ingredients present in Brassica nigra, which has been used in combination with other herbs for treatment of various diseases. The anti-proliferative activities of sinigrin were studied in a model of carcinogen-induced hepatotoxicity in rats. Rats were orally administered with sinigrin on a daily basis for three months before sacrifice. Sinigrin was found to significantly inhibit the proliferation of liver tumor cells; the number of surface tumors in the rat liver was dramatically reduced. Sinigrin induced apoptosis of liver cancer cells through up-regulation of p53 and down-regulation of Bcl-2 family members and caspases. Our findings indicated that the liver functions were gradually restored after treatment with sinigrin and that the agent did not cause liver toxicity. Cell cycle analysis indicated that sinigrin caused cell cycle arrest in G0/G1 phase. The results suggest that sinigrin exerts important anti-proliferative activities in carcinogen-induced hepatocarcinogenesis in rats, and highlight the potential of sinigrin as an anti-cancer agent for liver cancer.     

双向热循环消减-SELEX方法筛选肝癌血清核酸适配体

肝癌位于我国肿瘤死亡率第2位,生存率较低。目前用于肝癌早期诊断的临床检查及血清肿瘤标志物检测的特异性与敏感性均较低,不能满足肝癌早期诊断和治疗的需要。核酸适配体与靶标分子结合的灵敏度高、特异性强,有巨大的临床诊断和治疗应用前景。本文利用双向热循环消减指数富集的配基系统进化（systematic evolution of ligands by exponential enrichment, SELEX）技术,分别以肝癌血清和健康人血清为靶标,经过19轮筛选,获得了肝癌血清特异性核酸适配体序列1 000余条,以及健康人血清特异性核酸适配体序列1 000余条,并从中各挑取了1条高丰度适配体序列,分别命名为Tc1和Tn1。采取了50例肝癌病人血清和50例健康人血清,对适配体Tc1和Tn1与靶标血清的结合特异性进行了检测。结果显示,Tc1和Tn1对两种靶标血清的检出率分别为92%和94%。说明Tc1可特异性与肝癌血清结合,Tn1可特异性与健康人血清结合。肝癌血清特异性核酸适配体的筛选获得,将为建立基于核酸适配体的肝癌血清检测新方法奠定基础。     

Liver development and cancer formation in zebrafish

Liver is the largest organ in the human body, and it regulates many physiological processes. Many studies on liver development in different model organisms have demonstrated that the mechanism of hepatogenesis is conserved in vertebrates. The identification of the genes and regulatory pathways involved in liver formation provides a basis for the diagnosis of liver diseases and therapeutic interventions. Hepatocellular carcinoma is the third leading cause of mortality worldwide. In the last decade, genetic alterations, which include the gain and loss of DNA, as well as mutations and epigenomic changes, have been identified as important factors in liver cancer. Many genetic pathways are dysregulated during carcinogenesis. Here, we review the gene regulatory networks that underlie liver organogenesis and the dysregulation of these pathways in liver cancer. The genes and pathways involved in hepatogenesis and liver cancer are largely conserved between zebrafish and humans, making this an ideal model organism for the study of this disease. A better understanding of liver development may aid in the development of new diagnostic and therapeutic approaches to liver cancer.     

Incidence and survival for hepatic, pancreatic and biliary cancers in England between 1998 and 2007

Introduction: Hepatic, pancreatic and biliary (HPB) cancers are a group of diverse malignancies managed ideally in specialist centres. This study describes recent patterns in the incidence and survival of HPB cancers in England over a ten year period (1998–2007). Methods: Data on 99,379 English patients (50,656 males; 48,723 females) diagnosed with HPB cancers between 1998 and 2007 were extracted from the National Cancer Data Repository. Data were divided into six site-specific cancer groups; pancreas, ampulla of Vater, biliary tract, primary liver, gallbladder and duodenum. Age-standardised incidence rates (per 100,000 European standard population, (ASR(E))) were calculated for each of the six groups by year of diagnosis and by socioeconomic deprivation. Survival was estimated using the Kaplan–Meier method. Results: The largest group was pancreatic cancers (63%), followed by primary liver (14%) and biliary cancers (13%). ASR(E) were highest for pancreatic and primary liver cancers whereas cancers of the gallbladder, duodenum and ampulla of Vater had a very low incidence. Over time the incidence of all six groups remained relatively stable, although primary liver cancer increased slightly in males. Incidence rates were higher in males than in females in all groups except gallbladder cancer, and all six groups had a higher incidence in the more deprived quintiles. Overall survival was poor in each of the HPB cancer groups. Conclusions: HPB tumours are uncommon and are associated with poor long term survival reflecting the late stage at presentation. Incidence patterns suggest variable rates linked to socioeconomic deprivation and highlight a male predominance in all sites except the gallbladder. Identification of high risk populations should be emphasised in initiatives to raise awareness and facilitate earlier diagnosis.     

Disparities in cancer stage at diagnosis and survival of Aboriginal and non-Aboriginal South Australians

Background/AimThis study tested the utility of retrospectively staging cancer registry data for comparing stage and stage-specific survivals of Aboriginal and non-Aboriginal people. Differences by area level factors were also explored.MethodsThis test dataset comprised 950 Aboriginal cases and all other cases recorded on the South Australian cancer registry with a 1977–2010 diagnosis. A sub-set of 777 Aboriginal cases diagnosed in 1990–2010 were matched with randomly selected non-Aboriginal cases by year of birth, diagnostic year, sex, and primary site of cancer. Competing risk regression summarised associations of Aboriginal status, stage, and geographic attributes with risk of cancer death.ResultsAboriginal cases were 10 years younger at diagnosis, more likely to present in recent diagnostic years, to be resident of remote areas, and have primary cancer sites of head & neck, lung, liver and cervix. Risk of cancer death was associated in the matched analysis with more advanced stage at diagnosis. More Aboriginal than non-Aboriginal cases had distant metastases at diagnosis (31.3% vs 22.0, p < 0.001). After adjusting for stage, remote-living Aboriginal residents had higher risks of cancer death than Aboriginal residents of metropolitan areas. Non-Aboriginal cases had the lowest risk of cancer death.ConclusionRetrospective staging proved to be feasible using registry data. Results indicated more advanced stages for Aboriginal than matched non-Aboriginal cases. Aboriginal people had higher risks of cancer death, which persisted after adjusting for stage, and applied irrespective of remoteness of residence, with highest risk of death occurring among Aboriginal people from remote areas.