巨噬细胞移动抑制因子和细胞周期蛋白D1的表达与肝细胞癌生长和转移的关系

目的研究巨噬细胞移动抑制因子（MIF）、细胞周期蛋白D1（Cyclin D1）、细胞周期蛋白依赖激酶4（CDK4）、磷酸化视网膜母细胞瘤易感基因产物蛋白（phospho—Rb）在HeC组织中的表达及其与癌细胞生长和转移的关系。方法应用组织芯片技术和免疫组织化学方法检测93份HCC组织中MIF、Cyclin D1、CDK4和phospho—Rb的表达，分析它们的表达与HCC临床病理特征的关系。结果93份HCC组织中MIF、Cyclin D1、CDK4和phospho—Rb的表达率分别为71％、41％、82％和14％，MIF和Cyclin D1阳性表达率与正常肝脏组织表达率之间的差异有统计学意义（P〈0．01），CDK4和phospho—Rb阳性表达率与正常肝脏组织表达率之间的差异无统计学意义（P〉0．05）。在≥3．5cm的肿瘤中MIF表达率为79％，明显高于在〈3．5cm肿瘤中的表达率48％（P〈0．01）；有转移的肝癌组织中Cyclin D1阳性率为62％，明显高于无转移组织中的阳性率35％，差异有统计学意义（P〈0．05）。MIF表达强弱与Cyclin D1的表达呈正相关关系（P〈0，01）。CDK4和phospho—Rb的表达与肿瘤大小及是否转移的关系无统计学意义。结论MIF和Cyclin D1在HCC发展进程中可能促进肿瘤的生长和转移。     

卵巢上皮性肿瘤组织中泛素与Cyclin B1的表达及意义

采用免疫组化SP法检测20例正常卵巢组织、20例上皮性良性卵巢肿瘤组织及50例上皮性卵巢癌组织中的泛素和细胞周期蛋白B1（Cyclin B1）,分别与上皮性卵巢癌的组织学类型、病理分级、临床分期及淋巴结转移的关系。结果显示,泛素在上皮性卵巢癌、正常卵巢组织和良性卵巢肿瘤中的阳性表达率分别为34%（17/50）、5%（1/20）、10%（2/20）,Cyclin B1的阳性表达率分别为42%（21/50）、5%（1/20）、15%（3/20）,两者在卵巢癌中的阳性表达率均显著高于正常卵巢组织和良性卵巢肿瘤（P均〈0.05）;泛素和Cyclin B1在上皮性卵巢癌中的阳性表达率随细胞分化程度的降低、临床分期增加而增高（P均〈0.05）,伴区域淋巴结转移者,其表达增高（P〈0.05）;泛素和Cyclin B1在上皮性卵巢癌中的表达呈正相关（r=0.301,P〈0.05）。认为泛素、Cyclin B1与上皮性卵巢癌的发生发展密切相关,有可能成为评估上皮性卵巢癌恶性程度及判定预后的重要指标。     

肝癌组织中survivin、VEGF的表达及意义

目的探讨survivin与血管内皮生长因子（VEGF）在肝细胞肝癌（HCC）组织中的表达及其临床意义。方法采用免疫组化法检测50例HCC组织和20例正常肝组织中survivin、VEGF蛋白的表达,并分析其与HCC临床病理参数的关系。结果50例HCC组织中survivin、VEGF蛋白的阳性表达率分别为64.0%、68.0%,在正常肝组织中的表达率分别为0、10%,两者相比,P均〈0.05;survivin、VEGF蛋白表达与HCC临床分期及淋巴结转移相关（P〈0.05）;HCC中survivin、VEGF蛋白表达呈正相关（r=0.886,P〈0.05）。结论survivin和VEGF蛋白在HCC中表达率较高,为肝癌的分子靶向治疗提供了新的靶点;survivin和VEGF在HCC中的表达关系密切,对肝癌的发展可能有协同作用;测定HCC中survivin、VEGF蛋白的表达,对判断患者预后及指导治疗有较大帮助。     

舌鳞癌组织中Cyclin D1、VEGF的表达变化及其相关性

目的观察Cyclin D1、血管内皮生长因子（VEGF）在舌鳞癌组织中的表达及意义。方法采用免疫组化SP法检测45例舌鳞癌组织及正常舌黏膜组织中Cyclin D1、VECF的表达变化。结果舌鳞癌组织中Cyclin D1、VECF的阳性表达率分别为62．2％、71．1％,均高于正常舌黏膜（P均〈0．01）;Cyclin D1表达与舌鳞癌的组织分级、临床分期有关（P〈0．05）,VEGF表达与舌鳞癌的临床分期、淋巴结转移有关（P〈0．05）;Cyclin D1与VECF表达呈正相关（r=0．515,P〈0．01）。结论Cyclin D1和VEGF在舌鳞癌组织中呈过表达,二者表达呈正相关。联合检测Cyclin D1和VEGF可以做为判断舌鳞癌生物学行为和指导临床治疗的指标。     

星形细胞上调基因1、β-连环素及周期素D1在肝细胞癌中的表达及临床意义

目的探讨肝细胞癌(HCC)组织中星形细胞上调基因(AEG)1、β-连环素(β-catenin)及周期素D1(Cyclin D1)的表达及临床意义。方法随机选取2013年7月-2014年12月贵州省人民医院经手术及病理证实为HCC的癌组织标本和对应癌旁组织各40例,另选取8例正常肝组织作为对照组。采用免疫组化SP法检测AEG-1、β-catenin及Cyclin D1蛋白在HCC组织、对应癌旁肝组织及正常肝组织中的表达情况,并分析其表达与HCC临床病理因素的相关性。计数资料组间比较采用χ2检验或Fisher确切概率法,AEG-1、β-catenin、Cyclin D1在HCC中的相关性采用Spearman等级相关分析。结果 AEG-1、β-catenin及Cyclin D1在HCC组织及癌旁肝组织中的表达均高于正常肝组织,差异均有统计学意义(χ2值分别为7.840、4.274、8.817、4.274、9.919、4.850,P值分别为0.005、0.039、0.003、0.039、0.002、0.028)。AEG-1、β-catenin、Cyclin D1的阳性表达在性别、年龄、HBs Ag、肿瘤大小方面差异无统计学意义(P值均0.05),而在病理分化程度、肝癌TNM分期及转移方面差异有统计学意义(P值均0.05)。相关性分析显示,AEG-1蛋白的表达与β-catenin、Cyclin D1蛋白的表达呈正相关(r值分别为0.420、0.741,P值均0.01)。结论 AEG-1、β-catenin及Cyclin D1在HCC的发生、发展过程中起着重要的作用;AEG-1可能通过上调Cyclin D1、β-catenin的表达和活性而促进HCC的发生和转移;联合检测三者的表达,可作为HCC基因治疗及预后评价的重要指标。     

非小细胞肺癌组织中β-连环蛋白、Cyclin D1的表达及意义

目的观察非小细胞肺癌组织中的β-连环蛋白和Cychn D1的表达变化及意义。方法采用免疫组织化学SP法检测42例非小细胞肺癌及10例肺良性病变组织中的β-连环蛋白和Cyclin D1蛋白。结果在10例肺良性病变组织中β-连环蛋白表达正常,Cyclin D1均呈阴性表达;而在42例非小细胞肺癌组织中β-连环蛋白异常表达率为71．4％,Cyclin D1阳性表达率为76．2％。β-连环蛋白异常表达率与非小细胞肺癌的淋巴结转移情况和生存期有关（P均〈0．05）。Cyclin D1表达阳性率与非小细胞肺癌的分化程度和增殖活性密切相关（P均〈0．05）;β-连环蛋白异常表达与Cyclin D1阳性表达在非小细胞肺癌中呈显著的正相关性（r=0．324,P〈0．05）。结论非小细胞肺癌中β-连环蛋白表达异常、Cyclin D1蛋白表达上调。β-连环蛋白的异常表达可能是非小细胞肺癌转移的分子机制之一。     

主要细胞周期蛋白在人类正常胃肠道黏膜组织中的表达规律

目的研究人类主要细胞周期蛋白（Cyclin D1、E、A、B1）在正常胃肠道黏膜组织中的表达规律。方法收集手术切除正常胃肠道黏膜组织标本共33例，应用间接免疫荧光双标法在激光扫描共聚焦显微镜下检测Cyclins蛋白的表达及其差异；24例正常大小肠黏膜组织应用免疫组织化学研究人类主要细胞周期蛋白（Cyclin D1、E、A、B1）在正常胃肠黏膜组织中的表达规律。结果①在正常胃肠道黏膜组织中的Cyclins表达以CyclinA、B1为主，Cyclin D1，Cyclin E低表达或无表达，除了Cyclin D1和Cyclin E组间无统计学意义外，其余各组方差分析均有统计学意义，P〈0．0l；免疫组织化学染色结果和免疫荧光染色结果相符合；②胃和肠黏膜间4种Cyclins的表达，Cyclin B1有显著性差异（P〈0．01），其它Cyclins（A、Dl、E）的表达率无显著性差异（P〉0．05）。结论在人类正常胃肠道黏膜组织中的Cyclins表达以Cyclin A、B1为主，胃肠道黏膜组织中Cyclin B1表达有差异，大肠黏膜中Cyc1in Bl的表达显著高于胃组织中Cyclin Bl的表达。     

原发性肝癌组织中DLK1表达及意义

目的探讨DLK1在原发性肝细胞性肝癌（HCC）发生、发展中的作用。方法分别应用免疫组化sP法和原位杂交的方法检测150例原发性肝细胞癌、50例肝硬化、50例肝炎组织中和10例意外死亡（生前体健）者肝组织中DLK1表达。结果DLK1蛋白及DLK1mRNA在HCC中的表达明显高于肝硬化、肝炎和正常肝组织表达（P均〈0。05）。DLK1蛋白表达与肿瘤直径及临床分期有明显相关性（P均〈0．05）。结论DLK1高表达可促进HCC的发生、发展。     

肝细胞癌组织中E-cadherin、N-cadherin、Vimentin的表达变化及意义

目的观察肝细胞癌（HCC）中上皮型钙黏蛋白（E-cadherin）、神经型钙黏蛋白（N-cadherin）和波形蛋白（Vimentin）的表达变化,并探讨其意义。方法采用免疫组化EnVision法检测45例HCC患者肿瘤组织及6例癌旁正常肝脏组织中的E-cadherin、N-cadherin和Vimentin。结果与对照组相比,观察组E-cadherin阳性表达率升高,N-cadherin、Vimentin阳性表达率降低（P均〈0.05）;观察组中高分化者与中分化者及中分化者与低分化者相比,E-cadherin阳性表达率升高,N-cadherin、Vimentin阳性表达率降低（P均〈0.05）。HCC组织中E-cadherin、Vim-entin表达呈负相关（r=-0.107,P〈0.05）;N-cadherin与Vimentin表达呈正相关（r=0.578,P〈0.05）。淋巴结转移与E-cadherin表达呈负相关（r=-0.08,P〈0.05）;与N-cadherin、Vimentin表达呈正相关（r=0.222、0.282,P均〈0.05）。结论 HCC组织N-cadherin、Vimentin表达增高,而E-cadherin表达降低。HCC细胞存在上皮—间叶转化,且与肿瘤的分化程度和淋巴结转移有关。     

β-catenin，c-myc和Cyclin组织中的表达及意义D1在胰腺癌

目的 研究β-catenin异常表达、c-myc和Cyclin D1的高表达与胰腺癌发生、浸润、转移的关系。方法 应用免疫组织化学方法检测5例正常胰腺组织和40例胰腺癌及13例相应癌旁组织中β-catenin、cmyc和Cyclin D1的表达。结果 5例正常胰腺组织及13例胰腺癌旁组织中β-catenin为正常表达，c-myc和CyclinD1阴性表达，40例胰腺癌组织中25例有β-catenin的异常表达（25／40，62．5％），20例（20／40．50％）有c-myc的高表达，23例（23／10，57．5％）有Cyclin D1的高表达。β-catenin的异常表达率与淋巴结转移、浸润及病理分级相关（P〈0．05），c-myc和Cyclin D1的高表达与分化程度，浸润，转移及病理分级无关，β-catenin的异常表达与c-myc的阳性表达不相关，而与Cyclin D1的阳性表达相关。结论 β-catenin的异常表达可能主要是通过激活Cyclin D1引起细胞增殖，导致肿瘤的发生。     

Ki-67、VEGF、Cyclin D1的表达与肝细胞癌生物学行为的关系

目的:探讨肝细胞癌(hepatocellular carcinoma,HCC)、胆管癌、肝硬化及正常肝组织中增殖细胞核抗原(Ki-67)、血管内皮生长因子(vascular endothelial growth factor,VEGF)及周期素D1(Cyclin D1)蛋白表达的意义及其与肝癌生物学行为关系.方法:对HCC组织52例、胆管癌组织10例、肝硬化组织10例及正常肝组织10例,采用免疫组织化学S-P法检测Ki-67、VEGF及Cyclin D1蛋白.结果:Ki-67、VEGF及Cyclin D1在HCC的强阳性表达率分别为48.1%、55.8%及55.8%,均显著高于胆管癌、肝硬化及正常肝组织(?2=15.672、15.524、14.812,P<0.001).Ki-67与肿瘤大小、血管侵犯、分化程度有关;VEGF、Cyclin D1表达与肿瘤包膜完整、血管侵犯及肿瘤分化程度明显有关;Ki-67与VEGF及Cyclin D1间无相关.VEGF与Cyclin D1间的蛋白表达呈正相关(r=0.374,P<0.01).结论:Ki-67、VEGF及Cyclin D1表达与肝细胞癌生物学行为密切相关,与肝癌的发生和发展密切相关.关键词:肝细胞癌;增殖细胞核抗原;血管内皮生长因子;周期素D1;免疫组织化学     

Differential expression of cell cycle regulators in HCV-infection and related hepatocellular carcinoma

AIM: To investigate cell cycle proteins in chronic hepatitis C virus infection in order to analyze their role in the process of hepatocyte transformation and to characterize their prognostic properties.METHODS: Subjects of the current study included 50 cases of chronic hepatitis C (CHC) without cirrhosis, 30 cases of CHC with liver cirrhosis (LC), and 30 cases of hepatitis C-related hepatocellular carcinoma (HCC) admitted to the Department of Hepato-Gastroenterology, Theodor Bilharz Research Institute (TBRI), Giza, Egypt. Fifteen wedge liver biopsies, taken during laparoscopic cholecystectomy, were also included as normal controls. Laboratory investigations including urine and stool analysis, liver function tests and prothrombin concentration; serologic markers for viral hepatitis and ultrasonography were done for all cases of the study together with immunohistochemical analysis using primary antibodies against Cyclin D1, Cyclin E, p21, p27 and Rb/p105 proteins.RESULTS: Normal wedge liver biopsies didn’t express Cyclin E or Rb/p105 immunostaining but show positive staining for Cyclin D1, p21 and p27. Cyclin D1 expressed nuclear staining that was sequentially increased from CHC to LC (P < 0.01) to HCC (P < 0.001) cases; meanwhile, Cyclin E revealed nuclear positivity only in the case of HCCs patients that was directly correlated to Rb/p105 immuno-reactivity. The expression of p21 and p27 was significantly increased in CHC and LC cases compared to normal controls and HCCs with no significant difference between well- and poorly-differentiated tumors. p21 showed only a nuclear pattern of staining, while, p27 presented with either cytoplasmic and/or nuclear reactivity in all studied cases. Correlation analysis revealed a direct relation between Cyclin D1 and p21 in CHC cases (P < 0.001), between Cyclin D1 and Cyclin E in HCCs (P < 0.01); however, an inverse relationship was detected between Cyclin D1 and p21 or p27 (P < 0.001) and between p21 and Rb/p105 (P < 0.05) in HCCs.CONCLUSION: Upregulation of Cyclin D1 in CHC plays a vital role in the development and differentiation of HCC; while, Cyclin E may be a useful marker formonitoring tumor behavior. p21 and p27 can be used as predictive markers for HCC. Furthermore, higher expression of Rb/p105 as well as inverse relation with p21 and histologic grades suggests its important role in hepatic carcinogenesis.     

Expression of P450 and nuclear receptors in normal and end-stage Chinese livers

AIM: To investigate the expression of P450 enzyme genes by using end-stage liver disease samples and trimmed normal Chinese donor livers.METHODS: The end-stage liver disease samples [n = 93, including hepatocellular carcinoma (HCC), peri-HCC tissue, hepatitis B virus cirrhosis, alcoholic cirrhosis, and severe cirrhosis] and trimmed normal Chinese donor livers (n = 35) from The Institute of Organ Transplantation in Beijing, China. Total RNA was extracted, purified, and subjected to real-time RT-PCR analysis.RESULTS: For cytochrome P450 enzymes 1 (CYP1) family, the expression of CYP1A2 was decreased 90% in HCC, 80% in alcoholic cirrhosis, and 65% in severe cirrhosis. For CYP2 family, the expression of CAR was decreased 50% in HCC, but increased 50% in peri-HCC tissues. Similar decreases (about 50%) of CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP2E1 were observed in HCC, as compared to peri-HCC tissues and normal livers. CYP2C19 were decreased in all end-stage liver diseases and CYP2E1 also decreased in alcoholic cirrhosis and severe cirrhosis. For CYP3 family, the expression of PXR was decreased 60% in HCC, together with decreases in CYP3A4, CYP3A5, and CYP3A7. In contrast, the expression of CYP3A7 was slightly increased in HBV cirrhosis. The expression of CYP4A11 was decreased 85% in HCC, 7% in alcoholic cirrhosis and severe liver cirrhosis, along with decreases in PPARα. The 93 end-stage livers had much higher inter-individual variations in gene expression than 35 normal livers.CONCLUSION: The expression of CYP enzyme genes and corresponding nuclear receptors was generally decreased in end-stage liver diseases, and significant differences in gene expression were evident between peri-HCC and HCC.     

福建肝癌细胞EBV感染与HBV及P53蛋白表达的关系

目的探讨肝细胞癌（ＨＣＣ）中ＥＢＶ与ＨＢＶ感染的相关性及ＥＢＶ与Ｐ５３蛋白表达的关系．方法采用原位杂交技术以地高辛标记的单链ｃＤＮＡ探针、生物素标记的双链ｃＤＮＡ探针及免疫组化ＳＰ法检测ＨＣＣ５９例（含癌旁肝组织）和９例肝硬变组织中高拷贝数ＥＢＥＲ１（ＥＢＶ编码的小ＲＮＡ）、ＨＢＶＤＮＡ和Ｐ５３蛋白．结果肝癌细胞核内ＥＢＥＲ１阳性率为２０３％,显著高于癌旁肝组织（Ｐ＜００１）．肝癌组织内ＨＢＶＤＮＡ阳性率为５９３％,ＥＢＶ存在与ＨＢＶ感染无明显相关性（Ｐ＞００５）．肝癌组织内Ｐ５３蛋白表达率为３３９％,Ｐ５３表达与ＥＢＥＲ１无显著关系（Ｐ＞００５）．结论肝癌细胞内ＥＢＶ感染与ＨＢＶ存在无明显关系,肝癌中Ｐ５３表达与ＥＢＥＲ１无关     

Decreased expressions of hepsin in human hepatocellular carcinomas.

BACKGROUND/AIMS: Hepsin is a type II transmembrane protein predominantly expressed in the liver and has been implicated in participation in blood coagulation pathway and epithelial carcinogenesis. The aim of this current study is to investigate the role of hepsin in hepatocarcinogenesis. METHODS: Quantitative real-time RT-PCR was used to investigate the expression levels of hepsin in a total of 50 paired hepatocellular carcinomas (HCCs) and the corresponding non-tumor liver tissues. Hepsin was transfected to the hepsin-non-expressing SK-HEP-1 cells to study the change of cell proliferation. RESULTS: In 62% (31/50) patients, the expression levels of hepsin in non-tumor liver tissues are at least twofold higher than those in the corresponding HCC tissues. Positive hepatitis B surface antigen was more often detected in patients with hepsin underexpressed in the HCC tissues (74.2% vs. 31.6%, P=0.007). Patients with hepsin underexpressed in the HCC tissues survived shorter time than those without hepsin underexpression in the HCC tissues. The cell proliferation and for a colony formation of SK-HEP-1 HCC cells were inhibited by hepsin. CONCLUSIONS: Most HCC patients had hepsin underexpressed in the HCC tissues. These patients survived for a shorter time compared with those without hepsin underexpression in the HCC tissues. Hepsin expression could inhibit cell proliferation and colony formation of HCC cells.     

STAT3和Cyclin D1在胰腺癌中的表达及其临床意义

目的探讨信号转导和转录激活因子-3(STAT3)、磷酸化STAT3(PSTAT3)及Cyclin D1 的蛋白在胰腺癌中表达情况及活化STAT3的蛋白表达与胰腺癌临床病理特征的关系。方法用免疫组化法检测41例手术切除的胰腺癌组织和10例正常胰腺组织中STAT3、PSTAT3、Cyclin D1的蛋白表达。结果在41例胰腺癌标本中有31例(75.6%)STAT3、29例(70.7%)PSTAT3和25例(61.0%) Cyclin D1的蛋白表达阳性,明显高于正常胰腺组织。STAT3主要在细胞质表达,PSTAT3和Cyclin D1 主要在细胞核内表达。PSTAT3和Cyclin D1蛋白的阳性表达呈正相关(P<0.001)。PSTAT3在临床分期较晚和有淋巴结转移的胰腺癌中呈高表达(P<0.05),Cyclin D1的表达与淋巴结转移有关(P< 0.05)。结论本研究结果表明胰腺癌组织中存在STAT3、PSTAT3和Cyclin D1的过表达,并与临床病理分期和淋巴结转移有关,PSTAT3过表达与Cyclin D1的表达呈正相关,提示PSTAT3可能通过上调Cyclin D1表达,在胰腺癌的发生发展中起重要作用。     

肝细胞癌组织中Fas抗原和bcl-2蛋白的表达

目的 了解Ｆａｓ抗原及ｂｃｌ－２蛋白在肝癌中的意义。方法 用流式细胞技术对２６例肝细胞癌（ＨＣＣ）癌组织及相应硬变肝组织,以及１４例正常肝组织中Ｆａｓ抗原和ｂｃｌ－２蛋白的表达进行分析。结果 上述３种组织中均测到Ｆａｓ抗原和ｂｃｌ－２蛋白。ＨＣＣ组织中Ｆａｓ明显高于硬变肝组织中的表达（Ｐ〈０．０５）,而与正常肝组织Ｆａｓ表达差异无统计学意义（Ｐ〉０．０５）。ｂｃｌ－２在肝癌组织中明显低于正常组肝组     

Clinicopathological significance of expression of paxillin, syndecan-1 and EMMPRIN in hepatocellular carcinoma

AIM: To evaluate the relationship of expression of paxillin, syndecan-1 and EMMPRIN proteins with clinicopathological features in hepatocellular carcinoma (HCC). METHODS: Fifty-one patients who underwent HCC resection were recruited in the study. Paxillin, syndecan-1 and EMMPRIN proteins in HCC tissues were detected with immunohistochemical staining. RESULTS: Of 51 cases of HCC, 23 (45%) exhibited paxillin protein positive expression. Of 42 cases of adjacent non-tumor liver tissues, 24 (57%) exhibited positive expression. Positive paxillin protein expression was associated with low differentiation (r= 0.406, P= 0.004), with the presence of portal vein thrombosis (r = 0.325, P = 0.021), with extra-hepatic metastasis (r=0.346, P=0.014). Of 51 cases of HCC, 28 (55%) exhibited syndecan-1 protein positive expression. Of 42 cases of adjacent non-tumor liver tissues, 23 (55%) exhibited positive expression. Positive snydecan-1 protein expression was associated with well differentiation (r=0.491, P=0.001), with no extra-hepatic metastasis (r=0.346, P=0.014). Of 51 cases of HCC, 28 (55%) exhibited EMMPRIN protein positive expression. Of 42 cases of adjacent non-tumor liver tissues, 21 (50%) exhibited positive expression. Expression of EMMPRIN protein was not associated with serum AFP level, HBsAg status, presence of microsatellite nodule, tumor size, presence of cirrhosis and necrosis, differentiation, presence of portal vein thrombosis, extra-hepatic metastasis, disease-free survival and overall survival (P>0.05). Expression of paxillin protein was correlated conversely with the expression of syndecan-1 protein in HCC (r = -0.366, P = 0.010). CONCLUSION: Expression of paxillin and syndecan-1 proteins in HCC may affect its invasive and metastatic ability of the tumor. There may be a converse correlation between the expression of paxillin and syndecan-1 protein in HCC. Expression of EMMPRIN protein may be detected in HCC, but it may play little role in the invasion and metastasis of HCC.     

Cyclin D1 overexpression in hepatocellular carcinoma

BACKGROUND/AIMS: Cyclin D1 gene amplification and cyclin D1 protein overexpression have been reported in various human tumors, including hepatocellular carcinoma (HCC). However, their significance is still controversial. In the present study, we examined the expression of cyclin D1 and its relationships to p53 and Ki-67 in HCCs. METHODS: The expression and topological distribution of cyclin D1, p53 and Ki-67 in 50 cases of HCC were examined immunohistochemically, and the relationship between the expression of these proteins and their pathologic features was investigated. RESULTS: Overexpression of cyclin D1 was noted in 58% of the HCC cases, and significantly associated with a well-differentiated histology and a low Ki-67 labeling index (LI). Cyclin D1 overexpression was also observed in all (7 of 7) dysplastic nodules and in non-neoplastic hepatocytes. On the other hand, aberrant p53 expression was detected in 36% of the cases, which showed positive relationships with poor differentiation, portal vein invasion, and KI-67 LI. Only eight of the 50 cases examined (16%) were positive for both cyclin D1 and p53, which showed only a small number of cyclin D1-positive cells. There was no significant relationship between the expressions of cyclin D1 and p53. CONCLUSIONS: Our results suggest that cyclin D1 overexpression may be an early event in hepatocarcinogenesis and that it plays a role in tumor differentiation. In addition, cyclin D1 expression is not correlated with tumor cell proliferation in HCCs.