【作者】 郭薇；

【导师】 申丽娟； 章宗籍；

【作者基本信息】 昆明医学院 ， 病理学与病理生理学， 2007， 硕士

【摘要】 目的：研究肝细胞癌（HCC）发生过程中不同阶段乙型肝炎病毒X蛋白（HBx）、丝裂原活化蛋白激酶（MAPK）途径p38MAPK蛋白及p38MAPK通路相关因子Cdc25B、p34Cdc2、CyclinB₁的表达及其相互关系，探讨HCC发生机制。方法：应用免疫组织化学方法检测正常肝组织、慢性肝炎、肝硬化、癌周肝硬化和肝癌共86例标本中的HBx、p38MAPK、Cdc25B、CyclinB₁和p34Cdc2的表达情况，用半定量积分法进行结果判断，并用统计学方法对结果进行分析。结果：HBx蛋白阳性信号主要定位于胞核，HBx的表达以肝炎组及肝癌组多见，肝癌组与正常组之间的差异有统计学意义（P＜0.05），慢性肝炎组与正常组、肝硬化组、癌周肝硬化组之间的差异有统计学意义（P＜0.05）；p38MAPK蛋白及其通路相关因子Cdc25B蛋白阳性信号定位于胞核和／或胞浆，p38MAPK和Cdc25B的表达均以肝癌组最强，分别为78％和81％，在癌周肝硬化组中的表达仅次于肝癌组，分别为67％和78％，其与正常组的差异均有统计学意义（P＜0.05）。CyclinB₁蛋白阳性信号定位于胞核和胞浆，p34Cdc2蛋白阳性信号主要定位于胞核，两者在肝癌组都呈现出过表达现象，与正常组间的差异有统计学意义（P＜0.05）。P38MAPK、Cdc25B、CyclinB₁和p34cdc2四种蛋白从正常组、慢性肝炎组、肝硬化组、癌周肝硬化组到肝癌组中的表达呈逐渐增强的趋势，且在癌周肝硬化中的表达均高于不伴癌的肝硬化，其差异有统计学意义（P＜0.05）。5项指标的检测在肝癌组中分化好者与分化差者之间差异均无统计学意义（P＞0.05）。相关性分析发现，HBx与p38MAPK的表达成正相关，相关系数为0.326（P＜0.05）；CyclinB₁与p34cdc2的表达成正相关，相关系数为0.896（P＜0.05）。结论1、HBx通过p38MAPK途径引起细胞周期G2／M检验点活化，使细胞周期从G2期向M期转化的相关因子Cdc25B、p34Cdc2和CyclinB₁的表达发生改变，造成肿瘤细胞的异常增殖可能是肝细胞癌发生的机制之一。2、首次发现癌周肝硬化中p38MAPK、细胞周期G2／M期调控相关因子Cdc25B、CyclinB₁和p34cdc2蛋白表达的阳性率均介于癌周肝硬化和不伴癌的肝硬化之间，说明癌周肝硬化肝细胞与不伴蕉的肝硬化肝细胞很可能是性质不同的细胞群体，更具有癌前病变性质，可能是肝细胞癌变的关键时期。更多还原

【Abstract】 Objective: To investigate the expression of HBx protein and the factors Cdc25B、CyclinB1、p34cdc2 which are correlated to the p38MAPK pathway in human hepatocarcinogenesis.Methods: Expression of HBx、p38MAPK、Cdc25B、CyclinB1、p34cdc2 was detected in the tissues of nomal liver, chronic hepatitis, liver cirrhosis, paratumor cirrhosis and HCC （86 samples, totally） by s-p immunohistochemistry. All data were processed by SPSS 11.5 version in the computer.Results: HBx was localized in nuclear of chronic hepatitis and HCC. The expression of HBx in HCC was stronger than that in nomal liver and paratumor cirrhosis （p＜0.05）, however the expression of HBx in chronic hepatitis was stronger than that in other three groups（p＜0.05）. P38MAPK and Cdc25B was localized in cytoplasm and/or nuclear. The expression of p38MAPK and Cdc25B was the highest in HCC and the positive rates of them in paratumor cirrhosis was just lower than that in HCC.The expression of p38MAPK and Cdc25B in HCC and paratumor cirrhosis showed significant difference compared with normal liver（p＜0.05）. CyclinB₁ protein was localized in cytoplasm and nuclear and p34cdc2 protein was localized in nuclear. There was overexpression of CyclinB₁ and p34cdc2 in HCC and the expression showed significant difference between HCC and normal liver（p＜0.05）. The expression of p38MAPK、Cdc25B、CyclinB₁ and p34cdc2 gradually increased from normal liver、chronic hepatitis、liver cirrhosis、paratumor cirrhosis to HCC and the expression between liver cirrhosis and paratumor cirrhosis showed significant difference （p＜0.05）. Significant positive correlation was found between the expression of HBx and p38MAPK and the expression of CyclinB₁ and p34cdc2 in HCC.Conclusions: The p38MAPK signal transduction pathway could be activated by HBx protein so that cell cycle checkpoint of G2/M activated. The expression of Cdc25B、CyclinB1、p34cdc2 increaced and abnormal cells multiplicated out of the way. The p38MAPK signal transduction pathway activated by HBx may play a key role in human hepatocarcinogenesis. For the first time we found the positive rates of p38MAPK、Cdc25B、yclinB₁ and p34cdc2 were different between liver cirrhosis and paratumor cirrhosis which indicates that their characteristics maybe different.更多还原