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p38丝裂原活化蛋白激酶和乙型肝炎病毒X蛋白在人肝癌发生中对细胞增殖和凋亡的作用

The effects of p38MAPK and HBxAg on cell proliferation and apoptosis in human hepatocarcinogenesis

摘要:

目的 研究人肝癌发生过程中p38MAPK和乙型肝炎病毒X蛋白(HBX)对细胞增殖和凋亡的影响,探讨肝癌发生的机制. 方法 应用免疫组织化学和DNA原位末端标记(TUNEL)法原位检测人肝癌(36例)和相关慢性肝病组织(慢性乙型肝炎、肝硬化和癌周肝硬化分别为20、20、36例)的p38MAPK、HBX、细胞周期G2/M期相关因子(cdc25B,p34cdc2,细胞周期蛋白B1)、细胞增殖因子Ki-67和细胞凋亡情况.根据资料不同分别采用x2检验、One-Way ANOVA或t检验进行统计学处理. 结果 HBX在慢性乙型肝炎(65.0%)和肝癌组(44.4%)阳性率较高,主要表达于胞核; p38MAPK、cdc25B、细胞周期蛋白B1、p34cdc2的阳性率从正常肝组织(40.0%,20.0%,20.0%,30.0%)、慢性乙型肝炎(60.0%,65.0%,40.0%,50.0%)、肝硬化(65.0%,75.0%,70.0%,55.0%)、癌周肝硬化(66.7%,75.0%,75.0%,63.9%)到肝癌组(77.8%,80.6%,80.6%,72.2%)逐渐增高,表达部位发生改变.p38MAPK胞核表达主要见于慢性乙型肝炎组和肝硬化组,胞质表达见于癌周肝硬化组和肝癌组,癌周肝硬化组与肝癌组之间的差异无统计学意义(x2=1.11,P>0.05).正常肝、慢性乙型肝炎、肝硬化、癌周肝硬化和肝癌组织中的增殖指数(0.0000±0.000,0.0502±0.011,0.0411±0.009,0.0762±0.017,0.1810±0.036)和凋亡指数(0.0351±0.024,0.0607±0.022,0.0562±0.013,0.0716±0.011,0.1200±0.018)比较,除肝硬化外也逐渐增高,增殖指数在肝癌分化差组(0.2285±0.062)高于分化好组(0.1216±0.032,t=2.082,P=0.044),凋亡指数肝癌在分化好组(0.152±0.026)高于分化差组(0.081±0.022,t=2.129,P=0.041).结论 肝癌发生过程中,HBX可能通过p38MAPK通路引起细胞周期、细胞增殖和凋亡的异常改变.细胞增殖基本与凋亡相伴随,肝癌增殖程度高于凋亡程度.癌周肝硬化不同于不伴癌的肝硬化,与肝癌的关系更密切.

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abstracts:

Objective To investigate the effects of host-derived p38 mitogen-activated protein kinase subunit 38 (p38MAPK) and the hepatitis B virus X antigen (HbxAg) on cell proliferation and apoptosis in human hepatocellular carcinoma (HCC),and to study the mechanism underlying hepatocarcinogenesis.Methods Liver tissues were biopsied from healthy individuals and patients with chronic hepatitis B (CHB),liver cirrhosis,paratumor cirrhosis,and HCC.Immunohistochemical staining was used to detect expressions of HBxAg,p38MAPK,cell cycle G2/M phase-related factors (cdc25B,p34cdc2,cyclin B1),and cell proliferation factor ki-67.The terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling method (known as TUNEL) was used to detect apoptosis.Results The highest rates of HBxAg were detected in CHB (65.0%) and HCC (44.4%) liver samples,and the antigen was mainly expressed in nuclei.Increasingly higher rates of p38MAPK,cdc25B,cyclin B1,and p34cdc2 expression were detected with increases in disease severity:normal liver (40.0%,20.0%,20.0%,and 30.0%,respectively),chronic hepatitis B (60.0%,65.0%,40.0%,and 50.0%,respectively),liver cirrhosis (65.0%,75.0%,70.0%,and 55.0%,respectively),paratumor cirrhosis (66.7%,75.0%,75.0%,and 63.9%,respestively),and HCC (77.8%,80.6%,80.6%,and 72.2%,respectively).In addition,the intracellular location of p38MAPK expression was different under different disease conditions,showing nuclear expression in CHB and liver cirrhosis samples and cytoplasmic expression in paratumor cirrhosis and HCC samples (x2 =1.11,P > 0.05).The proliferation index (PI) and the apoptosis index (AI) were both increased along with disease severity (nommal > CHB > paratumor cirrhosis > HCC) (PI:0.0000 ± 0.000,0.0502 ± 0.011,0.0411 ± 0.009,0.0762 ± 0.017; AI:0.0351 ± 0.024,0.0607 ±0.022,0.0562 ± 0.013,0.0716 ± 0.011),with the notable exception for liver cirrhosis (PI:0.1810 ± 0.036 and AI:0.1200 ± 0.018).PI in poorly-differentiated HCC (0.2285 ± 0.062) was significantly higher than in welldifferentiated HCC (0.1216 ± 0.032,t =2.082,P =0.044).AI in well-differentiated HCC (0.152 ± 0.026) was significantly higher than in poorly-differentiated HCC (0.081 ± 0.022,t =2.129,P =0.041).Conclusions In the process of hepatocarcinogenesis,HBxAg may cause a series of abnormal changes in cell cycle,proliferation and apoptosis by affecting the expression of p38MAPK.

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