肝细胞癌中PGC-1α基因的表达下调及其意义

目的 探讨PGC-1α在肝细胞癌(HCC)组织中的表达及其在肝细胞癌发生发展中的调节作用.方法 采用定量逆转录聚合酶链反应(RT-PCR)分析HCC组织和正常肝组织中PGC-1α基因的表达,比较癌组织与正常组织的表达差异.采用siRNA干扰技术体外抑制人正常肝细胞株L02中PGC-1α基因的表达,并在光镜下观察细胞形态,电镜下观察细胞超微结构的改变.应用人全基因组Oligo DNA芯片分析比较肝组织和肝细胞基因的表达变化.结果 HCC组织中PGC-1α基因的表达明显下调,仅为正常肝组织的25.0%.抑制PGC-1α基因的表达可使人正常肝细胞株L02呈现出类似肝癌细胞的形态和超微结构变化,即细胞变小、变圆,胞质减少、核增大,细胞数量减少,成簇分布,线粒体膜呈髓鞘样变性等.基因芯片分析显示,抑制PGC-1α基因的表达可使人正常肝细胞株L02呈现出类似肝癌组织的基因变化趋势,即细胞黏附基因(TNFAIP6、ITGAX、ICAM1、FN1、EMR1、ITGA6、PARVA)、成瘤基因(PMAIP1、CRKL、FHIT、IRF1、PLK)和促进细胞增殖基因(STAT1、CCL3L1、IL6、WARS、PCK1、MUC2、PRKR、IFITM1)表达上调,肿瘤抑制基因(FHIT、PRKR、IL24、DLEU1、RCN2)表达下调.结论 PGC-1α表达下调能诱导人正常肝细胞株L02的肿瘤性转化,PGC-1α在肝癌发生发展中具有重要的调节作用.

Down-regulation of PGC-1α expression in human hepatocellular carcinoma

Objective To study the effect of PGc-1α in human liver carcinogenesis,and explore the regualatory role of PGC-1α in the development of liver cancer.Methods The changes of PGC-1α mRNA level in normal human liver tissues and human liver tumors was examined by quantitative RT-PCR.PGC-1α mRNA level was inteffered by siRNA in human liver cell line L02 in vitro.and their mowhologieal changes were observed by pathology with HE staining.The uhrastructure of cells was observed by electron microscopy.In addition.the gene expression pattem of decreasing PGC-1α in L02 cells and liver tumor tissue was compared by human genome 70-mer oligonucleotide mieroarray analysis.Results PGC-1α expression was weaker in the malignant liver tumors compared with that in normal liver tissues.When PGC-1α expression was suppressed in human liver L02 cells,the cells became smaller with eMarged nuclei,and myelin figures were observed in mitochondria by electron microscopy,similar with the ultrastmcture of liver cancer cells.Microarray analysis showed that the decrease of PGC-1α in L02 cells indueed up-regulation of some oncogenes and adhesive genes,and down-regulation of a number of tumor suppressor genes and cell proliferation suppressor genes.The changes of decreasing expression pattern of PGC-1α gene in L02 cells were similar to those in human liver cancer tissue.Conclusion The results of the present study show that PGC-1α is down-regulated in liver cancers and is involved in the malignant transformation in human normal liver cells in vitro,suggesting an important regulatory role of PGC-1α in the development of liver cancer.