基于生物信息学分析肝内胆管细胞癌与肝细胞癌基因表达和分子机制差异

Differences of gene expression and molecular mechanism between intrahepatic cholangiocarcinoma and hepatocellular carcinoma based on bioinformatics

目的 探讨肝内胆管细胞癌(ICC)和肝细胞癌(HCC)的基因表达及分子机制差异。方法 从基因表达数据库下载ICC和HCC基因表达矩阵,通过基因集富集分析探讨ICC与正常组织、ICC与HCC的差异,获得共激活和共抑制的特征基因集。提取核心基因,使用MCODE分析关键分子模块,通过基因本体和京都基因与基因百科全书(KEGG)分析关键分子模块中的基因潜在的生物学过程和信号通路,并基于细胞水平利用聚合酶链反应阵列评估上述基因的相对表达水平。结果 与HCC相比,ICC中激活的基因集主要体现在上皮间质转化、细胞周期及p53相关的基因集,而物质代谢相关的基因集则被明显抑制。共激活特征基因集中获得2个关键分子模块,其生物学过程和KEGG信号通路主要富集在细胞周期及细胞外基质相关的信号通路;共抑制基因集中获得3个关键分子模块,其生物学过程和KEGG信号通路主要富集在物质代谢的相关通路。聚合酶链反应阵列分析结果显示细胞周期相关基因在ICC、HCC中均高水平表达,ICC中与细胞外基质相关的胶原蛋白家族基因也呈现明显的高水平表达,而物质代谢相关的基因则被明显抑制。结论物质代谢和细胞周期的调控异常可能是ICC致病的重要环节,也是有别于HCC致病的关键所在,为从物质代谢和细胞周期角度挖掘ICC有价值的诊断和治疗的潜在分子靶点提供了参考。

Objective To investigate the differences in gene expression and potential molecular mechanisms between intrahepatic cholangiocarcinoma(ICC) and hepatocellular carcinoma(HCC). Methods Downloaded ICC and HCC gene expression data from public gene expression databases, and used gene set enrichment analysis(GSEA) to explore the differences in gene set enrichment between ICC and normal tissues, ICC and HCC tissues. Then integrated the results of the two groups, obtained the hallmarks gene set of co-activated and cosuppressed. We extracted the core genes in the GSEA results, and used molecular complex detection to analyze the key molecular modules, and then explored the potential biological processes and signal pathways of the genes in the key molecular modules via gene ontology and Kyoto Encyclopedia of Genes and Genomes(KEGG) analyses. The relative expression levels of genes in key molecular modules were evaluated by PCR array based on cell lines. Results Compared with HCC, the activated gene sets in ICC were mainly reflected in the gene sets related to epithelial-mesenchymal transition, cell cycle and p53, while the gene sets related to material metabolism were significantly inhibited. Two key molecular modules were obtained from the co-activated hallmark gene set. The biological process and KEGG signal pathway were mainly enriched in the cell cycle and extracellular matrix-related signaling pathways, while the co-suppressed gene set obtained three key molecular modules. Biological processes and KEGG signaling pathways were mainly concentrated in related pathways of material metabolism. PCR array analysis showed that cell cycle-related genes were highly expressed in ICC and HCC, and genes from collagen family related to extracellular matrix were also significantly highly expressed, while genes related to substance metabolism were significantly inhibited in ICC. Conclusion Abnormality of material metabolism and the regulation of cell cycle may be an important link in the pathogenesis of ICC, it is also a key difference from the pathogenesis of HCC. These evidences provided reference for us to explore the valuable diagnostic and therapeutic potential molecular target for ICC from the perspective of material metabolism and cell cycle.