Université de Technologie de Compiègne, BP 20529, 60205 Compiègne Cedex, France.
BMC Genomics. 2012 Feb 1;13:54. doi: 10.1186/1471-2164-13-54.
Understanding hepatic zonation is important both for liver physiology and pathology. There is currently no effective systemic chemotherapy for human hepatocellular carcinoma (HCC) and its pathogenesis is of special interest. Genomic and proteomic data of HCC cells in different culture models, coupled to pathway-based analysis, can help identify HCC-related gene and pathway dysfunctions.
We identified zonation-related expression profiles contributing to selective phenotypes of HCC, by integrating relevant experimental observations through gene set enrichment analysis (GSEA). Analysis was based on gene and protein expression data measured on a human HCC cell line (HepG2/C3A) in two culture conditions: dynamic microfluidic biochips and static Petri dishes. Metabolic activity (HCC-related cytochromes P450) and genetic information processing were dominant in the dynamic cultures, in contrast to kinase signaling and cancer-specific profiles in static cultures. That, together with analysis of the published literature, leads us to propose that biochips culture conditions induce a periportal-like hepatocyte phenotype while standard plates cultures are more representative of a perivenous-like phenotype. Both proteomic data and GSEA results further reveal distinct ubiquitin-mediated protein regulation in the two culture conditions.
Pathways analysis, using gene and protein expression data from two cell culture models, confirmed specific human HCC phenotypes with regard to CYPs and kinases, and revealed a zonation-related pattern of expression. Ubiquitin-mediated regulation mechanism gives plausible explanations of our findings. Altogether, our results suggest that strategies aimed at inhibiting activated kinases and signaling pathways may lead to enhanced metabolism-mediated drug resistance of treated tumors. If that were the case, mitigating inhibition or targeting inactive forms of kinases would be an alternative.
理解肝分区对于肝脏生理学和病理学都很重要。目前，针对人类肝细胞癌（HCC）尚无有效的系统性化疗方法，而其发病机制尤其值得关注。不同培养模型中 HCC 细胞的基因组和蛋白质组数据，加上基于通路的分析，有助于识别与 HCC 相关的基因和通路功能障碍。
我们通过基因集富集分析（GSEA）整合了相关的实验观察结果，确定了与肝分区相关的表达谱，这些表达谱有助于选择性表型的 HCC。分析基于在两种培养条件下对人 HCC 细胞系（HepG2/C3A）进行的基因和蛋白质表达数据：动态微流控生物芯片和静态培养皿。在动态培养中，代谢活性（与 HCC 相关的细胞色素 P450）和遗传信息处理占主导地位，而在静态培养中则以激酶信号和癌症特异性特征为主。这一点，再加上对已发表文献的分析，使我们提出生物芯片培养条件诱导出类似于门脉周围的肝细胞表型，而标准板培养则更具代表性的类似于中心静脉的表型。这两种培养条件的蛋白质组数据和 GSEA 结果进一步揭示了不同的泛素介导的蛋白质调控。
使用两种细胞培养模型的基因和蛋白质表达数据进行通路分析，证实了特定的人类 HCC 表型与 CYPs 和激酶有关，并揭示了与肝分区相关的表达模式。泛素介导的调节机制为我们的发现提供了合理的解释。总之，我们的研究结果表明，旨在抑制激活的激酶和信号通路的策略可能导致治疗肿瘤的代谢介导的药物耐药性增强。如果情况确实如此，那么减轻抑制或针对激酶的非活性形式可能是一种替代方法。
