Hepatocyte-stellate cell cross-talk in the liver engenders a permissive inflammatory microenvironment that drives progression in hepatocellular carcinoma.
Hepatocyte-stellate cell cross-talk in the liver engenders a permissive inflammatory microenvironment that drives progression in hepatocellular carcinoma.
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肝脏中的肝细胞粘液细胞串扰会产生一种宽松的炎症微环境，可在肝细胞癌中进展。
DOI：
10.1158/0008-5472.can-11-3317
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发表时间：
2012-05-15
期刊：
影响因子：
11.2
通讯作者：
Clément B
中科院分区：
文献类型：
--
作者：
Coulouarn C;Corlu A;Glaise D;Guénon I;Thorgeirsson SS;Clément B
许多实体恶性肿瘤发生在炎症和/或纤维化组织的背景下，这些特征在80%以上的肝细胞癌（HCC）中发现。活化的肝星状细胞（HSC）在与HCC发生和进展相关的纤维形成中起着关键作用，但其对肝细胞命运的功能影响在很大程度上仍未被探索。在这里，我们使用共培养模型来研究肝细胞（人类肝癌细胞）和活化的人类HSC之间的串扰。无监督的全基因组表达谱表明，肝细胞- hsc串扰是双向的，并导致功能相关基因网络的失调。值得注意的是，共培养增加了促炎细胞因子的表达，并改变了肝细胞向运动细胞的表型。肝细胞-HSC串扰也产生了一个允许的促血管生成微环境，特别是通过诱导VEGFA和MMP9在HSC中的表达。一项综合基因组分析显示，与肝细胞- hsc串扰相关的基因表达与小鼠HCC进展相关，并可预测人类HCC的不良预后和转移倾向。有趣的是，串扰对迁移和血管生成的影响被组蛋白去乙酰化酶抑制剂trichostatin a逆转。因此，我们的研究结果表明，肝癌细胞和活化的HSC之间的串扰是HCC进展的一个重要特征，这可能是表观遗传调控的目标。
Many solid malignant tumors arise on a background of inflamed and/or fibrotic tissues, features which are found in more than 80% hepatocellular carcinomas (HCC). Activated hepatic stellate cells (HSC) play a critical role in fibrogenesis associated with HCC onset and progression, yet their functional impact on hepatocyte fate remains largely unexplored. Here, we used a coculture model to investigate the crosstalk between hepatocytes (human hepatoma cells) and activated human HSC. Unsupervised genome-wide expression profiling demonstrated that hepatocyte-HSC crosstalk is bidirectional and results in the deregulation of functionally relevant gene networks. Notably, coculturing increased the expression of pro-inflammatory cytokines and modified the phenotype of hepatocytes toward motile cells. Hepatocyte-HSC crosstalk also generated a permissive pro-angiogenic microenvironment, particularly by inducing VEGFA and MMP9 expression in HSC. An integrative genomic analysis revealed that the expression of genes associated with hepatocyte-HSC crosstalk correlated with HCC progression in mice and was predictive of a poor prognosis and metastasis propensity in human HCC. Interestingly, the effects of crosstalk on migration and angiogenesis were reversed by the histone deacetylase inhibitor trichostatin A. Our findings therefore indicate that the crosstalk between hepatoma cells and activated HSC is an important feature of HCC progression, which may be targeted by epigenetic modulation.