EA 4427 SeRAIC-IRSET, Université de Rennes 1, IFR 140 Rennes, France.
Eur J Cancer. 2012 Jan;48(1):138-48. doi: 10.1016/j.ejca.2011.06.044. Epub 2011 Jul 19.
Development of hepatocellular carcinoma (HCC) is a complex and progressive disease that involves cycles of liver cell death, inflammation, and tissue regeneration/remodelling. Chemokines and chemokine receptors play numerous and integral roles in the disease progression of HCC. Here we investigated the novel chemokine receptor CXCR7/RDC1 in HCC progression, its two known ligands CXCL12 and CXCL11, as well as the other CXCL12 receptor, CXCR4. Our results show that in a cohort of 408 human HCCs, CXCR7 and CXCL11 were significantly higher in tumours compared to normal liver controls (5- and 10-fold, respectively). Immunohistochemical (IHC) staining on human HCC sections confirmed that both CXCL11 and CXCR7 were much higher in cancer tissues. Furthermore, IHC staining revealed that CXCR7 protein was only expressed in endothelial cells whereas CXCL11 exhibited a much broader tissue expression. At the cellular level we observed that in vitro, human microvascular endothelial cells (HMEC-1) up-regulated CXCR7 under hypoxic and acidic pH conditions, which are well known characteristics of the HCC tumour micro-environment. As for its ligand, we observed that IFNγ robustly induced CXCL11 in hepatic stellate cells, hepatocytes, and HMEC-1s. In addition, in the mouse Diethylnitrosamine model of hepatocarcinogenesis we observed a very strong induction of CXCR7 and CXCL11 transcripts, confirming that CXCR7/CXCL11 up-regulation is conserved between human and mice liver cancer. Altogether, our results strongly support the hypothesis that the CXCL11/CXCR7 pathway is involved HCC progression.
肝细胞癌（HCC）的发生发展是一个复杂而渐进的过程，涉及肝细胞死亡、炎症和组织再生/重塑的循环。趋化因子及其受体在 HCC 的疾病进展中发挥着众多不可或缺的作用。在这里，我们研究了趋化因子受体 CXCR7/RDC1 在 HCC 进展中的作用，以及其两个已知配体 CXCL12 和 CXCL11，以及另一个 CXCL12 受体 CXCR4。我们的结果表明，在 408 例人类 HCC 样本中，与正常肝对照相比，肿瘤中 CXCR7 和 CXCL11 的表达显著升高（分别为 5 倍和 10 倍）。对人类 HCC 切片进行免疫组织化学（IHC）染色证实，CXCL11 和 CXCR7 在癌组织中表达更高。此外，IHC 染色显示，CXCR7 蛋白仅在血管内皮细胞中表达，而 CXCL11 则表现出更广泛的组织表达。在细胞水平上，我们观察到在体外，人微血管内皮细胞（HMEC-1）在低氧和酸性 pH 条件下上调 CXCR7，这是 HCC 肿瘤微环境的典型特征。至于其配体，我们观察到 IFNγ 在肝星状细胞、肝细胞和 HMEC-1s 中强烈诱导 CXCL11 的表达。此外，在二乙基亚硝胺诱导的小鼠肝癌发生模型中，我们观察到 CXCR7 和 CXCL11 转录物的强烈诱导，证实 CXCR7/CXCL11 的上调在人类和小鼠肝癌中是保守的。总之，我们的研究结果有力地支持了 CXCL11/CXCR7 通路参与 HCC 进展的假说。
