Essential contribution of a chemokine, CCL3, and its receptor, CCR1, to hepatocellular carcinoma progression
Essential contribution of a chemokine, CCL3, and its receptor, CCR1, to hepatocellular carcinoma progression
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趋化因子 CCL3 及其受体 CCR1 对肝细胞癌进展的重要贡献
DOI：
10.1002/ijc.21596
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发表时间：
2006-04-15
影响因子：
6.4
通讯作者：
Mukaida, N
中科院分区：
文献类型：
--
作者：
Yang, XQ;Lu, PR;Mukaida, N
我们之前观察到一种趋化因子巨噬细胞炎症蛋白-1 α /CCL3及其受体CCR1在人肝细胞癌（HCC）组织中异常表达。在这里，我们发现CCL3和CCR1也在2种不同的癌症模型中表达；n-亚硝基二乙胺（DEN）诱导的HCC和乙型肝炎病毒表面（HBs）抗原引发的脾细胞转移到骨髓消融的同源HBs抗原转基因小鼠诱导的HCC在DEN治疗10个月后，与野生型（WT）小鼠相比，CCR1-和ccl3缺陷小鼠的病灶数量和大小显着减少，尽管CCR1-和ccl3缺陷小鼠的肿瘤发生率轻微但显著高于野生型小鼠。值得注意的是，CCL3-和ccr1缺陷小鼠的肿瘤血管生成也明显减少，同时肿瘤内库普弗细胞数量减少，库普弗细胞是生长因子和基质金属蛋白酶（MMPs）的丰富来源。在我们检测的生长因子和MMPs中，DEN处理后WT小鼠肝脏中只有MMP9和MMP13基因表达逐渐增强。此外，与WT小鼠相比，CCR1-和ccl3缺陷小鼠的MMP9基因表达减弱，而MMP13基因表达不减弱。此外，MMP9主要在单个核细胞中表达，而不是在肝癌细胞中表达，与WT小鼠相比，CCR1-或ccl3缺陷小鼠中表达MMP9的细胞数量减少。这些观察结果提示CCR1-CCL3轴对HCC进展的贡献。(c) 2005 Wiley-Liss, Inc。
We previously observed that a chemokine, macrophage inflammatory protein-1 alpha/CCL3, and its receptor, CCR1, were aberrantly expressed in human hepatocellular carcinoma (HCC) tissues. Here, we show that CCL3 and CCR1 are also expressed in 2 different models of this cancer; N-nitrosodiethylamine (DEN)-induced HCC and HCC induced by hepatitis B virus surface (HBs) antigen-primed splenocyte transfer to myelo-ablated syngeneic HBs antigen transgenic mice. At 10 months after DEN treatment, foci number and sizes were remarkably reduced in CCR1- and CCL3-deficient mice, compared with those or wild-type (WT) mice, although tumor incidence were marginally, but significantly, higher in CCR1- and CCL3-deficient mice than in WT mice. Of note is that tumor angiogenesis was also markedly diminished in CCL3- and CCR1-deficient mice, with a concomitant reduction in the number of intratumoral Kupffer cells, a rich source of growth factors and matrix metalloproteinases (MMPs). Among growth factors and MMPs that we examined, only MMP9 and MMP13 gene expression was augmented progressively in liver of WT mice after DEN treatment. Moreover, MMP9, but not MMP13, gene expression was attenuated in CCR1- and CCL3-deficient mice, compared with that of WT mice. Furthermore, MMP9 was expressed mainly by mononuclear cells but not hepatoma cells, and MMP9-expressing cell numbers were decreased in CCR1- or CCL3-deficient mice, compared with WT mice. These observations suggest the contribution of the CCR1-CCL3 axis to HCC progression. (c) 2005 Wiley-Liss, Inc.