癌症研究
CXCL5型
间质细胞
转移
趋化因子受体
基质金属蛋白酶
血管生成
基质细胞衍生因子1
趋化因子
肿瘤进展
肿瘤微环境
CXCR4型
生物
医学
免疫学
内科学
癌症
炎症
肿瘤细胞
作者
Oihane García-Irigoyen,María U. Latasa,Simone Carotti,Iker Uriarte,María Elizalde,Raquel Urtasun,Umberto Vespasiani Gentilucci,Sergio Morini,Paula G. Benito,José M. Ladero,José Antonio Rodríguez,Jesús Prieto,Josune Orbe,José A. Páramo,Maite G. Fernández‐Barrena,Carmen Berasain,Matías A. Ávila
出处
期刊:Hepatology
[Wiley]
日期:2015-04-22
卷期号:62 (1): 166-178
被引量:56
摘要
Matrix metalloproteinases (MMPs) participate in tissue repair after acute injury, but also participate in cancer by promoting a protumorigenic microenvironment. Previously, we reported on a key role for MMP10 in mouse liver regeneration. Herein, we investigated MMP10 expression and function in human hepatocellular carcinoma (HCC) and diethylnitrosamine (DEN)-induced mouse hepatocarcinogenesis. MMP10 was induced in human and murine HCC tissues and cells. MMP10-deficient mice showed less HCC incidence, smaller histological lesions, reduced tumor vascularization, and less lung metastases. Importantly, expression of the protumorigenic, C-X-C chemokine receptor-4 (CXCR4), was reduced in DEN-induced MMP10-deficient mice livers. Human HCC cells stably expressing MMP10 had increased CXCR4 expression and migratory capacity. Pharmacological inhibition of CXCR4 significantly reduced MMP10-stimulated HCC cell migration. Furthermore, MMP10 expression in HCC cells was induced by hypoxia and the CXCR4 ligand, stromal-derived factor-1 (SDF1), through the extracellular signal-regulated kinase 1/2 pathway, involving an activator protein 1 site in MMP10 gene promoter. Conclusion: MMP10 contributes to HCC development, participating in tumor angiogenesis, growth, and dissemination. We identified a new reciprocal crosstalk between MMP10 and the CXCR4/SDF1 axis contributing to HCC progression and metastasis. To our knowledge, this is the first report addressing the role of a MMP in hepatocarcinogenesis in the corresponding genetic mouse model. (Hepatology 2015;62:166-178)
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