Expression of connective tissue growth factor in the livers of non-viral hepatocellular carcinoma patients with metabolic risk factors
Expression of connective tissue growth factor in the livers of non-viral hepatocellular carcinoma patients with metabolic risk factors
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DOI：
10.1007/s00535-015-1159-8
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发表时间：
2016-09-01
影响因子：
6.3
通讯作者：
Tanabe, Minoru
中科院分区：
文献类型：
--
作者：
Akahoshi, Keiichi;Tanaka, Shinji;Tanabe, Minoru
与代谢危险因素如糖尿病和肥胖相关的肝细胞癌（HCC）的发病率一直在增加。然而，潜在的机制，这些疾病的联系仍然不清楚。我们进行了全基因组表达分析的非病毒性肝癌患者的人类肝组织有或没有代谢危险因素。通过体内外实验和免疫组化方法研究了糖尿病和肥胖相关基因的表达上调情况，其中结缔组织生长因子（CTGF）的表达在葡萄糖和胰岛素联合作用的人肝癌细胞中有明显的上调。全基因组表达分析揭示了CTGF过表达肝癌细胞中趋化因子网络的上调，这显示出诱导巨噬细胞体外激活和肝脏巨噬细胞体内浸润的能力增强。人肝组织的免疫组化证实了CTGF表达与糖尿病或肥胖以及非病毒性HCC患者肝巨噬细胞活化之间的相关性。与CTGF阴性患者相比，CTGF阳性患者的无复发生存率明显较差（p = 0.002）。多因素分析显示CTGF表达（HR 2.361; 95% CI 1.195-4.665; p = 0.013）和血管浸润（HR 2.367; 95% CI 1.270-4.410; p = 0.007）是非病毒性肝癌复发的独立预后因素。病毒性HCC通过诱导肝脏炎症与代谢危险因素相关，有望成为新的HCC风险生物标志物和潜在的治疗靶点。
The incidence of hepatocellular carcinoma (HCC) associated with metabolic risk factors, such as diabetes and obesity, has been increasing. However, the underlying mechanism that links these diseases remains unclear.We performed genome-wide expression analysis of human liver tissues of non-viral HCC patients with or without metabolic risk factors. The upregulated genes that associated with diabetes and obesity were investigated by in vitro and in vivo experiments, and immunohistochemistry of human liver tissues was performed.Among the upregulated genes, connective tissue growth factor (CTGF) expression was induced to a greater extent by combined glucose and insulin administration to human hepatoma cells. Genome-wide expression analysis revealed upregulation of a chemokine network in CTGF-overexpressing hepatoma cells, which displayed an increased ability to induce in vitro activation of macrophages, and in vivo infiltration of liver macrophages. Immunohistochemistry of human liver tissues validated the correlations between CTGF expression and diabetes or obesity as well as activation of liver macrophages in patients with non-viral HCC. Recurrence-free survival was significantly poorer in the CTGF-positive patients compared with the CTGF-negative patients (p = 0.002). Multivariate analysis determined that CTGF expression (HR 2.361; 95 % CI 1.195-4.665; p = 0.013) and vascular invasion (HR 2.367; 95 % CI 1.270-4.410; p = 0.007) were independent prognostic factors for recurrence of non-viral HCC.Our data suggest that CTGF could be involved in oncogenic pathways promoting non-viral HCC associated with metabolic risk factors via induction of liver inflammation and is expected to be a novel HCC risk biomarker and potential therapeutic target.