Akahoshi Keiichi, Tanaka Shinji, Mogushi Kaoru, Shimada Shu, Matsumura Satoshi, Akiyama Yoshimitsu, Aihara Arihiro, Mitsunori Yusuke, Ban Daisuke, Ochiai Takanori, Kudo Atsushi, Arii Shigeki, Tanabe Minoru
Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
J Gastroenterol. 2016 Sep;51(9):910-22. doi: 10.1007/s00535-015-1159-8. Epub 2016 Jan 6.
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.
与糖尿病和肥胖等代谢危险因素相关的肝细胞癌（HCC）发病率一直在上升。然而，将这些疾病联系起来的潜在机制仍不清楚。
我们对有或无代谢危险因素的非病毒性HCC患者的肝脏组织进行了全基因组表达分析。通过体外和体内实验研究了与糖尿病和肥胖相关的上调基因，并对人类肝脏组织进行了免疫组织化学分析。
在上调基因中，联合给予葡萄糖和胰岛素可更大程度地诱导人肝癌细胞中结缔组织生长因子（CTGF）的表达。全基因组表达分析显示，CTGF过表达的肝癌细胞中趋化因子网络上调，其诱导巨噬细胞体外活化和肝脏巨噬细胞体内浸润的能力增强。人类肝脏组织的免疫组织化学验证了CTGF表达与非病毒性HCC患者糖尿病或肥胖以及肝脏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期明显更差（p = 0.002）。多变量分析确定，CTGF表达（HR 2.361；95% CI 1.195 - 4.665；p = 0.013）和血管侵犯（HR 2.367；95% CI 1.270 - 4.410；p = 0.007）是非病毒性HCC复发的独立预后因素。
我们的数据表明，CTGF可能通过诱导肝脏炎症参与促进与代谢危险因素相关的非病毒性HCC的致癌途径，有望成为一种新的HCC风险生物标志物和潜在治疗靶点。
