Fatty Acid Binding Protein 4 (FABP4) Overexpression in Intratumoral Hepatic Stellate Cells within Hepatocellular Carcinoma with Metabolic Risk Factors
Fatty Acid Binding Protein 4 (FABP4) Overexpression in Intratumoral Hepatic Stellate Cells within Hepatocellular Carcinoma with Metabolic Risk Factors
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DOI：
10.1016/j.ajpath.2018.01.012
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发表时间：
2018-05-01
影响因子：
6
通讯作者：
Tanaka, Shinji
中科院分区：
文献类型：
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作者：
Chiyonobu, Norimichi;Shimada, Shu;Tanaka, Shinji
代谢综合征是新发现的肝细胞癌的危险因素，然而，肿瘤特异性生物标志物仍不清楚。我们进行了跨物种分析，以比较来自人类患者和黑素皮质素4受体敲除小鼠的肝癌的基因特征，这些小鼠患上了伴有肥胖、胰岛素抵抗和血脂异常的肝癌。对746个差异表达的同源基因进行无监督的系统聚类和主成分分析，将152名人类患者的肝癌和黑素皮质素4受体敲除小鼠分为两个不同的亚组，其中一个亚组包括小鼠肝癌，与代谢危险因素有关。共鉴定出9个在人类和小鼠代谢性疾病相关肝癌中高表达的基因；脂肪酸结合蛋白4(FABP4)在肿瘤内激活的肝星状细胞(HSCs)中显著富含。从人HSC细胞系中建立了FABP4的组成性表达亚克隆，在该细胞系中，包括IL-1A和IL-6在内的炎性趋化因子的表达水平通过核因子-kappaB核转位而上调，从而导致巨噬细胞的募集。免疫组织化学验证研究表明，FABP-4阳性的肝干细胞分布于38例肿瘤中，与FABP-4低表达组相比，FABP-4高表达组包括非病毒性、非酒精性肝癌(P=0.027)和具有多种代谢危险因素的患者(P<；0.001)。因此，FABP4在肝星状细胞中的过度表达可能通过调节炎症途径而促进具有代谢危险因素的患者的肝癌发生。
Metabolic syndrome is a newly identified risk factor for hepatocellular carcinoma (HCC); however, tumor specific biomarkers still remain unclear. We performed cross-species analysis to compare gene signatures of HCC from human patients and melanocortin 4 receptor-knockout mice, which develop HCC with obesity, insulin resistance, and dyslipidemia. Unsupervised hierarchical clustering and principle component analysis of 746 differentially expressed orthologous genes classified HCC of 152 human patients and melanocortin 4 receptor-knockout mice into two distinct subgroups, one of which included mouse HCC and was causatively associated with metabolic risk factors. Nine genes commonly overexpressed in human and mouse metabolic disease-associated HCC were identified; fatty acid binding protein 4 (FABP4) was remarkably enriched in intratumoral activated hepatic stellate cells (HSCs). Subclones constitutively expressing FABP4 were established from a human HSC cell line in which expression levels of inflammatory chemokines, including IL-1A and IL-6, were up-regulated through NF-kappa B nuclear translocation, resulting in recruitment of macrophages. An immunohistochemical validation study of 106 additional human HCC samples indicated that FABP4-positive HSCs were distributed in tumors of 38 cases, and the FABP4-high group consisted of patients with nonviral and nonalcoholic HCC (P = 0.027) and with multiple metabolic risk factors (P < 0.001) compared with the FABP4-low group. Thus, FABP4 overexpression in HSCs may contribute to hepatocarcinogenesis in patients with metabolic risk factors by modulation of inflammatory pathways.s