RRC ID 50461
著者 Chiyonobu N, Shimada S, Akiyama Y, Mogushi K, Itoh M, Akahoshi K, Matsumura S, Ogawa K, Ono H, Mitsunori Y, Ban D, Kudo A, Arii S, Suganami T, Yamaoka S, Ogawa Y, Tanabe M, Tanaka S.
タイトル Fatty Acid Binding Protein 4 (FABP4) Overexpression in Intratumoral Hepatic Stellate Cells within Hepatocellular Carcinoma with Metabolic Risk Factors.
ジャーナル Am J Pathol
Abstract 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-κB 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.
巻・号 188(5)
ページ 1213-1224
公開日 2018-5-1
DOI 10.1016/j.ajpath.2018.01.012
PII S0002-9440(17)30959-8
PMID 29454748
MeSH Animals Carcinoma, Hepatocellular / genetics Carcinoma, Hepatocellular / metabolism* Carcinoma, Hepatocellular / pathology Cell Line, Tumor Cell Proliferation Fatty Acid-Binding Proteins / genetics Fatty Acid-Binding Proteins / metabolism* Hepatic Stellate Cells / metabolism* Hepatic Stellate Cells / pathology Humans Interleukin-1alpha / genetics Interleukin-1alpha / metabolism Interleukin-6 / genetics Interleukin-6 / metabolism Liver / metabolism Liver / pathology Liver Neoplasms / genetics Liver Neoplasms / metabolism* Liver Neoplasms / pathology Mice Mice, Knockout Receptor, Melanocortin, Type 4 / genetics Receptor, Melanocortin, Type 4 / metabolism Risk Factors
IF 3.491
引用数 8
リソース情報
遺伝子材料 CSII-EF-MCS (RDB04378).