Fatty Acid Binding Protein 4 (FABP4) Overexpression in Intratumoral Hepatic Stellate Cells within Hepatocellular Carcinoma with Metabolic Risk Factors

Norimichi Chiyonobu, Shu Shimada, Yoshimitsu Akiyama, Kaoru Mogushi, Michiko Itoh, Keiichi Akahoshi, Satoshi Matsumura, Kosuke Ogawa, Hiroaki Ono, Yusuke Mitsunori, Daisuke Ban, Atsushi Kudo, Shigeki Arii, Takayoshi Suganami, Shoji Yamaoka, Yoshihiro Ogawa, Minoru Tanabe, Shinji Tanaka

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1213-1224
Number of pages12
JournalAmerican Journal of Pathology
Volume188
Issue number5
DOIs
Publication statusPublished - May 2018

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Fatty Acid-Binding Proteins
Hepatic Stellate Cells
Hepatocellular Carcinoma
Knockout Mice
Genes
Validation Studies
Metabolic Diseases
Tumor Biomarkers
Dyslipidemias
Chemokines
Cluster Analysis
Insulin Resistance
Interleukin-6
Obesity
Macrophages
Cell Line

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

Fatty Acid Binding Protein 4 (FABP4) Overexpression in Intratumoral Hepatic Stellate Cells within Hepatocellular Carcinoma with Metabolic Risk Factors. / Chiyonobu, Norimichi; Shimada, Shu; Akiyama, Yoshimitsu; Mogushi, Kaoru; Itoh, Michiko; Akahoshi, Keiichi; Matsumura, Satoshi; Ogawa, Kosuke; Ono, Hiroaki; Mitsunori, Yusuke; Ban, Daisuke; Kudo, Atsushi; Arii, Shigeki; Suganami, Takayoshi; Yamaoka, Shoji; Ogawa, Yoshihiro; Tanabe, Minoru; Tanaka, Shinji.

In: American Journal of Pathology, Vol. 188, No. 5, 05.2018, p. 1213-1224.

Research output: Contribution to journalArticle

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 2018, 'Fatty Acid Binding Protein 4 (FABP4) Overexpression in Intratumoral Hepatic Stellate Cells within Hepatocellular Carcinoma with Metabolic Risk Factors', American Journal of Pathology, vol. 188, no. 5, pp. 1213-1224. https://doi.org/10.1016/j.ajpath.2018.01.012
Chiyonobu, Norimichi ; Shimada, Shu ; Akiyama, Yoshimitsu ; Mogushi, Kaoru ; Itoh, Michiko ; Akahoshi, Keiichi ; Matsumura, Satoshi ; Ogawa, Kosuke ; Ono, Hiroaki ; Mitsunori, Yusuke ; Ban, Daisuke ; Kudo, Atsushi ; Arii, Shigeki ; Suganami, Takayoshi ; Yamaoka, Shoji ; Ogawa, Yoshihiro ; Tanabe, Minoru ; Tanaka, Shinji. / Fatty Acid Binding Protein 4 (FABP4) Overexpression in Intratumoral Hepatic Stellate Cells within Hepatocellular Carcinoma with Metabolic Risk Factors. In: American Journal of Pathology. 2018 ; Vol. 188, No. 5. pp. 1213-1224.
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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.",
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AU - Chiyonobu, Norimichi

AU - Shimada, Shu

AU - Akiyama, Yoshimitsu

AU - Mogushi, Kaoru

AU - Itoh, Michiko

AU - Akahoshi, Keiichi

AU - Matsumura, Satoshi

AU - Ogawa, Kosuke

AU - Ono, Hiroaki

AU - Mitsunori, Yusuke

AU - Ban, Daisuke

AU - Kudo, Atsushi

AU - Arii, Shigeki

AU - Suganami, Takayoshi

AU - Yamaoka, Shoji

AU - Ogawa, Yoshihiro

AU - Tanabe, Minoru

AU - Tanaka, Shinji

PY - 2018/5

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N2 - 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.

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