FABP4 overexpressed in intratumoral hepatic stellate cells within hepatocellular carcinoma with metabolic risk factors (part 2)

BACKGROUND & AIMS: Metabolic syndrome is a newly identified risk factor for hepatocellular carcinoma (HCC), however the molecular mechanisms still remain unclear. To elucidate this issue, cross-species analysis was performed to compare gene expression patterns of HCC from human patients and melanocortin 4 receptor-knockout (MC4R-KO) mice, developing HCC with obesity, insulin resistance and dyslipidemia. METHODS: Unsupervised hierarchical clustering and principle component analysis of 746 differentially expressed orthologous genes classified HCC of 152 human patients and MC4R-KO mice into two distinct subgroups, one of which included all the mouse HCC was etiologically associated with metabolic risk factors, such as obesity and diabetes. A specific biomarker was identified by the integrative analysis, and validated with in vitro studies and other cohort patients. RESULTS: As commonly overexpressed in human and mouse metabolic disease-associated HCC, FABP4 was remarkably enriched in intratumoral activated hepatic stellate cells (HSCs). Then, we established subclones constitutively expressing FABP4 from a human HSC cell line, in which the expression levels of inflammatory chemokines including IL1A and IL6 was upregulated through NF-κB nuclear translocation. An immunohistochemical validation study of other 106 human HCC samples indicated that FABP4-positive HSCs were distributed in tumors of 38 cases, and that the FABP4-high group was composed of patients with non-viral and non-alcoholic HCC (P=0.027) and with multiple metabolic risk factors (P<0.001) compared with the FABP4-low. CONCLUSIONS: FABP4 overexpression in HSCs could contribute to hepatocellular carcinogenesis in patients with metabolic risk factors via modulation of inflammatory pathway, and is a promising novel biomarker as well as a potential therapeutic target for this subtype of HCC. A total of 152 patients who underwent curative hepatic resection for HCC between 2006 and 2011 at Tokyo Medical and Dental University Hospital participated in integrated gene expression microarray analysis. Fourteen adjacent liver tissues obtained from patients with metastasis of colorectal cancer who had not received chemotherapy were used as control.