843 SULF1 and SULF2 Correlated Genes in Hepatocellular Carcinoma (HCC) as Revealed by Genome-Wide Gene Expression Microarray Analysis

Abstract

The majority of hepatocullular carcinoms (HCC) developed in cirrhotic liver. Unfortunately, effective strategies for HCC prevention in patients are still limited to date. It has been well demonstrated that hepatocyte nuclear factor 4α (HNF4α) plays a key role in hepatocyte differentiation and hepatic functions. Our previous study has indicated that up-regulation of HNF4α could induce the differentiation of both hepatoma cells and liver cancer stem cells into hepatocytes, implying that HNF4α might present as a novel therapeutic agent for HCC (Hepatology 2008). More recently, we also demonstrated that HNF4α plays a critical role in hepatic fibrogenesis, and forced expression of HNF4α remarkably ameliorated hepatic fibrosis in rats (Gut, 2009). In this study, rats were subjected to intraperitoneal injections of diethylinitrosamine for 10 weeks to establish HCC model. The rats were then divided into model group, GFP group and HNF4α group, which were infused with PBS, 5×109 pfu AdGFP (adenovirus carrying GFP gene) or AdHNF4α (adenovirus carrying HNF4α gene) via the tail vein every other week up to 10 weeks, respectively. Our results revealed the gradual reduction of HNF4α and epithelial-mesenchymal transition (EMT) during hepatocarcinogenesis, which could be significantly attenuated by adenovirus-mediated HNF4α delivery. More interestingly, the introduction of HNF4α remarkably alleviated hepatic fibrosis and entirely blocked HCC occurrence in rats. In contrast, all livers of model group and GFP control group exhibited neoplastic nodules at the 22nd week. Meanwhile, the expression of the potential markers for liver cancer stem/progenitor cells (CD133, CD90, EpCAM2 and OV6) were dramatically blocked by HNF4α introduction. Furthermore, forced expression of HNF4α not only decreased the activation of Wnt/β-catenin signaling, but also inhibited NF-ΚB signaling pathway, which were closely associated with EMT and hepatocarcinogenesis, suggesting the preventive effect of HNF4α on HCC development might be attributed to the suppression of β-catenin and NF-ΚB signaling. In conclusion, up-regulation of HNF4α may present as a promising strategy for HCC prevention in clinical practice, and the strategy using differentiation determining transcription factor for cancer preventionmight be extended to other diseases.