Down-regulation of Toll-like receptor 7 expression in hepatitis-virus–related human hepatocellular carcinoma

• Published in: Human pathology 2013-04, Vol.44 (4), p.534-541
• Main Authors: Lin, Kai-Jen, MD, Lin, Tsun-Mei, PhD, Wang, Chiou-Huey, MA, Liu, Hsiang-Chun, BA, Lin, Yen-Li, BA, Eng, Hock-Liew, MD
• Format: Article
• Language: English
• Subjects: Aged; Antiviral Agents - pharmacology; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - surgery; Carcinoma, Hepatocellular - virology; Cell Line, Tumor; Dose-Response Relationship, Drug; Down-Regulation; Female; Gene Expression Regulation, Neoplastic - physiology; Hep G2 Cells - drug effects; Hep G2 Cells - metabolism; Hepatectomy; Hepatitis; Hepatitis B - genetics; Hepatitis B - surgery; Hepatitis B - virology; Hepatitis C - genetics; Hepatitis C - surgery; Hepatitis C - virology; Hepatitis virus infection; Hepatoma; Humans; Immune system; Interferon-gamma; Interferon-gamma - pharmacology; Liver cirrhosis; Liver Neoplasms - genetics; Liver Neoplasms - surgery; Liver Neoplasms - virology; Male; Middle Aged; Pathology; Proteins; Real-Time Polymerase Chain Reaction; Retrospective Studies; RNA, Messenger - metabolism; Rodents; Toll-like receptor 7; Toll-Like Receptor 7 - genetics; Toll-Like Receptor 7 - metabolism
• ISSN: 0046-8177; 1532-8392
• DOI: 10.1016/j.humpath.2012.06.015

Summary Toll-like receptors (TLRs) play a pivotal role in innate immunity, controlling inflammatory responses, and further development of adaptive immunity. Hepatitis virus can establish chronic infection, and the associated inflammatory responses are important determinants of virus-associated liver damage. However, the contributions of the host immune system to chronic presence of virus are not clear in patients with hepatitis virus infection. Chronic inflammatory conditions caused by persistent hepatitis virus infections and interferon (IFN)- γ -related immunopathology are known to be related to carcinogenesis. To gain insight into the role of immune modulation in the pathogenesis of hepatocellular carcinoma (HCC), we studied the expression of TLR7 in cancerous and non-cancerous liver tissue from 87 patients with HCC. Our results showed that TLR7 is significantly down-regulated in neoplastic hepatocytes ( P < .001), especially in the patients with hepatitis B (n = 52) or C (n = 24) virus infection. We confirmed this decreased TLR7 expression by quantitative analysis of mRNA using real-time reverse transcription-polymerase chain reaction in 26 liver specimens of HCC patients. Using serial deletion analysis of the TLR7 promoter, a hepatocyte-specific regulatory region was found at nucleotides −156 to −98 in the TLR7 promoter. Furthermore, the effects of IFN- γ on TLR7 expression in a hepatoma cell line (HepG2) were investigated in vitro. We demonstrated that IFN- γ significantly decreased TLR7 promoter activity and expression in a dose-dependent manner. We thus propose that hepatitis virus induces down-regulation of TLR7 gene expression through IFN- γ , thereby modulating inflammatory signaling in hepatoma cells.