Mohamed Fatma E, Al-Jehani Rajai M, Minogue Shane S, Andreola Fausto, Winstanley Alison, Olde Damink Steven W M, Habtesion Abeba, Malagó Massimo, Davies Nathan, Luong Tu Vinh, Dhillon Amar P, Mookerjee Rajeshwar P, Dhar Dipok K, Jalan Rajiv
UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK; Pathology Department, Minia University, El-Minia, Egypt.
Liver Int. 2015 Mar;35(3):1063-76. doi: 10.1111/liv.12626. Epub 2014 Jul 30.
BACKGROUND & AIMS: Chronic liver disease is a predisposing factor for development of hepatocellular carcinoma (HCC). Toll-like receptors play a crucial role in immunity against microbial pathogens and recent evidence suggests that they may also be important in pathogenesis of chronic liver disease. The purpose of this study was to determine whether TLR7 and TLR9 are potential targets for prevention and progression of HCC.
Tissue microarrays containing liver samples from patients with cirrhosis, viral hepatitis and HCC were examined for expression of TLR7 and TLR9 and the data obtained was validated in liver specimens from the hospital archives. Proliferation of human HCC cell lines was studied following stimulation of TLR7 and TLR9 using agonists (imiquimod and CpG-ODN respectively) and inhibition with a specific antagonist (IRS-954) or chloroquine. The effect of these interventions was confirmed in a xenograft model and diethylnitrosamine (DEN)/nitrosomorpholine (NMOR)-induced model of HCC.
TLR7 and TLR9 expression was up-regulated in human HCC tissue. Proliferation of HuH7 cells in vitro increased significantly in response to stimulation of TLR7. TLR7 and TLR9 inhibition using IRS-954 or chloroquine significantly reduced HuH7 cell proliferation in vitro and inhibited tumour growth in the mouse xenograft model. HCC development in the DEN/NMOR rat model was also significantly inhibited by chloroquine (P < 0.001).
The data suggest that inhibiting TLR7 and TLR9 with IRS-954 or chloroquine could potentially be used as a novel therapeutic approach for preventing HCC development and/or progression in susceptible patients.
慢性肝病是肝细胞癌（HCC）发生的一个易感因素。Toll样受体在抵抗微生物病原体的免疫过程中起关键作用，最近有证据表明它们在慢性肝病的发病机制中可能也很重要。本研究的目的是确定Toll样受体7（TLR7）和Toll样受体9（TLR9）是否为预防HCC发生及进展的潜在靶点。
对包含肝硬化、病毒性肝炎及HCC患者肝脏样本的组织芯片进行TLR7和TLR9表达检测，并在医院存档的肝脏标本中验证所得数据。分别使用激动剂（咪喹莫特和CpG-寡脱氧核苷酸）刺激TLR7和TLR9，并用特异性拮抗剂（IRS-954）或氯喹抑制，研究人HCC细胞系的增殖情况。在异种移植模型以及二乙基亚硝胺（DEN）/亚硝基吗啉（NMOR）诱导的HCC模型中证实了这些干预措施的效果。
人HCC组织中TLR7和TLR9表达上调。体外培养的HuH7细胞在受到TLR7刺激后增殖显著增加。使用IRS-954或氯喹抑制TLR7和TLR9可显著降低体外培养的HuH7细胞增殖，并抑制小鼠异种移植模型中的肿瘤生长。氯喹也显著抑制了DEN/NMOR大鼠模型中的HCC发生（P < 0.001）。
数据表明，用IRS-954或氯喹抑制TLR7和TLR9可能作为一种新的治疗方法，用于预防易感患者发生HCC及/或其进展。
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