Effect of toll‐like receptor 7 and 9 targeted therapy to prevent the development of hepatocellular carcinoma

Abstract

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. Methods: 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. Results: 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). Conclusion: 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.

Agonist and antagonist ligands of toll-like receptors 7 and 8: Ingenious tools for therapeutic purposes

“…Stimulation of TLR7 in a pancreatic cancer model expressing TLR7 induces tumor growth acceleration and reduction in antitumor molecules expression [299,300]. Similarly, TLR7 stimulation in hepatocellular carcinoma model expressing TLR7 boost malignant cells proliferation [301].…”

“…All these mechanisms of action highlight the anti-inflammatory and immuno-suppressive activity of this antimalarial drugs by acting on endosomal TLR signaling (TLRs 7/8/9). Moreover, CQ was under investigation for diseases associated with uncontrolled acute or chronic inflammation (severe sepsis [313]), to prevent and treat viral infections (HIV, influenza, and dengue) [314,315], cardiovascular diseases [316] or cancer by notably modulating autophagy [317]. Long term HCQ administration ameliorate hypertension and aortic endothelial dysfunction in a SLE mouse model [318].…”

Toll-like receptor 7 involves the injury in acute kidney ischemia/reperfusion of STZ-induced diabetic rats

“…Chloroquine (CQ), the antimalarial drug that inhibits the function of endosomal TLRs, has been shown to inhibit the endosomal TLR7 signalling effectively 17,18 . Although most studies have been reported on the role of TLR7 in inflammation and cancer, little is known in AKI with T1DM.…”

Expression of toll-like receptors in hepatic cirrhosis and hepatocellular carcinoma

“…These data indicate that TLR7 is downregulated in HCV-related HCC. However, Mohamed et al (2015) reported different results. Their data, produced by immunohistochemistry staining, showed that TLR7 and TLR9 were both overexpressed in the HCC tissues compared with those from cirrhosis and viral hepatitis cases.…”