Inhibition of TLR7 and TLR9 Reduces Human Cholangiocarcinoma Cell Proliferation and Tumor Development.

Autor: Mohamed FEZ; UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK.; Pathology Department, Minia University, El-Minia, Egypt., Jalan R; UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK., Minogue S; UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK., Andreola F; UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK., Habtesion A; UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK., Hall A; UCL Institute for Liver and Digestive Health, Royal Free London NHS Foundation Trust, London, UK., Winstanley A; Department of Cellular Pathology, University College London Hospitals NHS Foundation Trust, London, UK., Damink SO; Academic Department of Surgery and Interventional Sciences, Royal Free Hospital, London, UK., Malagó M; Academic Department of Surgery and Interventional Sciences, Royal Free Hospital, London, UK., Davies N; UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK., Luong TV; Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London, UK., Dhillon A; Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London, UK., Mookerjee R; UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK., Dhar D; UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK., Al-Jehani RM; UCL Institute for Liver and Digestive Health, Royal Free London NHS Foundation Trust, London, UK. r.al-jehani@ucl.ac.uk.
Jazyk: angličtina
Zdroj: Digestive diseases and sciences [Dig Dis Sci] 2022 May; Vol. 67 (5), pp. 1806-1821. Date of Electronic Publication: 2021 May 03.
DOI: 10.1007/s10620-021-06973-9
Abstrakt: Background: Toll-like receptors (TLRs) are key players in innate immunity and modulation of TLR signaling has been demonstrated to profoundly affect proliferation and growth in different types of cancer. However, the role of TLRs in human intrahepatic cholangiocarcinoma (ICC) pathogenesis remains largely unexplored.
Aims: We set out to determine if TLRs play any role in ICCs which could potentially make them useful treatment targets.
Methods: Tissue microarrays containing samples from 9 human ICCs and normal livers were examined immunohistochemically for TLR4, TLR7, and TLR9 expression. Proliferation of human ICC cell line HuCCT1 was measured by MTS assay following treatment with CpG-ODN (TLR9 agonist), imiquimod (TLR7 agonist), chloroquine (TLR7 and TLR9 inhibitor) and IRS-954 (TLR7 and TLR9 antagonist). The in vivo effects of CQ and IRS-954 on tumor development were also examined in a NOD-SCID mouse xenograft model of human ICC.
Results: TLR4 was expressed in all normal human bile duct epithelium but absent in the majority (60%) of ICCs. TLR7 and TLR9 were expressed in 80% of human ICCs. However, TLR7 was absent in all cases of normal human bile duct epithelium and only one was TLR9 positive. HuCCT1 cell proliferation in vitro significantly increased following IMQ or CpG-ODN treatment (P < 0.03 and P < 0.002, respectively) but decreased with CQ (P < 0.02). In the mouse xenograft model there was significant reduction in size of tumors from CQ and IRS-954 treated mice compared to untreated controls.
Conclusion: TLR7 and TLR9 should be further explored for their potential as actionable targets in the treatment of ICC.
(© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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