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03-05-2021 | Chloroquin | Original Article

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

Authors: Fatma El Zahraa Mohamed, Rajiv Jalan, Shane Minogue, Fausto Andreola, Abeba Habtesion, Andrew Hall, Alison Winstanley, Steven Olde Damink, Massimo Malagó, Nathan Davies, Tu Vinh Luong, Amar Dhillon, Rajeshwar Mookerjee, Dipok Dhar, Rajai Munir Al-Jehani

Published in: Digestive Diseases and Sciences | Issue 5/2022

Abstract

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.

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Title: Inhibition of TLR7 and TLR9 Reduces Human Cholangiocarcinoma Cell Proliferation and Tumor Development
Authors: Fatma El Zahraa Mohamed
Rajiv Jalan
Shane Minogue
Fausto Andreola
Abeba Habtesion
Andrew Hall
Alison Winstanley
Steven Olde Damink
Massimo Malagó
Nathan Davies
Tu Vinh Luong
Amar Dhillon
Rajeshwar Mookerjee
Dipok Dhar
Rajai Munir Al-Jehani
Publication date: 03-05-2021
Publisher: Springer US
Keywords: Chloroquin
Cholangiocarcinoma
Chloroquin
Cholangiocarcinoma
Published in: Digestive Diseases and Sciences / Issue 5/2022
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI: https://doi.org/10.1007/s10620-021-06973-9

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