Modulation of biliary cancer chemo‐resistance through microRNA‐mediated rewiring of the expansion of CD133+ cells

Carotenuto, P. et al. (2020) Modulation of biliary cancer chemo‐resistance through microRNA‐mediated rewiring of the expansion of CD133+ cells. Hepatology, 72(3), pp. 982-996. (doi: 10.1002/hep.31094) (PMID:31879968) (PMCID:PMC7590111)

[img] Text
207248.pdf - Published Version
Available under License Creative Commons Attribution.



Background and aims: Changes in single microRNA (MIR) expression have been associated with chemo‐resistance in Biliary Tract Cancer (BTC). However, a global assessment of the dynamic role of the microRNome has never been performed to identify potential therapeutic targets that are functionally relevant in the BTC cell response to chemotherapy. Approach and Results: High‐throughput‐screening of 997 LNA‐MIR‐inhibitors was performed in 6 CCA cell lines treated with Cisplatin‐Gemcitabine (CG) seeking changes in cell viability. Validation experiments were performed with miRvana probes. MIR and gene expression was assessed by TaqMan‐assay, RNA‐sequencing and in‐situ‐hybridization in 4 indepedent cohorts of human BTC. Knock‐out of microRNA was achieved by CRISPR‐CAS9 in CCLP cells (MIR1249KO) and tested for effects on chemotherapy sensitivity in‐vitro and in‐vivo. High‐throughput‐screening revealed that MIR1249‐inhibition enhanced chemotherapy sensitivity across all cell lines. MIR1249 expression was increased in 41% of cases in human BTC. In validation experiments, MIR1249‐inhibition did not alter cell viability in untreated or DMSO‐treated cells; however it did increase CG effect. MIR1249 expression was increased in CD133+ biliary cancer cells freshly isolated from the stem niche of human BTC, as well as in CD133+ chemo‐resistant CCLP cells. MIR1249 modulated the chemotherapy‐induced enrichment of CD133+ cells by controlling their clonal expansion via the Wnt‐regulator FZD8. MIR1249KO cells had impaired expansion of the CD133+ subclone and its enrichment after chemotherapy, reduced expression of Cancer‐Stem‐Cell markers, and increased chemosensitivity. MIR1249KO xenograft BTC models showed tumour shrinkage after exposure to weekly CG, while WT models showed only stable disease over treatment. Conclusions: MIR1249 mediates resistance to CG in BTC and may be tested as a novel target for therapeutics.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Cunningham, Dr David and Valeri, Dr Nicola and Braconi, Dr Chiara
Authors: Carotenuto, P., Hedayat, S., Fassan, M., Cardinale, V., Lampis, A., Guzzardo, V., Vicentini, C., Scarpa, A., Cascione, L., Costantini, D., Carpino, G., Alvaro, D., Ghidini, M., Trevisani, F., Te Poele, R., Salati, M., Ventura, S., Vlachogiannis, G., Hahne, J. C., Boulter, L., Forbes, S. J., Guest, R., Cillo, U., Said‐Huntingford, I., Begum, R., Smyth, E., Michalarea, V., Cunningham, D., Rimassa, L., Santoro, A., Roncalli, M., Kirnkin, V., Clarke, P., Workman, P., Valeri, N., and Braconi, C.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Hepatology
ISSN (Online):1527-3350
Published Online:26 December 2019
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Hepatology 72(3): 982-996
Publisher Policy:Reproduced under a Creative Commons license

University Staff: Request a correction | Enlighten Editors: Update this record