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Regeneration linked miRNA modify tumor phenotype and can enforce multi-lineage growth arrest in vivo

Research output: Contribution to journalArticlepeer-review

Siamak Salehi, Oliver D. Tavabie, Augusto Villanueva, Julie Watson, David Darling, Alberto Quaglia, Farzin Farzaneh, Varuna R. Aluvihare

Original languageEnglish
Article number10538
JournalScientific Reports
Volume11
Issue number1
DOIs
PublishedDec 2021

Bibliographical note

Funding Information: This work was supported by National Institute for Health Research (NIHR) Clinical Research Facility and NIHR Biomedical Research Centre, Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. Work in the Molecular Medicine Group at King’s College London is supported by CRUK City of London Centre Grant, The experimental Cancer Medicine Centre and the NIHR Biomedical Research Centre at King’s Health Partners. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. We are grateful to; M.J. Arno, Genomics Centre, King’s College London, London, UK, for providing microarray facility, J.P. Banga, Endocrine Immunology King’s College London School of Medicine, Division of Diabetes and Nutritional Sciences, The Rayne Institute London, UK, for help with in vivo studies, N. Shaun B. Thomas, King’s College London, Department of Haematological Medicine, Rayne Institute, London, UK, and P. Lavender, MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, King’s College London, Guy’s Hospital, London, UK, for providing help with methylation arrays, H.C. Brereton, Institute of Liver Studies, King’s College Hospital, London, UK, for her laboratory assistance and J. McCall, Institute of Liver Studies, King’s College Hospital, London, UK for reviewing the manuscript. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

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Abstract

Regulated cell proliferation is an effector mechanism of regeneration, whilst dysregulated cell proliferation is a feature of cancer. We have previously identified microRNA (miRNA) that regulate successful and failed human liver regeneration. We hypothesized that these regulators may directly modify tumor behavior. Here we show that inhibition of miRNAs -503 and -23a, alone or in combination, enhances tumor proliferation in hepatocyte and non-hepatocyte derived cancers in vitro, driving more aggressive tumor behavior in vivo. Inhibition of miRNA-152 caused induction of DNMT1, site-specific methylation with associated changes in gene expression and in vitro and in vivo growth inhibition. Enforced changes in expression of two miRNA recapitulating changes observed in failed regeneration led to complete growth inhibition of multi-lineage cancers in vivo. Our results indicate that regulation of regeneration and tumor aggressiveness are concordant and that miRNA-based inhibitors of regeneration may constitute a novel treatment strategy for human cancers.

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