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Lookup NU author(s): Bassier Zadran, Daniel Wainwright, Dr Yvonne BuryORCiD, Dr Saimir Luli, Rachel Howarth, Misti McCainORCiD, Robyn Watson, Fanni Palinkas, John CasementORCiD, Professor Derek Mann, Professor Fiona OakleyORCiD, Professor John LunecORCiD, Professor Helen ReevesORCiD, Dr Ruchi ShuklaORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2023, The Author(s). Background: Molecular characterisation of hepatocellular carcinoma (HCC) is central to the development of novel therapeutic strategies for the disease. We have previously demonstrated mutagenic consequences of Long-Interspersed Nuclear Element-1 (LINE1s/L1) retrotransposition. However, the role of L1 in HCC, besides somatic mutagenesis, is not well understood. Methods: We analysed L1 expression in the TCGA-HCC RNAseq dataset (n = 372) and explored potential relationships between L1 expression and clinical features. The findings were confirmed by immunohistochemical (IHC) analysis of an independent human HCC cohort (n = 48) and functional mechanisms explored using in vitro and in vivo model systems. Results: We observed positive associations between L1 and activated TGFβ-signalling, TP53 mutation, alpha-fetoprotein and tumour invasion. IHC confirmed a positive association between pSMAD3, a surrogate for TGFβ-signalling status, and L1 ORF1p (P < 0.0001, n = 32). Experimental modulation of L1 ORF1p levels revealed an influence of L1 ORF1p on key hepatocarcinogenesis-related pathways. Reduction in cell migration and invasive capacity was observed upon L1 ORF1 knockdown, both in vitro and in vivo. In particular, L1 ORF1p increased PIN1 cytoplasmic localisation. Blocking PIN1 activity abrogated L1 ORF1p-induced NF-κB-mediated inflammatory response genes while further activated TGFβ-signalling confirming differential alteration of PIN1 activity in cellular compartments by L1 ORF1p. Discussion: Our data demonstrate a causal link between L1 ORF1p and key oncogenic pathways mediated by PIN1, presenting a novel therapeutic avenue. [Figure not available: see fulltext.].
Author(s): Zadran B, Sudhindar PD, Wainwright D, Bury Y, Luli S, Howarth R, McCain MV, Watson R, Huet H, Palinkas F, Palmini RB, Casement J, Mann DA, Oakley F, Lunec J, Reeves H, Faulkner GJ, Shukla R
Publication type: Article
Publication status: Published
Journal: British Journal of Cancer
Year: 2023
Volume: 128
Pages: 1236-1248
Print publication date: 30/03/2023
Online publication date: 27/01/2023
Acceptance date: 11/01/2023
Date deposited: 09/02/2023
ISSN (print): 0007-0920
ISSN (electronic): 1532-1827
Publisher: Nature Publishing Group
URL: https://doi.org/10.1038/s41416-023-02154-9
DOI: 10.1038/s41416-023-02154-9
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