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Impact of retrotransposon protein L1 ORF1p expression on oncogenic pathways in hepatocellular carcinoma: the role of cytoplasmic PIN1 upregulation

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

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 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.].


Publication metadata

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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Funding

Funder referenceFunder name
C9380/A26813
C18342/A23390Cancer Research UK CRUK (open competition)
JGW Patterson Special grant
GNT1173711
MR/K0019494/1
MRC-DiMeN DTP studentship programme
JGW Patterson Pump priming award
MR/R023026/1Medical Research Council (MRC)
Newcastle University
RES/0190/7948
RES/0260/0217
Pathological Society of Great Britain and Ireland

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