TY - JOUR
T1 - Impact of retrotransposon protein L1 ORF1p expression on oncogenic pathways in hepatocellular carcinoma
T2 - the role of cytoplasmic PIN1 upregulation
AU - Zadran, Bassier
AU - Sudhindar, Praveen Dhondurao
AU - Wainwright, Daniel
AU - Bury, Yvonne
AU - Luli, Saimir
AU - Howarth, Rachel
AU - McCain, Misti Vanette
AU - Watson, Robyn
AU - Huet, Hannah
AU - Palinkas, Fanni
AU - Palmini, Rolando Berlinguer
AU - Casement, John
AU - Mann, Derek A.
AU - Oakley, Fiona
AU - Lunec, John
AU - Reeves, Helen
AU - Faulkner, Geoffrey J
AU - Shukla, Ruchi
N1 - Funding information: BZ’s PhD was supported by Newcastle University; PDS’s PhD was supported by Newcastle University Overseas Research Scholarship scheme and JGW Patterson Special grant (RES/0190/7948); FP’s PhD is supported by the MRC-DiMeN DTP studentship programme. DW was supported by JGW Patterson Pump priming award (RES/0260/0217) and HH MRes project was supported by the Pathological Society of Great Britain and Ireland. RS is funded by Newcastle University’s Research Fellowship funds. HLR, DAM and MVM are supported by grant from Cancer Research UK (C18342/A23390); HLR, DAM, FO and RW are supported by a Cancer Research UK Accelerator award (HUNTER: Hepatocellular Carcinoma Expediter Network C9380/A26813). GJF is supported by a CSL Centenary Fellowship and NHMRC Investigator Grant GNT1173711. DAM and FO are supported by MRC MICA programme grants (MR/K0019494/1 and MR/R023026/1).
PY - 2023/3/30
Y1 - 2023/3/30
N2 - 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.
AB - 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.
KW - Carcinoma, Hepatocellular/genetics
KW - Humans
KW - Liver Neoplasms/genetics
KW - Long Interspersed Nucleotide Elements/genetics
KW - NIMA-Interacting Peptidylprolyl Isomerase/genetics
KW - Retroelements
KW - Transforming Growth Factor beta/genetics
KW - Up-Regulation
UR - http://www.scopus.com/inward/record.url?scp=85146946323&partnerID=8YFLogxK
U2 - 10.1038/s41416-023-02154-9
DO - 10.1038/s41416-023-02154-9
M3 - Article
C2 - 36707636
SN - 0007-0920
VL - 128
SP - 1236
EP - 1248
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 7
ER -
