LINE-1 ORF1p mimics viral innate immune evasion mechanisms in pancreatic ductal adenocarcinoma Journal Article
| Authors: | You, E.; Patel, B. K.; Rojas, A. S.; Sun, S.; Danaher, P.; Ho, N. I.; Phillips, I. E.; Raabe, M. J.; Song, Y.; Xu, K. H.; Kocher, J. R.; Richieri, P. M.; Shin, P.; Taylor, M. S.; Nieman, L. T.; Greenbaum, B. D.; Ting, D. T. |
| Article Title: | LINE-1 ORF1p mimics viral innate immune evasion mechanisms in pancreatic ductal adenocarcinoma |
| Abstract: | Repeat element viral mimicry is a common feature in pancreatic ductal adenocarcinoma (PDAC) that requires mechanisms to manage this repeat “viral” load and attenuate innate immune responses. In this study, we show that the long interspersed nuclear element 1 (LINE-1) open reading frame 1 protein (ORF1p) in PDAC cells plays a role in shielding repeat RNAs from activating a pathogen recognition receptor–mediated antiviral response that is independent of retrotransposition. Suppression of ORF1p using short hairpin RNA induces innate immune responses through the double-stranded RNA (dsRNA) sensors RIG-I and MAVS. Low ORF1p PDAC cell lines have suppressed expression of pathogen recognition receptors demonstrating convergent mechanisms to suppress innate immune signaling. Localization of ORF1p in processing bodies with the dsRNA helicase MOV10 was found to be important for these antiviral responses. Loss of ORF1p resulted in significant growth reduction in tumorspheres and mouse xenografts with an enriched epithelial cell state, and high ORF1p expression was associated with worsened survival in a cohort of human patients with PDAC. Significance: This study uncovers PDAC-specific mechanisms that dampen immune responses to viral-repeat RNA via long interspersed nuclear element 1 ORF1p. Suppression of ORF1p activates antiviral responses, reducing tumor growth and epithelial–mesenchymal transition. High ORF1p expression correlates with poor prognosis, highlighting its potential as a therapeutic target for PDAC. © 2025 The Authors; Published by the American Association for Cancer Research. |
| Keywords: | immunohistochemistry; signal transduction; controlled study; human tissue; protein expression; unclassified drug; human cell; genetics; nonhuman; pancreatic neoplasms; cd8+ t lymphocyte; t lymphocyte; mouse; animal; animals; mice; cell viability; apoptosis; gene expression; confocal microscopy; tumor volume; carcinoma, pancreatic ductal; animal experiment; animal model; cohort analysis; immunofluorescence; pathology; cell line, tumor; virology; immunology; immune response; messenger rna; pancreas tumor; tumor cell line; western blotting; immunoprecipitation; immunoblotting; innate immunity; immunity, innate; upregulation; tissue microarray; tumor growth; transcriptome; short hairpin rna; rna extraction; lamivudine; epithelial-mesenchymal transition; open reading frame; immune evasion; epithelial mesenchymal transition; rna isolation; stavudine; pancreatic ductal carcinoma; long interspersed nucleotide elements; tenofovir; pattern recognition receptor; sanger sequencing; humans; human; female; article; rna sequencing; luciferase assay; hek293t cell line; mia paca-2 cell line; bxpc-3 cell line; pancreatic ductal carcinoma cell line; long interspersed nuclear element; long interspersed nuclear element 1; emtricitabine; necrostatin 1; capan-1 cell line |
| Journal Title: | Cancer Discovery |
| Volume: | 15 |
| Issue: | 5 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2025-05-01 |
| Start Page: | 1063 |
| End Page: | 1082 |
| Language: | English |
| DOI: | 10.1158/2159-8290.Cd-24-1317 |
| PUBMED: | 39919290 |
| PROVIDER: | scopus |
| PMCID: | PMC12046326 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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