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Satellite repeat RNA expression in epithelial ovarian cancer associates with a tumor-immunosuppressive phenotype
Rebecca L. Porter, … , Benjamin D. Greenbaum, David T. Ting
Rebecca L. Porter, … , Benjamin D. Greenbaum, David T. Ting
Published June 16, 2022
Citation Information: J Clin Invest. 2022;132(16):e155931. https://doi.org/10.1172/JCI155931.
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Research Article Oncology Article has an altmetric score of 10

Satellite repeat RNA expression in epithelial ovarian cancer associates with a tumor-immunosuppressive phenotype

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Abstract

Aberrant expression of viral-like repeat elements is a common feature of epithelial cancers, and the substantial diversity of repeat species provides a distinct view of the cancer transcriptome. Repeatome profiling across ovarian, pancreatic, and colorectal cell lines identifies distinct clustering independent of tissue origin that is seen with coding gene analysis. Deeper analysis of ovarian cancer cell lines demonstrated that human satellite II (HSATII) satellite repeat expression was highly associated with epithelial-mesenchymal transition (EMT) and anticorrelated with IFN-response genes indicative of a more aggressive phenotype. SATII expression — and its correlation with EMT and anticorrelation with IFN-response genes — was also found in ovarian cancer RNA-Seq data and was associated with significantly shorter survival in a second independent cohort of patients with ovarian cancer. Repeat RNAs were enriched in tumor-derived extracellular vesicles capable of stimulating monocyte-derived macrophages, demonstrating a mechanism that alters the tumor microenvironment with these viral-like sequences. Targeting of HSATII with antisense locked nucleic acids stimulated IFN response and induced MHC I expression in ovarian cancer cell lines, highlighting a potential strategy of modulating the repeatome to reestablish antitumor cell immune surveillance.

Authors

Rebecca L. Porter, Siyu Sun, Micayla N. Flores, Emily Berzolla, Eunae You, Ildiko E. Phillips, Neelima KC, Niyati Desai, Eric C. Tai, Annamaria Szabolcs, Evan R. Lang, Amaya Pankaj, Michael J. Raabe, Vishal Thapar, Katherine H. Xu, Linda T. Nieman, Daniel C. Rabe, David L. Kolin, Elizabeth H. Stover, David Pepin, Shannon L. Stott, Vikram Deshpande, Joyce F. Liu, Alexander Solovyov, Ursula A. Matulonis, Benjamin D. Greenbaum, David T. Ting

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Figure 6

Repeat RNA-enriched extracellular vesicles can induce changes in the tumor immune microenvironment.

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Repeat RNA-enriched extracellular vesicles can induce changes in the tum...
(A) Schema of experimental design relating to data in B–E. (B) Gene set enrichment analysis of IFN-response signatures and inflammatory response in extracellular vesicle–treated (EV-treated) versus untreated samples. NES, normalized enrichment score. (C) Volcano plot depicting the differential expression of coding genes between EV-treated and untreated EOC cell lines. Genes driving the enrichment in IFN-α, IFN-γ, and inflammatory hallmark pathways are noted. (D) Quantitative RT-PCR of IFN-response genes from THP-1 monocyte cell line treated with high-dose or low-dose EVs from ovarian cell lines, OAW28 (left) and IGROV1 (right). (E) Schema of THP-1 cells treated with HSATII or GFP RNA transfection and quantitative RT-PCR of IFN-response genes without transfection (TF) or with transfection of GFP RNA or HSATII RNA. For RT-PCR, all data points are shown as mean ± SD. One-way ANOVA analysis was performed with Tukey’s multiple comparisons test; significance is shown between EV treatment and PBS or HSATII and GFP RNA. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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