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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 7

Modulation of HSATII RNA with LNA is cytotoxic, induces IFN response, and increases MHC class I expression.

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Modulation of HSATII RNA with LNA is cytotoxic, induces IFN response, an...
(A) Expression levels of HSATII and other repeat RNAs in EOC cell lines transfected with HSATII-specific LNA relative to scramble control LNA over time, plotted as fold change over control on days 0 through 6 after transfection. (B) Expression heatmap depicting relative expression of innate immune-response genes and IFN-stimulated genes (ISGs) in EOC cell lines transfected with HSATII-specific LNA relative to scramble control LNA over time. (C) Effect of HSATII-specific LNA (LNA1) on tumorsphere growth in EOC cell lines, as determined by 3D CellTiter-Glo viability assays. Plots represent 4 separate experiments for each cell line, with 2-tailed unpaired t test performed at each time point. **P < 0.01, ****P < 0.0001. (D) Flow cytometric analysis of MHC-I and MHC-II cell surface protein expression on EOC cell lines transfected with LNA1 compared with control LNA. (E) Expression heatmap depicting relative expression of MHC class I genes and PD-L1 in EOC cell lines transfected with HSATII-specific LNA relative to scramble control LNA over time.

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

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