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A5943 - A Herpesvirus Noncoding RNA Controls NSCLC Tumor Progression Through Selective Degradation of miR-27 in Immune Cells
Author Block: A. Korde1, M. Gwin1, P. Pawlica2, J. Steitz2, S. Takyar3; 1Internal Medicine, Yale school of Medicine, New Haven, CT, United States, 2Molecular Biophysics and Biochemistry, Yale school of Medicine, New Haven, CT, United States, 3Pulm and Crit Care, Yale School of Med, New Haven, CT, United States.
Introduction: HSUR-1 is a noncoding RNA expressed by HVS upon infection of T-cells. Expression of this RNA is critical for malignant transformation and leads to the sequence-specific and binding-dependent degradation of mature miR-27. IL-10 is one of miR-27 targets and a prime regulator of immune tolerance within tumors. Hypothesis: HSUR-1 alters tumor progression through selective degradation of miR-27 in tumor immune cells.
Methods: MicroRNA levels were measured by quantitative stem-loop RT-PCR. For in vivo tumor studies, we used Lewis lung carcinoma (LLC) xenograft. We created HSUR-1 overexpression vector by cloning HSUR-1 sequence in a lentiviral transfer vector. This vectors and its control (parental vector) were delivered to cells in culture or injected into the tumors. Immune cells were isolated from LLC tumors by Magnetic-activated cell sorting (MACS).
Results: In an animal model of non-small cell lung cancer, HSUR-1 delivery enhanced tumor progression and led to a significant increase in the size of LLC xenografts. Fractionation of these tumors showed selective degradation of mature miR-27 in immune cells. In cell culture studies overexpression of HSUR-1 decreased miR-27 levels in Jurkat cells without altering those levels in A549 or THP-1 cells. In accord with targeting of IL-10 by miR-27, IL-10 levels were increased in the HSUR-1-treated tumors and specifically in the immune (CD45+) cells isolated from these tumors. We measured the expression of other miR-27 targets and the enzymes involved in mature miRNA degradation in these fractions. In biopsies from NSCLC patients, miR-27 levels were lower, and IL-10 levels were higher in tumors compared to the adjacent uninvolved lung tissue. An exploratory expression study on NSCLC tumor samples showed overexpression of HSUR-1-like RNA sequences in a number of NSCLC patients.
Conclusion: HSUR-1 regulates NSCLC tumor progression through sequence-dependent degradation of miR-27 within immune cells. This mechanism illustrates a novel and targetable pathogenic pathway utilized by oncogenic viruses