Oncotarget

Research Papers:

Identification of novel microRNAs regulating HLA-G expression and investigating their clinical relevance in renal cell carcinoma

Simon Jasinski-Bergner _, Adi Reches, Christine Stoehr, Chiara Massa, Evamaria Gonschorek, Stefan Huettelmaier, Juliane Braun, Sven Wach, Bernd Wullich, Verena Spath, Ena Wang, Francesco M. Marincola, Ofer Mandelboim, Arndt Hartmann and Barbara Seliger

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Oncotarget. 2016; 7:26866-26878. https://doi.org/10.18632/oncotarget.8567

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Abstract

Simon Jasinski-Bergner1, Adi Reches2, Christine Stoehr3, Chiara Massa1, Evamaria Gonschorek1, Stefan Huettelmaier4, Juliane Braun4, Sven Wach5, Bernd Wullich5, Verena Spath2, Ena Wang6, Francesco M. Marincola6, Ofer Mandelboim2, Arndt Hartmann3, Barbara Seliger1

1Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle, Germany

2Faculty of Medicine, The Hebrew University of Jerusalem, Ein Kerem, Jerusalem, Israel

3Institute of Pathology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany

4Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany

5Clinic of Urology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany

6Sidra Medical and Research Center, Qatar Foundation, Doha, Qatar

Correspondence to:

Barbara Seliger, e-mail: [email protected]

Keywords: non-classical HLA class I molecules, microRNA, HLA-G, immune escape, renal cell carcinoma

Received: October 06, 2015    Accepted: March 11, 2016    Published: April 4, 2016

ABSTRACT

The non-classical human leukocyte antigen G (HLA-G) is expressed at a high frequency in renal cell carcinoma (RCC) and is associated with a higher tumor grade and a poor clinical outcome. This might be caused by the HLA-G-mediated inhibition of the cytotoxicity of T and NK cells. Therefore a selective targeting of HLA-G might represent a powerful strategy to enhance the immunogenicity of RCC lesions. Recent studies identified a number of HLA-G-regulating microRNAs (miRs) and demonstrated an inverse expression of some of these miRs with HLA-G in RCC in vitro and in vivo. However, it was postulated that further miRs might exist contributing to the tightly controlled selective HLA-G expression.

By application of a miR enrichment assay (miTRAP) in combination with in silico profiling two novel HLA-G-regulatory miRs, miR-548q and miR-628-5p, were identified. Direct interactions of both miRs with the 3’ untranslated region of HLA-G were confirmed with luciferase reporter gene assays. In addition, qPCR analyses and immunohistochemical staining revealed an inverse, expression of miR-628-5p, but not of miR-548q to the HLA-G protein in primary RCC lesions and cell lines. Stable overexpression of miR-548q and miR-628-5p caused a downregulation of HLA-G mRNA and protein. This leads in case of miR-548q to an enhanced NK cell-mediated HLA-G-dependent cytotoxicity, which could be reverted by ILT2 blockade suggesting a control of the immune effector cell activity at least by this miR. The identification of two novel HLA-G-regulatory miRs extends the number of HLA-G-relevant miRs tuning the HLA-G expression and might serve as future therapeutic targets.


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