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, Barbara Seliger

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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.

Original languageEnglish
Pages (from-to)26866-26878
Number of pages13
JournalOncotarget
Volume7
Issue number18
DOIs
Publication statusPublished - 1 May 2016

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Keywords

  • HLA-G
  • Immune escape
  • microRNA
  • Non-classical HLA class I molecules
  • Renal cell carcinoma

ASJC Scopus subject areas

  • Oncology

Cite this

Jasinski-Bergner, S., Reches, A., Stoehr, C., Massa, C., Gonschorek, E., Huettelmaier, S., Braun, J., Wach, S., Wullich, B., Spath, V., Wang, E., Marincola, F. M., Mandelboim, O., Hartmann, A., & Seliger, B. (2016). Identification of novel microRNAs regulating HLA-G expression and investigating their clinical relevance in renal cell carcinoma. Oncotarget, 7(18), 26866-26878. https://doi.org/10.18632/oncotarget.8567