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

Research output: Contribution to journalArticle

17 Citations (Scopus)

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

Fingerprint

HLA Antigens
MicroRNAs
Renal Cell Carcinoma
Natural Killer Cells
3' Untranslated Regions
Luciferases
Reporter Genes
GTP-Binding Proteins
Computer Simulation
Down-Regulation

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., ... 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

Identification of novel microRNAs regulating HLA-G expression and investigating their clinical relevance in renal cell carcinoma. / Jasinski-Bergner, Simon; Reches, Adi; Stoehr, Christine; Massa, Chiara; Gonschorek, Evamaria; Huettelmaier, Stefan; Braun, Juliane; Wach, Sven; Wullich, Bernd; Spath, Verena; Wang, Ena; Marincola, Francesco M.; Mandelboim, Ofer; Hartmann, Arndt; Seliger, Barbara.

In: Oncotarget, Vol. 7, No. 18, 01.05.2016, p. 26866-26878.

Research output: Contribution to journalArticle

Jasinski-Bergner, S, Reches, A, Stoehr, C, Massa, C, Gonschorek, E, Huettelmaier, S, Braun, J, Wach, S, Wullich, B, Spath, V, Wang, E, Marincola, FM, 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, vol. 7, no. 18, pp. 26866-26878. https://doi.org/10.18632/oncotarget.8567
Jasinski-Bergner S, Reches A, Stoehr C, Massa C, Gonschorek E, Huettelmaier S et al. Identification of novel microRNAs regulating HLA-G expression and investigating their clinical relevance in renal cell carcinoma. Oncotarget. 2016 May 1;7(18):26866-26878. https://doi.org/10.18632/oncotarget.8567
Jasinski-Bergner, Simon ; Reches, Adi ; Stoehr, Christine ; Massa, Chiara ; Gonschorek, Evamaria ; Huettelmaier, Stefan ; Braun, Juliane ; Wach, Sven ; Wullich, Bernd ; Spath, Verena ; Wang, Ena ; Marincola, Francesco M. ; Mandelboim, Ofer ; Hartmann, Arndt ; Seliger, Barbara. / Identification of novel microRNAs regulating HLA-G expression and investigating their clinical relevance in renal cell carcinoma. In: Oncotarget. 2016 ; Vol. 7, No. 18. pp. 26866-26878.
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