The RNA-binding protein HuR inhibits expression of CCL5 and limits recruitment of macrophages into tumors

Research output: Contribution to journalArticle

Abstract

The RNA-binding protein HuR promotes tumor growth by affecting proliferation, metastasis, apoptosis, and angiogenesis. Although immune cells, especially tumor-associated macrophages, are critical components of the tumor stroma, the influence of HuR in tumors on the recruitment of immune cells remains poorly understood. In the present study, we, therefore, aimed to elucidate the impact of tumor cell HuR on the interaction between tumor cells and macrophages. To this end, we stably depleted HuR in human MCF-7 breast cancer cells. We found that HuR-deficient cells not only showed reduced proliferation, they further expressed elevated levels of the chemokine CCL5. HuR-dependent repression of CCL5 was neither caused by altered CCL5 mRNA stability, nor by changes in CCL5 translation. Instead, loss of HuR augmented transcription of CCL5, which was mediated via an interferon-stimulated response element in the CCL5 promoter. Furthermore, HuR depletion enhanced macrophage recruitment into MCF-7 tumor spheroids, an effect which was completely lost upon neutralization of CCL5. HuR expression further negatively correlated with CCL5 expression and macrophage appearance in a cohort of breast tumors. Thus, while HuR is well-characterized to support various pro-tumorigenic features in tumor cells, we provide evidence that it limits the recruitment of macrophages into tumors by repressing CCL5. As macrophage infiltration is associated with poor prognosis, our findings underline the highly cell-type and context specific role of HuR in tumorigenesis.

Details

Authors
  • Thilo F. Brauß
  • Sofia Winslow
  • Sebastian Lampe
  • Anica Scholz
  • Andreas Weigert
  • Nathalie Dehne
  • Kristoffer von Stedingk
  • Tobias Schmid
  • Bernhard Brüne
Organisations
External organisations
  • Goethe University
  • Academic Medical Center
  • University of Amsterdam
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology
  • Cancer and Oncology

Keywords

  • breast cancer, ELAVL1, interferon beta, RANTES, tumor-associated macrophages
Original languageEnglish
Pages (from-to)2620-2629
Number of pages10
JournalMolecular Carcinogenesis
Volume56
Issue number12
Publication statusPublished - 2017 Dec 1
Publication categoryResearch
Peer-reviewedYes