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

Brauß, Thilo F. ; Winslow, Sofia LU ; Lampe, Sebastian ; Scholz, Anica ; Weigert, Andreas ; Dehne, Nathalie ; von Stedingk, Kristoffer LU ; Schmid, Tobias and Brüne, Bernhard (2017) In Molecular Carcinogenesis 56(12). p.2620-2629
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... (More)

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.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
breast cancer, ELAVL1, interferon beta, RANTES, tumor-associated macrophages
in
Molecular Carcinogenesis
volume
56
issue
12
pages
10 pages
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:85026432573
  • pmid:28731284
  • wos:000414615700008
ISSN
0899-1987
DOI
10.1002/mc.22706
language
English
LU publication?
yes
id
0b512001-7fdb-4af2-b339-5146f258e650
date added to LUP
2017-11-22 08:25:04
date last changed
2025-01-21 02:22:46
@article{0b512001-7fdb-4af2-b339-5146f258e650,
  abstract     = {{<p>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.</p>}},
  author       = {{Brauß, Thilo F. and Winslow, Sofia and Lampe, Sebastian and Scholz, Anica and Weigert, Andreas and Dehne, Nathalie and von Stedingk, Kristoffer and Schmid, Tobias and Brüne, Bernhard}},
  issn         = {{0899-1987}},
  keywords     = {{breast cancer; ELAVL1; interferon beta; RANTES; tumor-associated macrophages}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{12}},
  pages        = {{2620--2629}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Molecular Carcinogenesis}},
  title        = {{The RNA-binding protein HuR inhibits expression of CCL5 and limits recruitment of macrophages into tumors}},
  url          = {{http://dx.doi.org/10.1002/mc.22706}},
  doi          = {{10.1002/mc.22706}},
  volume       = {{56}},
  year         = {{2017}},
}