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Open Access Research

Interferon-γ-induced activation of Signal Transducer and Activator of Transcription 1 (STAT1) up-regulates the tumor suppressing microRNA-29 family in melanoma cells

Martina J Schmitt1, Demetra Philippidou1, Susanne E Reinsbach1, Christiane Margue1, Anke Wienecke-Baldacchino2, Dorothee Nashan3, Iris Behrmann1 and Stephanie Kreis1*

Author Affiliations

1 Signal Transduction Laboratory, University of Luxembourg, 162A Avenue de la Faïencerie, Luxembourg, L-1511, Luxembourg

2 Life Sciences Research Unit, University of Luxembourg, 162A Avenue de la Faïencerie, Luxembourg, L-1511, Luxembourg

3 Hautklinik, Klinikum Dortmund GmbH, Beurhausstraße 40, Dortmund, 44137, Germany

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Cell Communication and Signaling 2012, 10:41  doi:10.1186/1478-811X-10-41

Published: 17 December 2012

Abstract

Background

The type-II-cytokine IFN-γ is a pivotal player in innate immune responses but also assumes functions in controlling tumor cell growth by orchestrating cellular responses against neoplastic cells. The role of IFN-γ in melanoma is not fully understood: it is a well-known growth inhibitor of melanoma cells in vitro. On the other hand, IFN-γ may also facilitate melanoma progression. While interferon-regulated genes encoding proteins have been intensively studied since decades, the contribution of miRNAs to effects mediated by interferons is an emerging area of research.

We recently described a distinct and dynamic regulation of a whole panel of microRNAs (miRNAs) after IFN-γ-stimulation. The aim of this study was to analyze the transcriptional regulation of miR-29 family members in detail, identify potential interesting target genes and thus further elucidate a potential signaling pathway IFN-γ → Jak→ P-STAT1 → miR-29 → miR-29 target genes and its implication for melanoma growth.

Results

Here we show that IFN-γ induces STAT1-dependently a profound up-regulation of the miR-29 primary cluster pri-29a~b-1 in melanoma cell lines. Furthermore, expression levels of pri-29a~b-1 and mature miR-29a and miR-29b were elevated while the pri-29b-2~c cluster was almost undetectable. We observed an inverse correlation between miR-29a/b expression and the proliferation rate of various melanoma cell lines. This finding could be corroborated in cells transfected with either miR-29 mimics or inhibitors. The IFN-γ-induced G1-arrest of melanoma cells involves down-regulation of CDK6, which we proved to be a direct target of miR-29 in these cells. Compared to nevi and normal skin, and metastatic melanoma samples, miR-29a and miR-29b levels were found strikingly elevated in certain patient samples derived from primary melanoma.

Conclusions

Our findings reveal that the miR-29a/b1 cluster is to be included in the group of IFN- and STAT-regulated genes. The up-regulated miR-29 family members may act as effectors of cytokine signalling in melanoma and other cancer cells as well as in the immune system.

Keywords:
IFN-γ; Jak/STAT pathway; STAT1; Signaling; Melanoma; miR-29; Tumor-suppressor