The role of miR-146a in melanoma progression and metastasis

Identification: 2056


Description

The role of miR-146a in melanoma progression and metastasis

Justin Mastroianni1,3*, Wolfgang Melchinger1, Heide Dierbach1 , Silke Lassman2, Robert Zeiser1,3

1University Medical Center Freiburg, Dept. of Hematology/Oncology, 79106 Freiburg;

2University of Medical Center Freiburg, Dept. of Pathology, 79106 Freiburg; 3University of Freiburg, Dept. of Biology, 79106 Freiburg

*Corresponding Author

Immunotherapy has revolutionized the treatment of melanoma. Still,a better understanding of the immune response in the tumor microenvironment is crucial to improve immune checkpoint inhibitor therapy. Micro-RNAs (miRs) are small non-coding RNAs that regulate gene expression on the post-transcriptional level. miR-146a has been shown to be involved in multiple inflammatory diseases, yet its role in the melanoma microenvironment remains unclear.

Results: We aimed to clarify the role of miR-146a in the melanoma microenvironment during tumor development and progression. We found miR-146a levels increased in tumor microenviromental tissue, such as the skin, in a B16 F10 in vivo melanoma model. Furthermore, mice deficient in mir-146a survived longer and developed less metastases in comparison to wildtype animals. Both, in vitro activated miR-146a-/- T cells and T cells isolated from tumor bearing miR-146a-/- mice revealed higher expression levels of the transcription factor STAT1. In addition, those in vivo activated CD4+ and CD8+ T cells displayed a larger population of Interferon-γ (IFN-γ)+ cells. IFN-γ inhibition using a blocking antibody in this model, altered survival and metastasis patterns of the miR-146a-/- group to resemble the wildtype group.

Conclusion: The results we present here reveal the influential role of miR-146a in the tumor microenvironment of an advanced stage metastatic melanoma. The hyperactivity of the immune system deficient in miR-146a serves as a counter-measure to the disease progression, by modulation of IFN-γ production, downstream of Stat1 phosphorylation.

Our evidence indicate that endogenous miR-146a could be suppressing auto-immune control of metastasis in a murine model making it a potential target for future immunomodulating therapy.

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