The miR-25-93-106b cluster regulates tumor metastasis and immune evasion via modulation of CXCL12 and PD-L1
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Michele Cioffi1, Sara M. Trabulo1,2, Mireia Vallespinos1, Deepak Raj2, Tony Bou Kheir2, Meng-Lay Lin2, Julfa Begum2, Ann-Marie Baker3, Ala Amgheib2, Jaimy Saif4, Manuel Perez5, Joaquim Soriano5, Manuel Desco6,7,8, Maria Victoria Gomez-Gaviro6,7,8, Lorena Cusso6,7,8, Diego Megias5, Alexandra Aicher1,2, Christopher Heeschen1,2
1Stem Cells & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
2Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, UK
3Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
4School of Clinical Sciences, University of Bristol, Bristol, UK
5Confocal Microscopy Unit, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain
6Departamento de Ingenieria Biomedica e Ingeniería Aeroespacial, Universidad Carlos III de Madrid, Leganés, Spain
7Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
8Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain
Alexandra Aicher, email: firstname.lastname@example.org
Christopher Heeschen, email: email@example.com
Keywords: metastasis, CD274, bone marrow, stromal niche, MDSC
Received: June 29, 2016 Accepted: January 10, 2017 Published: February 17, 2017
The stromal microenvironment controls response to injury and inflammation, and is also an important determinant of cancer cell behavior. However, our understanding of its modulation by miRNA (miR) and their respective targets is still sparse. Here, we identified the miR-25-93-106b cluster and two new target genes as critical drivers for metastasis and immune evasion of cancer cells. Using miR-25-93-106b knockout mice or antagomiRs, we demonstrated regulation of the production of the chemoattractant CXCL12 controlling bone marrow metastasis. Moreover, we identified the immune checkpoint PD-L1 (CD274) as a novel miR-93/106b target playing a central role in diminishing tumor immunity. Eventually, upregulation of miR-93 and miR-106b via miR-mimics or treatment with an epigenetic reader domain (BET) inhibitor resulted in diminished expression of CXCL12 and PD-L1. These data suggest a potential new therapeutic rationale for use of BET inhibitors for dual targeting of cancers with strong immunosuppressive and metastatic phenotypes.
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