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PMID: 28423491 Published · ppublish English Journal Article

The miR-25-93-106b cluster regulates tumor metastasis and immune evasion via modulation of CXCL12 and PD-L1.

Oncotarget ·Vol. 8 ·No. 13 ·2017-03-28 ·Pages 21609-21625

Cioffi M, Trabulo SM, Vallespinos M, Raj D, Kheir TB, Lin ML, Begum J, Baker AM, Amgheib A, Saif J, Perez M, Soriano J, Desco M, Gomez-Gaviro MV, Cusso L, Megias D, Aicher A, Heeschen C

Abstract

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.

Keywords
CD274 MDSC bone marrow metastasis stromal niche
MeSH Terms
Animals B7-H1 Antigen/metabolism Chemokine CXCL12/metabolism Flow Cytometry Gene Expression Regulation, Neoplastic/genetics Gene Knockout Techniques Humans Immunohistochemistry In Situ Hybridization Mice MicroRNAs/genetics Multigene Family/genetics Neoplasm Invasiveness/genetics Polymerase Chain Reaction Tumor Escape/genetics
Chemicals
B7-H1 Antigen Chemokine CXCL12 MicroRNAs
Authors & Affiliations
18 authors, click to expand affiliations / ORCID
Cioffi Michele
Stem Cells & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Trabulo Sara M
Stem Cells & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. | Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, UK.
Vallespinos Mireia
Stem Cells & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Raj Deepak
Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, UK.
Kheir Tony Bou
Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, UK.
Lin Meng-Lay
Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, UK.
Begum Julfa
Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, UK.
Baker Ann-Marie
Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK.
Amgheib Ala
Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, UK.
Saif Jaimy
School of Clinical Sciences, University of Bristol, Bristol, UK.
Perez Manuel
Confocal Microscopy Unit, Centro Nacional de Investigaciones Oncológicas, Spain.
Soriano Joaquim
Confocal Microscopy Unit, Centro Nacional de Investigaciones Oncológicas, Spain.
Desco Manuel
Departamento de Ingenieria Biomedica e Ingeniería Aeroespacial, Universidad Carlos III de Madrid, Leganés, Spain. | Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain. | Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.
Gomez-Gaviro Maria Victoria
Departamento de Ingenieria Biomedica e Ingeniería Aeroespacial, Universidad Carlos III de Madrid, Leganés, Spain. | Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain. | Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.
Cusso Lorena
Departamento de Ingenieria Biomedica e Ingeniería Aeroespacial, Universidad Carlos III de Madrid, Leganés, Spain. | Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain. | Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.
Megias Diego
Confocal Microscopy Unit, Centro Nacional de Investigaciones Oncológicas, Spain.
Aicher Alexandra
Stem Cells & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. | Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, UK.
Heeschen Christopher
Stem Cells & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. | Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, UK.
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Article Info
Journal
Oncotarget
Abbr.
Oncotarget
ISSN
1949-2553
DOI
10.18632/oncotarget.15450
Published
2017-03-28
Pages
21609-21625
Language
English
Region
United States
NLM ID
101532965
PMCID
PMC5400610
Subset
IM
External Links
PubMed source DOI: 10.18632/oncotarget.15450 PMC Full Text View journal details
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