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

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.

Publication DOI: https://doi.org/10.18632/oncotarget.15450
Divisions: College of Health & Life Sciences > Aston Medical School
Additional Information: Licensed under a Creative Commons Attribution 3.0 License.
Uncontrolled Keywords: 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
Full Text Link:
Related URLs: http://www.onco ... 50&path[]=49361 (Publisher URL)
PURE Output Type: Article
Published Date: 2017-02-17
Accepted Date: 2017-01-10
Authors: Cioffi, Michele
Trabulo, Sara M
Vallespinos, Mireia
Raj, Deepak
Kheir, Tony Bou
Lin, Meng-Lay
Begum, Julfa
Baker, Ann-Marie
Amgheib, Ala
Saif, Jaimy
Perez, Manuel
Soriano, Joaquim
Desco, Manuel
Gomez-Gaviro, Maria Victoria
Cusso, Lorena
Megias, Diego
Aicher, Alexandra
Heeschen, Christopher

Download

[img]

Version: Published Version

License: Creative Commons Attribution

| Preview

Export / Share Citation


Statistics

Additional statistics for this record