TY - JOUR
T1 - The miR-25-93-106b cluster regulates tumor metastasis and immune evasion via modulation of CXCL12 and PD-L1
AU - Cioffi, Michele
AU - Trabulo, Sara M
AU - Vallespinos, Mireia
AU - Raj, Deepak
AU - Kheir, Tony Bou
AU - Lin, Meng-Lay
AU - Begum, Julfa
AU - Baker, Ann-Marie
AU - Amgheib, Ala
AU - Saif, Jaimy
AU - Perez, Manuel
AU - Soriano, Joaquim
AU - Desco, Manuel
AU - Gomez-Gaviro, Maria Victoria
AU - Cusso, Lorena
AU - Megias, Diego
AU - Aicher, Alexandra
AU - Heeschen, Christopher
N1 - Licensed under a Creative Commons Attribution 3.0 License.
PY - 2017/2/17
Y1 - 2017/2/17
N2 - 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.
AB - 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.
KW - Animals
KW - B7-H1 Antigen/metabolism
KW - Chemokine CXCL12/metabolism
KW - Flow Cytometry
KW - Gene Expression Regulation, Neoplastic/genetics
KW - Gene Knockout Techniques
KW - Humans
KW - Immunohistochemistry
KW - In Situ Hybridization
KW - Mice
KW - MicroRNAs/genetics
KW - Multigene Family/genetics
KW - Neoplasm Invasiveness/genetics
KW - Polymerase Chain Reaction
KW - Tumor Escape/genetics
UR - http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=15450&path[]=49361
U2 - 10.18632/oncotarget.15450
DO - 10.18632/oncotarget.15450
M3 - Article
C2 - 28423491
VL - 8
SP - 21609
EP - 21625
JO - Oncotarget
JF - Oncotarget
IS - 13
ER -