TY - JOUR
T1 - TGF-ß1 downregulates the expression of CX3CR1 by inducing miR-27a-5p in primary human NK cells
AU - Regis, Stefano
AU - Caliendo, Fabio
AU - Dondero, Alessandra
AU - Casu, Beatrice
AU - Romano, Filomena
AU - Loiacono, Fabrizio
AU - Moretta, Alessandro
AU - Bottino, Cristina
AU - Castriconi, Roberta
PY - 2017/7/25
Y1 - 2017/7/25
N2 - Activity of human natural killer (NK) cells against cancer cells is deeply suppressed by TGF-ß1, an immunomodulatory cytokine that is released and activated in the tumor microenvironment. Moreover, our previous data showed that TGF-ß1 modifies the chemokine receptor repertoire of NK cells. In particular, it decreases the expression of CX3CR1 that drives these effectors toward peripheral tissues, including tumor sites. To identify possible mechanisms mediating chemokine receptors modulation, we analyzed the microRNA profile of TGF-ß1-treated primary NK cells. The analysis pointed out miR-27a-5p as a possible modulator of CX3CR1. We demonstrated the functional interaction of miR-27a-5p with the 3' untranslated region (3'UTR) of CX3CR1 mRNA by two different experimental approaches: by the use of a luciferase assay based on a reporter construct containing the CX3CR1 3'UTR and by transfection of primary NK cells with a miR-27a-5p inhibitor. We also showed that the TGF-ß1-mediated increase of miR-27a-5p expression is a consequence of miR-23a-27a-24-2 cluster induction. Moreover, we demonstrated that miR-27a-5p downregulates the surface expression of CX3CR1. Finally, we showed that neuroblastoma cells induced in resting NK cells a downregulation of the CX3CR1 expression that was paralleled by a significant increase of miR-27a-5p expression. Therefore, the present study highlights miR-27a-5p as a pivotal TGF-ß1-induced regulator of CX3CR1 expression.
AB - Activity of human natural killer (NK) cells against cancer cells is deeply suppressed by TGF-ß1, an immunomodulatory cytokine that is released and activated in the tumor microenvironment. Moreover, our previous data showed that TGF-ß1 modifies the chemokine receptor repertoire of NK cells. In particular, it decreases the expression of CX3CR1 that drives these effectors toward peripheral tissues, including tumor sites. To identify possible mechanisms mediating chemokine receptors modulation, we analyzed the microRNA profile of TGF-ß1-treated primary NK cells. The analysis pointed out miR-27a-5p as a possible modulator of CX3CR1. We demonstrated the functional interaction of miR-27a-5p with the 3' untranslated region (3'UTR) of CX3CR1 mRNA by two different experimental approaches: by the use of a luciferase assay based on a reporter construct containing the CX3CR1 3'UTR and by transfection of primary NK cells with a miR-27a-5p inhibitor. We also showed that the TGF-ß1-mediated increase of miR-27a-5p expression is a consequence of miR-23a-27a-24-2 cluster induction. Moreover, we demonstrated that miR-27a-5p downregulates the surface expression of CX3CR1. Finally, we showed that neuroblastoma cells induced in resting NK cells a downregulation of the CX3CR1 expression that was paralleled by a significant increase of miR-27a-5p expression. Therefore, the present study highlights miR-27a-5p as a pivotal TGF-ß1-induced regulator of CX3CR1 expression.
KW - Chemokine receptors
KW - microRNAs
KW - NK cells
KW - TGF-ß1
KW - Tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85026504958&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85026504958&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2017.00868
DO - 10.3389/fimmu.2017.00868
M3 - Article
AN - SCOPUS:85026504958
VL - 8
JO - Frontiers in Immunology
JF - Frontiers in Immunology
SN - 1664-3224
IS - JUL
M1 - 868
ER -