In this study, we identify miR-146a as a negative regulator of immune activation, comparable to immune-checkpoint molecules. miR-146a levels were increased in melanoma microenvironmental tissue, and <i>miR-146a<sup>-/-</sup></i> mice survived longer and developed less metastases in comparison with wild-type melanoma-bearing mice.
Mir-371, mir-150, mir-21 and mir-7d were found to be potential prognostic markers, while mir-134, mir-146a, mir-338 and mir-371 were associated with metastases.
Lower levels of miR-146a in primary tumor tissue samples were correlated with a shorter progression-free survival (P=0.04) and platinum-resistance of metastases (P=0.006).
Of 82 miRNAs that were modulated during tumor progression, 22 were involved in EMT. qRT-PCR confirmed the down-regulation of miR-150 and miR-10b in both primary tumor and metastasis compared to normal mucosa and of miR-146a in metastases compared to primary tumor.
MKN-45 cells stably expressing miR-146a or the negative control were transplanted into nude mice through the lateral tail vein to explore the effect of miR-146a on tumor metastasis in vivo.
These findings implicate miR-146a/b as a negative regulator of constitutive NF-kappaB activity in a breast cancer setting and suggest that modulating miR-146a/b levels has therapeutic potential to suppress breast cancer metastases.