Identification of a JAK/STAT/miR155HG positive feedback loop in regulating NK cell proliferation and effector functions

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway control NK cell development, expansion and cytotoxic functions. Whether lncRNA regulates the JAK-STAT signaling in NK cells remains unknown. We found that miR155HG was upregulated in activated NK cells and promoted their proliferation and effector functions. Mechanistically, miR155HG bound to miR-6756 and relieved its repression of JAK3 expression, resulting in increased JAK3 level and enhanced NK cells proliferation and function. Further investigations disclosed that upon cytokine stimulation, STAT3 directly interacts with miR155HG promoter and induces miR155HG transcription. Collectively, we identify a miR155HG-mediated positive feedback loop of the JAK-STAT signaling. In brief, STAT3 interacts with miR155HG promoter and induces miR155HG transcription upon cytokine stimulation, and miR155HG may work as a sponge for miR-6756, preventing the miR-6756-mediated repression of JAK3 expression, thereby promoting the JAK-STAT pathway and enhancing NK cell proliferation and function. These findings may provide a promising therapeutic target to improve NK cell therapy. Overall design: RNA-seq of NK-92-shCtrl/shmiR155HG cells with three replicates