miR-22 gene therapy as a novel option for HCC treatment in part via augmentation of retinoic acid but silencing IL17 signaling in orthotopic murine models

miR-22 expression is reduced in hepatocellular carcinoma (HCC), a deadly cancer with very limited treatment options. Our published data showed that retinoic acid (RA) via its receptor RARβ induces miR-22. Moreover, miR-22 increase the expression of RARβ, which signifies the significance of RA signaling in tumor suppression. Using orthotopic HCC mice models including β-catenin positive HCC, we studied the anti-HCC effect of miR-22 for the first time focusing on the potential roles of RA signaling in regulating tumor immunity based on transcriptomic profiling data found in both mouse and human HCC. Our data showed that miR-22 treated HCC without toxicity, with improved survival compared with Lenvatinib. Reduced RA signaling and increased IL17 signaling found in mouse HCC as well as isolated T cells were consistently found in miR-22 low human HCC, whereas miR-22 treatment of mouse HCC reversed both pathways verified in β-catenin positive HCC. Moreover, in isolated T cells, miR-22 silenced the Il17a gene, which lead to Th17 cell reduction, by reducing the recruitment of HIFα to the Rorc gene as well as the RORγT, HIF1α, and STAT3 to the Il17a gene. Further, IL23-driven IL17 signaling expansion attenuated the anti-HCC effects of miR-22. Additionally, CD8 blockade diminished the therapeutic effects of miR-22. Together, via regulating tumor immunity, miR-22 can be a novel option for HCC treatment. To uncover the underlying mechanism by which miR-22 treats HCC, we performed gene expression profiling using data obtained from RNA-seq of RAS/AKT-induced-HCCs treated with AAV control or miR-22 as well as WT FVB/N normal livers (n=3/groups)