miR-615-5p was characterized by our group as a tumour suppressor. IGF-1 R activates a downstream signalling pathway, well characterized in liver cells, however, its role in immunity especially Natural Killer cells (NKs) remains vague. This study aimed at investigating the regulatory role of miR-615-5p on IGF signalling and its impact on NKs cytotoxicity in HCC. Our results showed an upregulation in miR-615-5p and IGF-1 R in NKs of 130 HCC patients compared to 35 controls. Forcing the expression of miR-615-5p, repressed IGF-IR, attenuated NKs cytotoxicity, decreased CD56dim, increased CD56bright NK subsets and reduced the cytotoxic markers NKG2D, TNF-α and perforins. It repressed NKG2D ligand (ULBP2) in Huh-7 cells. In conclusion, miR-615-5p represses IGF-1 R in NKs and their target hepatocytes; however, it has a contradicting impact on HCC progression on both cell types. These findings might pave the way for better understanding the role of microRNAs in NKs function and HCC immune-pathogenesis.
Keywords: Hepatocellular carcinoma; immunotherapy; insulin-like growth factor axis; microRNA "miR-615-5p"; natural killer cells.