Enhancing NK cell cytotoxicity by miR-182 in hepatocellular carcinoma.

ABSTRACT

BACKGROUND AND AIM: NK-cells are the principle defense line against different malignancies. Their activation status is determined by the balance between activating and inhibitory receptors such as NKG2D and NKG2A, respectively. MicroRNAs are crucial post-transcriptional regulators of gene expression, playing key roles in modulating NK-cell development and function. The aim of this study is to investigate the role of miRNAs in regulating the activation and cytotoxic function of NK-cells in HCC. METHODS: In silico analysis was performed to predict a potential miRNA that might target NKG2D and NKG2A mRNAs. NK-cells were isolated from HCC patients and healthy controls, after which miRNA and mRNA were quantified. Manipulating miRNA expression was performed followed by investigating downstream targets and the cytotoxic activity of NK-cells against Huh-7 cell lines. RESULTS: NK-cells of HCC patients showed miR-182 overexpression compared to controls. NKG2D and NKG2A were upregulated and downregulated, respectively, in HCC NK-cells. Upon forcing miR-182 expression in the HCC NK-cells, upregulation of both receptors was observed. Finally, miR-182 was reported to induce NK-cell cytotoxicity represented in Perforin-1 upregulation and increase in cytolytic killing of co-cultured Huh-7 cells. CONCLUSION: Our findings suggest that miR-182 may augment NK-cell cytotoxicity against liver cancer via modulating NKG2D and NKG2A expressions.