Overexpression of miR-382 Sensitizes Hepatocellular Carcinoma Cells to γδ T Cells by Inhibiting the Expression of c-FLIP

Human γδ T lymphocytes were reported to display anti-tumor effects against multiple cancers, including hepatocellular carcinoma (HCC). Aberrant expression of microRNAs (miRNAs) leads to a low response to immunotherapy. Thirty-five HCC tumor tissues and their adjacent healthy tissues were collected from patients with primary HCC who underwent tumor resection in the Third People’s Hospital of Hainan Province, China. The purity of the resulting γδ T cells was identified by anti-γδ-T cell receptor-phycoerythrin (anti-γδ-TCR-PE) and anti-CD3-fluorescein isothiocyanate (anti-CD3-FITC) antibodies on flow cytometry. Human HCC cell lines HepG2 and PLC were cultured. We observed that ex vivo, expanded human γδ T cells were able to induce cell lysis of HCC. Furthermore, as miR-382 was observed to be downregulated in HCC tissues and cell lines, we found that overexpression of miR-382 increased the sensitivity of HCC cells to γδ T cells. We proved that mRNA of cellular FADD-like interleukin-1β-converting enzyme-inhibitory protein (c-FLIP) was the target of miR-382. Inhibition of c-FLIP by miR-382 significantly promotes the cell lysis of HCC through strengthening the activation caspase 8 induced by γδ T cell treatment. In conclusion, overexpression of miR-382 promotes HCC cell lysis induced by γδ T cells through inhibiting the expression of c-FLIP.