Molecular mechanism of the ectodomain shedding of the NKG2D ligand MHC class I-related chain A in hepatocellular carcinoma and its therapeutic implication

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MHC class I-related chain A (MICA), a ligand for the NKG2D activating receptor NKG2D, is expressed in hepatocellular carcinoma (HCC) and determines its sensitivity to NK cells. In the present study, we have shown that 1) the serum levels of soluble form of MICA increase in chronic liver disease and HCC as disease progresses, 2) ADAM9 and ADAM 10 are critically involved in shedding of MICA from HCC and 4) anti-tumor agents including sorafenib and epirubicin inhibit expression of ADA9 and ADAM 10, respectively, and shedding of MICA in HCC. These results indicate that ADAM family proteins are involved in ectodomain shedding of MICA from HCC and could be novel therapeutic targets for improving anti-tumor immune responses.