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

MHC I类相关链A（云母）是NKG2D激活受体NKG2D的配体，在肝细胞癌（HCC）中表达，并决定其对NK细胞的敏感性。在本研究中，我们已经表明：1）随着疾病进展，慢性肝病和HCC中可溶性形式的云母的血清水平增加，2）ADAM 9和ADAM 10与HCC中云母的脱落密切相关，4）包括索拉非尼和表阿霉素在内的抗肿瘤药物分别抑制ADA 9和ADAM 10的表达以及HCC中云母的脱落。这些结果表明，ADAM家族蛋白参与云母从HCC的胞外域脱落，并且可能是用于改善抗肿瘤免疫应答的新的治疗靶点。

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.