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(MICA)是NKG2D激活受体NKG2D的配体，在肝细胞癌中表达，并决定其对NK细胞的敏感性。在本研究中，我们发现：1)慢性肝病和肝细胞癌患者血清中可溶性MICA水平随着疾病进展而升高；2)ADAM9和ADAM 10在肝细胞癌的MICA脱落中起关键作用；4)包括索拉非尼和表阿霉素在内的抗肿瘤药物分别抑制ADA9和ADAM 10的表达，并抑制肝细胞癌中MICA的脱落。这些结果表明，ADAM家族蛋白参与了肝癌MICA的胞外区脱落，并可能成为提高抗肿瘤免疫反应的新的治疗靶点。

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.