Kohga Keisuke, Takehara Tetsuo, Tatsumi Tomohide, Miyagi Takuya, Ishida Hisashi, Ohkawa Kazuyoshi, Kanto Tatsuya, Hiramatsu Naoki, Hayashi Norio
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.
Cancer Res. 2009 Oct 15;69(20):8050-7. doi: 10.1158/0008-5472.CAN-09-0789. Epub 2009 Oct 13.
MHC class I-related chain A (MICA) is a ligand for the NKG2D-activating immunoreceptor that mediates activation of natural killer (NK) cells. The ectodomain of MICA is shed from tumor cells, which may be an important means of evading antitumor immunity. We previously reported that patients with hepatocellular carcinoma (HCC) display high levels of soluble MICA in circulation, which could be downregulated by chemotherapy. The present study shows that anti-HCC drugs suppress MICA ectodomain shedding by inhibiting expression of a disintegrin and metalloproteinase 10 (ADAM10). Both ADAM10 and CD44, a typical substrate of the ADAM10 protease, were expressed in human HCC tissues and HCC cells but not in normal liver tissues or cultured hepatocytes. Small interfering RNA-mediated knockdown experiments revealed that ADAM10 is a critical sheddase for both MICA and CD44 in HCC cells. Of interest is the finding that epirubicin clearly downregulated ADAM10 expression and MICA shedding in HCC cells; its suppressive effect on MICA shedding was abolished in ADAM10-depleted cells. Epirubicin treatment also enhanced the NKG2D-mediated NK sensitivity of HCC cells. Patients with HCC had significantly higher levels of serum-soluble CD44, which correlated well with serum-soluble MICA levels, thus suggesting a close link between ADAM10 activity and MICA shedding in these patients. Soluble MICA and CD44 levels were downregulated with a significant correlation in patients treated by transarterial chemoembolization using epirubicin. In conclusion, anticancer drugs can modulate expression of ADAM10, which is critically involved in MICA ectodomain shedding. Epirubicin therapy may have a previously unrecognized effect on antitumor immunity in HCC patients.
MHC I类相关链A（MICA）是NKG2D激活免疫受体的配体，可介导自然杀伤（NK）细胞的激活。MICA的胞外域可从肿瘤细胞上脱落，这可能是肿瘤逃避免疫的重要方式。我们之前报道过，肝细胞癌（HCC）患者循环中可溶性MICA水平较高，化疗可使其下调。本研究表明，抗HCC药物通过抑制去整合素和金属蛋白酶10（ADAM10）的表达来抑制MICA胞外域的脱落。ADAM10和CD44（ADAM10蛋白酶的典型底物）在人HCC组织和HCC细胞中均有表达，但在正常肝组织或培养的肝细胞中不表达。小干扰RNA介导的敲低实验表明，ADAM10是HCC细胞中MICA和CD44的关键裂解酶。有趣的是，表柔比星可明显下调HCC细胞中ADAM10的表达和MICA的脱落；在ADAM10缺失的细胞中，其对MICA脱落的抑制作用消失。表柔比星处理还增强了NKG2D介导的HCC细胞对NK的敏感性。HCC患者血清可溶性CD44水平显著更高，且与血清可溶性MICA水平密切相关，这表明这些患者中ADAM10活性与MICA脱落之间存在紧密联系。在接受表柔比星经动脉化疗栓塞治疗的患者中，可溶性MICA和CD44水平下调，且具有显著相关性。总之，抗癌药物可调节ADAM10的表达，而ADAM10在MICA胞外域脱落中起关键作用。表柔比星治疗可能对HCC患者的抗肿瘤免疫有此前未被认识到的作用。
