title: Anticancer chemotherapy inhibits MHC class I-related chain a ectodomain shedding by downregulating ADAM10 expression in hepatocellular carcinoma.
abstract: 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.
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kohga
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tatsumi
authors.forename: Takuya
authors.initials: T
authors.lastname: Miyagi
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ishida
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Ohkawa
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kanto
authors.forename: Naoki
authors.initials: N
authors.lastname: Hiramatsu
authors.forename: Norio
authors.initials: N
authors.lastname: Hayashi
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D015251:Epirubicin / Q000627:therapeutic use*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D015395:Histocompatibility Antigens Class I / Q000187:drug effects*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; C497483:CD44 protein, human; D015395:Histocompatibility Antigens Class I; D018960:Hyaluronan Receptors; C099187:MHC class I-related chain A; D008565:Membrane Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D015251:Epirubicin; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein