title: Expression and role of MICA and MICB in human hepatocellular carcinomas and their regulation by retinoic acid.
abstract: Natural killer (NK) cells are important effector cells for the first line of defense against tumor, but the mechanisms by which they recognize and kill human hepatocellular carcinoma (HCC) remains to be elucidated. Distant MHC class I homologs MICA and MICB are recently identified human ligands for NK cell activating receptor NKG2D. In our present study, MICA or MICB transcript was detected in 6 of 10 human hepatocellular carcinoma tissues, but not in the surrounding non-cancerous tissues. Immunohistochemical analysis showed that MICA/B were expressed in the tumor cells of the cancerous tissues. Huh7 and HepG2 hepatoma cells, but not Hep3B cells, substantially expressed MICA/B on their cell surface. MICA/B expressed on hepatoma cells contributed to their NK sensitivity, because Huh7 and HepG2 were less susceptible to NK cytolysis when MAb against MICA/B was added during the cytolysis assay. Of interest is the finding that retinoic acid upregulated expression of MICA/B in Huh7 and HepG2 cells. Retinoic acid-treated hepatoma cells induced IFN gamma production from cocultured NK cells and rendered themselves more susceptible to NK cells. This was clearly dependent on upregulation of MICA/B, because both the enhanced IFN gamma production and NK cytolysis were completely abolished by MAb-mediated masking of MICA/B. These results suggest that MICA/B, expressed on a subset of human HCCs, may play an important role in their susceptibility to NK cells. Furthermore, retinoic acid can function as a modulator of MICA/B expression and thereby further activate NK cells.
authors.affiliation: Osaka University Graduate School of Medicine, Department of Molecular Therapeutics, Suita, Osaka, Japan.
authors.forename: Masahisa
authors.initials: M
authors.lastname: Jinushi
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tatsumi
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kanto
authors.forename: Veronika
authors.initials: V
authors.lastname: Groh
authors.forename: Thomas
authors.initials: T
authors.lastname: Spies
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Kimura
authors.forename: Takuya
authors.initials: T
authors.lastname: Miyagi
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Mochizuki
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Norio
authors.initials: N
authors.lastname: Hayashi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D017931:DNA Primers / Q000737:chemistry; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D007074:Immunoglobulin G / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D017931:DNA Primers; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; C099187:MHC class I-related chain A; C098080:MICB antigen; D012333:RNA, Messenger; D014212:Tretinoin; D007371:Interferon-gamma