MicroRNA miR-29 modulates expression of immunoinhibitory molecule B7-H3: potential implications for immune based therapy of human solid tumors.
B7-H3, a surface immunomodulatory glycoprotein, inhibits natural killer cells and T cells. The monoclonal antibody (mAb) 8H9 is specific for 4Ig-B7-H3, the long and principal form of B7-H3. Early results from radioimmunotherapy using 8H9 have shown promise in patients with metastatic solid tumors to the central nervous system. Whereas B7-H3 transcript was ubiquitously expressed in a wide spectrum of human solid tumors as well as human normal tissues, B7-H3 protein was preferentially expressed only in tumor tissues. By quantitative reverse transcription-PCR, all three isoforms of microRNA miR-29 (a, b, and c) were highly expressed in normal tissues. However, they were down-regulated in a broad spectrum of solid tumors, including neuroblastoma, sarcomas, brain tumors, and tumor cell lines. B7-H3 protein expression was inversely correlated with miR-29 levels in both cell lines and tumor tissues tested. Using luciferase reporter assay, miR-29a was shown to directly target B7-H3 3' untranslated region, and knock-in and knockdown of miR-29a led to down-regulation and up-regulation, respectively, of B7-H3 protein expression. The ability of miR-29 to control B7-H3 protein expression has implications in immune escape by solid tumors. Differential modulation of this key immunoinhibitory molecule in tumor versus normal tissues may advance both cell-mediated immunotherapy and antibody-based targeted strategies using the B7-H3-specific mAb 8H9.
Xu
Hong
H
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Cheung
Irene Y
IY
Guo
Hong-Fen
HF
Cheung
Nai-Kong V
NK
D020413:3' Untranslated Regions; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology / Q000302:isolation & purification; D060887:B7 Antigens; D045744:Cell Line, Tumor; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011971:Receptors, Immunologic / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D020413:3' Untranslated Regions; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D060887:B7 Antigens; C423237:CD276 protein, human; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D011971:Receptors, Immunologic