title: Dose dependent activation of retinoic acid-inducible gene-I promotes both proliferation and apoptosis signals in human head and neck squamous cell carcinoma.
abstract: The retinoic-acid-inducible gene (RIG)-like receptor (RLR) family proteins are major pathogen reorganization receptors (PRR) responsible for detection of viral RNA, which initiates antiviral response. Here, we evaluated the functional role of one RLR family member, RIG-I, in human head and neck squamous cell carcinoma (HNSCC). RIG-I is abundantly expressed both in poorly-differentiated primary cancer and lymph node metastasis, but not in normal adjacent tissues. Activation of RIG-I by transfection with low dose of 5'-triphosphate RNA (3p-RNA) induces low levels of interferon and proinflammatory cytokines and promotes NF-κB- and Akt-dependent cell proliferation, migration and invasion. In contrast, activation of RIG-I by a high dose of 3p-RNA induces robust mitochondria-derived apoptosis accompanied by decreased activation of Akt, which is independent of the interferon and TNFα receptor, but can be rescued by over-expression of constitutively active Akt. Furthermore, co-immunoprecipitation experiments indicate that the CARD domain of RIG-I is essential for inducing apoptosis by interacting with caspase-9. Together, our results reveal a dual role of RIG-I in HNSCC through regulating activation of Akt, in which RIG-I activation by low-dose viral dsRNA increases host cell survival, whereas higher level of RIG-I activation leads to apoptosis. These findings highlight the therapeutic potential of dsRNA mediated RIG-I activation in the treatment of HNSCC.
authors.affiliation: Department of Oral & Maxillofacial-Head & Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jingzhou
authors.initials: J
authors.lastname: Hu
authors.forename: Yue
authors.initials: Y
authors.lastname: He
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.forename: Chao
authors.initials: C
authors.lastname: Zhu
authors.forename: Weimin
authors.initials: W
authors.lastname: Ye
authors.forename: Hanguang
authors.initials: H
authors.lastname: Zhu
authors.forename: Wantao
authors.initials: W
authors.lastname: Chen
authors.forename: Chenping
authors.initials: C
authors.lastname: Zhang
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects*; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D000072640:Interferon-Induced Helicase, IFIH1; D034741:RNA, Small Interfering / Q000235:genetics; D011971:Receptors, Immunologic; D014162:Transfection
chemical_list: D034741:RNA, Small Interfering; D011971:Receptors, Immunologic; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1