title: MDA5 complements TLR3 in suppression of neuroblastoma.
abstract: Toll-like receptor3 (TLR3) has been confirmed to be differentially expressed in neuroblastoma (NB), and predicts a favorable prognosis with a high expression in tumor tissues. Treatment with TLR3 agonist--polyinosinic-polycytidylic acid [poly(I:C)] could induce significant but limited apoptosis in TLR3-expressing NB cells, suggesting that other viral RNA sensors, including melanoma differentiation-associated gene 5 (MDA5) and retinoic acid-inducible gene-I (RIG-I) in the cytosolic compartment might also be implicated in poly(I:C)-induced NB cell death. MDA5 and RIG-I were induced by poly(I:C) to express in two of six NB cell lines, SK-N-AS (AS) and SK-N-FI, which were associated with up-regulation of caspase9 and active caspase3. While knockdown of either MDA5 or RIG-I alone is ineffective to decrease caspase9 and active caspase3, simultaneously targeting MDA5 and TLR3 showed the best effect to rescue poly(I:C) induced up-regulation of mitochondrial antiviral signaling protein (MAVS), caspase9, active caspase3, and apoptosis in AS cells. Over-expression of MDA5 in FaDu cells resulted in significantly less colony formation and more poly(I:C)-induced cell death. Further studies in human NB tissue samples revealed that MDA5 expression in NB tissues predicted a favorable prognosis synergistically with TLR3. Our findings indicate that MDA5 may serve as a complementary role in the TLR3 activated suppression of NB.
authors.affiliation: Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Wen-Ming
authors.initials: WM
authors.lastname: Hsu
authors.affiliation: Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Chao-Cheng
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Department of Life Science and Institute of Zoology, National Taiwan University, Taipei, Taiwan.
authors.forename: Hsin-Yu
authors.initials: HY
authors.lastname: Lee
authors.affiliation: Department of Life Science and Institute of Zoology, National Taiwan University, Taipei, Taiwan.
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Wu
authors.affiliation: Department of Pediatric Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Min-Tsui
authors.initials: MT
authors.lastname: Wu
authors.affiliation: Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Hui-Ching
authors.initials: HC
authors.lastname: Chuang
authors.affiliation: Department of Pediatric Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.|Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Li-Ling
authors.initials: LL
authors.lastname: Lin
authors.affiliation: Department of Pediatric Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Jiin-Haur
authors.initials: JH
authors.lastname: Chuang
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D000072640:Interferon-Induced Helicase, IFIH1; D053208:Kaplan-Meier Estimate; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011070:Poly I-C / Q000494:pharmacology*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D011971:Receptors, Immunologic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D011971:Receptors, Immunologic; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D053148:Caspase 3; D053453:Caspase 9; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D011070:Poly I-C
keywords: MDA5; RIG-I; TLR3; neuroblastoma; poly(I:C)