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Updated: Apr 6, 2026
Zebrafish Model of Neuroblastoma Metastasis
Published on: March 14, 2021
MDA5 complements TLR3 in suppression of neuroblastoma
Wen-Ming Hsu1, Chao-Cheng Huang2, Hsin-Yu Lee3
1Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
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.
Insights
Toll-like receptor 3 (TLR3) agonists show limited neuroblastoma (NB) cell death. Co-targeting melanoma differentiation-associated gene 5 (MDA5) with TLR3 enhances apoptosis, suggesting MDA5 complements TLR3 in NB suppression.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Toll-like receptor 3 (TLR3) is differentially expressed in neuroblastoma (NB) and associated with favorable prognosis.
- TLR3 agonists like polyinosinic-polycytidylic acid [poly(I:C)] induce limited apoptosis in NB cells, suggesting involvement of other cytosolic viral RNA sensors.
- Melanoma differentiation-associated gene 5 (MDA5) and retinoic acid-inducible gene-I (RIG-I) are cytosolic sensors potentially involved in poly(I:C)-induced NB cell death.
Purpose of the Study:
- To investigate the role of MDA5 and RIG-I in poly(I:C)-induced neuroblastoma cell death.
- To determine if MDA5 expression predicts prognosis in neuroblastoma tissues, synergistically with TLR3.
- To explore therapeutic strategies involving TLR3 and MDA5 in neuroblastoma.
Main Methods:
- Treatment of NB cell lines with poly(I:C) and assessment of MDA5 and RIG-I expression.
- Analysis of caspase-9 and active caspase-3 levels following poly(I:C) treatment.
- Knockdown of MDA5 and RIG-I, and simultaneous targeting of MDA5 and TLR3.
- Overexpression of MDA5 in FaDu cells and evaluation of colony formation and cell death.
- Analysis of MDA5 and TLR3 expression in human NB tissue samples.
Main Results:
- Poly(I:C) induced MDA5 and RIG-I expression in SK-N-AS and SK-N-FI NB cell lines, correlating with caspase-9 and active caspase-3 upregulation.
- Simultaneous knockdown of MDA5 and TLR3 most effectively rescued poly(I:C)-induced apoptosis and MAVS, caspase-9, and active caspase-3 upregulation in AS cells.
- MDA5 overexpression in FaDu cells led to reduced colony formation and increased poly(I:C)-induced cell death.
- MDA5 expression in NB tissues predicted a favorable prognosis synergistically with TLR3.
Conclusions:
- MDA5 plays a complementary role in TLR3-mediated suppression of neuroblastoma.
- Combined targeting of MDA5 and TLR3 may represent a promising therapeutic strategy for neuroblastoma.
- MDA5 serves as a potential prognostic biomarker for neuroblastoma.
