Retinoic Acid– Inducible Gene I ((Rig-I))–Like Receptor Family Is Implicated in Differentiation and Survival of Neuroblastoma Cells

Neuroblastoma (NB) is one of the most common and malignant extra-cranial solid tumors in children. The prognosis depends on interplay of three factors, notably age, stage and MYCN protooncogene status. However, MYCN amplification alone is not sufficient to predict the outcome of the patients with NB. Some other internal or external stimuli may modify its expression. Our published studies have established a role for TLR3 agonist poly(I:C), which is a viral RNA mimetic, in induction of apoptotic response in TLR3 expressing, MYCN-nonamplified NB cells, but not in TLR3 non- or low-expressing, MYCN-amplified NB cells. Obviously, some other viral RNA mimetic and other receptors are waited to be developed to overcome the gap. Retinoic acid– inducible gene I (RIG-I)–like receptors (RLRs) are a group of cytosolic viral RNA recognition receptors, which includes two active members— retinoic acid inducible gene I (RIG-I), melanoma differentiation associated gene 5 (MDA5). Both RIG-I and MDA5 are known to actively participate in cell death of cancers including melanoma. Our previous work on TLR3 and the preliminary data on RIG-I and MDA5 expression in human NB tissues and RIG-I and MDA5 signaling of NB cell death or differentiation suggest a complementary role for RIG-I and MDA5 in immunotherapy of NB. A three-year study is thus proposed to achieve the following specific aims: 1. To study human NB tissue samples by using immunohistochemistry to correlate the findings with the clinical characteristics of the patients. 2. Characterization of RIG-I and MDA5 signaling of cell death or differentiation by using different viral RNA mimetics, including poly(I:C) and 5' ppp-dsRNA in NB cells with different RIG-I and MDA5 expression and MYCN amplification. 3. To change the MYCN oncogene status in NB cell lines and to observe if RIG-I and MDA5 signaling of NB cell death will be affected and to identify effective viral RNA mimetics for in vivo inhibition of tumor growth 4. To study direct cytotoxic effect of viral RNA mimetics, alone or with commonly used chemotherapeutic agents such as cisplatin in immuno-deficient NOD/SCID mice loaded with human NB cells. The significance of this study is that we may implement the auxiliary function of immunotherapy to augment anti-tumor effect of chemotherapeutic agents, particularly in patients with refractory NB.

Project ID:PC10108-0887
External Project ID:NSC101-2314-B182-029-MY3