Neuroblastoma (NB) is a pediatric
malignancy that arises in the peripheral nervous system, and the prognosis in the high-risk group remains dismal, despite the breakthroughs in multidisciplinary treatments. The oral treatment with
13-cis-retinoic acid (RA) after high-dose
chemotherapy and stem cell transplant has been proven to reduce the incidence of
tumor relapse in children with high-risk
neuroblastoma. However, many patients still have
tumors relapsed following
retinoid therapy, highlighting the need for the identification of resistant factors and the development of more effective treatments. Herein, we sought to investigate the potential oncogenic roles of the
tumor necrosis factor (
TNF) receptor-associated factor (TRAF) family in
neuroblastoma and explore the correlation between TRAFs and
retinoic acid sensitivity. We discovered that all TRAFs were efficiently expressed in
neuroblastoma, but
TRAF4, in particular, was found to be strongly expressed. The high expression of
TRAF4 was associated with a poor prognosis in human
neuroblastoma. The inhibition of
TRAF4, rather than other TRAFs, improved
retinoic acid sensitivity in two human
neuroblastoma cell lines, SH-SY5Y and SK-N-AS cells. Further in vitro studies indicated that
TRAF4 suppression induced
retinoic acid-induced cell apoptosis in
neuroblastoma cells, probably by upregulating the expression of
Caspase 9 and AP1 while downregulating Bcl-2,
Survivin, and IRF-1. Notably, the improved anti-
tumor effects from the combination of
TRAF4 knockdown and
retinoic acid were confirmed in vivo using the SK-N-AS human
neuroblastoma xenograft model. In conclusion, the highly expressed
TRAF4 might be implicated in developing resistance to
retinoic acid treatment in
neuroblastoma, and the combination
therapy with
retinoic acid and
TRAF4 inhibition may offer significant therapeutic advantages in the treatment of relapsed
neuroblastoma.