METTL3-induced lncARSR aggravates neuroblastoma tumorigenic properties through stabilizing PHOX2B

Abstract

Neuroblastoma (NB), the most common extracranial solid tumor in pediatric patients, manifests with considerable variability across multiple primary sites. Despite this, the extent of genetic heterogeneity within these tumor foci and the identification of consistent oncogenic drivers remains largely unexplored. Of particular interest, genetic mutations in PHOX2B have been linked to familial cases of NB, yet the underlying molecular mechanisms are not fully delineated. In our research, we focus on unraveling the role of a novel functional long non-coding RNA (lncRNA) associated with PHOX2B in the context of NB. Using NB cell models with overexpressed PHOX2B, combined with lncRNA microarray analysis, we discovered that lncARSR is significantly upregulated in response to PHOX2B overexpression. Subsequent biological assays demonstrated that lncARSR promotes both the proliferation and metastasis of NB cells. Further molecular investigations revealed that lncARSR plays a crucial role in stabilizing PHOX2B expression within NB cells. Moreover, we identified that the expression of lncARSR is regulated by methylation through methyltransferase-like 3 (METTL3), which itself is positively correlated with PHOX2B expression. Rescue experiments underscored the functional importance of METTL3, lncARSR, and PHOX2B in NB cells. In summary, our findings provide new insights into the molecular functions of PHOX2B in the progression of neuroblastoma and propose a novel therapeutic target for this aggressive malignancy.