| Popis: |
MYCNamplification and disruption of tumor suppressor microRNA (TSmiR) function are central drivers of poor outcomes in neuroblastoma (NB). MYC, MYCN, and TSmiRs regulate glucose metabolism, yet their role in unsaturated fatty acid synthesis (UFAS) remains poorly understood. We show here thatde novoand UFAS pathway genesFASN, ELOVL6, SCD, FADS2, andFADS1are upregulated in high-risk NB and associate with poor prognosis. Our RNA-Seq analysis of eight human NB cell lines reveals a parallel UFAS gene expression pattern. Consistent with this, we find that NB-related TSmiRs are predicted to extensively target these genes. In addition, we observe that both MYC and MYCN upregulate UFAS pathway genes while suppressing TSmiR host gene expression, creating a possible UFAS regulatory network betweenMYCNand TSmiRs in NB. Further, NB cells are high in omega 9 (ω9) unsaturated fatty acids that can be synthesizedde novo, and low in both ω6 and ω3, providing a plausible means for NB to limit cell-autonomous immune stimulation and reactive oxygen species (ROS)-driven apoptosis from ω6 and ω3 unsaturated fatty acid derivatives, respectively. We propose a model where the UFAS pathway, through novel regulation byMYCNand TSmiRs, plays a key role in neuroblastoma pathology, with implications for otherMYC-driven cancers. |
