High level of p37δ-mRNA relative to p110δ-mRNA in neuroblastoma tumors correlates with poor patient survival.

Alterations in the PI3K/Akt pathway, a pathway that promotes proliferation and oncogenic transformation, are common in various cancers. In neuroblastoma, activation of Akt is correlated with aggressive disease although mutations in genes of this pathway are rare. Previous findings include a few mutations in PIK3CD, the gene encoding PI3K catalytic subunit delta, p110δ. We recently reported that an alternatively spliced form of p110δ, called p37δ, had cell proliferative properties and was over-expressed in ovarian and colorectal tumors. Here, we investigated p37δ in neuroblastoma primary tumors of different stages using qPCR (TaqMan) for gene expression analysis (46 samples) and Western blot for protein analysis (22 samples). Elevated levels of both p37δ-mRNA and p110δ-mRNA were detected in metastasizing neuroblastoma tumors compared to normal adrenal gland (P < 0.05), and higher expression of p37δ-mRNA relative to p110δ-mRNA in neuroblastoma non-survivor patients compared to survivors (P < 0.01). p37δ-Protein levels but not p110δ levels correlated with increased pAKT(T308) and pERK levels. The p37δ-mRNA levels did not correlate with the protein levels, indicating major regulation at the translational/protein level. Deregulation of signaling pathways is a hallmark of cancer development. Here, we show that p37δ, a kinase-dead isoform of the PI3K catalytic subunit p110δ, is over-expressed in neuroblastoma tumors, and that it correlates with the activation of both PI3K/Akt- and RAS-signaling pathways.