Differential regulation of the pro-inflammatory biomarker, YKL-40/CHI3L1, by PTEN/Phosphoinositide 3-kinase and JAK2/STAT3 pathways in glioblastoma

Constitutive activation of the phosphoinositide 3-kinase/AKT signaling pathway is frequently observed in high-grade gliomas with high frequency of losing PTEN tumor suppressor. To identify transcriptomic profiles associated with a hyperactivated PI3K pathway, RNA-sequencing analysis was performed in a glioblastoma cell line stably expressing PTEN. RNA-sequencing revealed enriched transcripts of pro-inflammatory mediators, and among the genes that displayed high differential expression was the secreted glycoprotein YKL-40. Treatment with chemical inhibitors that target the PI3K/AKT pathway elicited differential effects on YKL-40 expression in selected GBM cell lines, indicating that its expression displayed tumor cell-specific variations. This variability appeared to be correlated with the ability to transactivate the immune signaling molecules JAK2 and STAT3. In summary, the differential expression of the immunomodulatory molecule YKL-40 may affect the treatment efficacy of PI3K/AKT-based pathway inhibitors in glioblastoma.