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

Yubing Wang; Chi Wai Wong; Mingfei Yan; Lisha Li; Tian Liu; Penelope Mei-Yu Or; Stephen Kwok-Wing Tsui; Mary Miu-Yee Waye; Andrew Man-Lok Chan

doi:10.1016/j.canlet.2018.04.040

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

Cancer Lett. 2018 Aug 10:429:54-65. doi: 10.1016/j.canlet.2018.04.040. Epub 2018 May 3.

Authors

Yubing Wang¹, Chi Wai Wong¹, Mingfei Yan¹, Lisha Li¹, Tian Liu¹, Penelope Mei-Yu Or¹, Stephen Kwok-Wing Tsui¹, Mary Miu-Yee Waye², Andrew Man-Lok Chan³

Affiliations

¹ School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
² The Nethersole School of Nursing, The Chinese University of Hong Kong, Hong Kong SAR, China.
³ School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China. Electronic address: [email protected].

PMID: 29729901
DOI: 10.1016/j.canlet.2018.04.040

Abstract

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.

Keywords: JAK2/STAT3; PI3K; PTEN; Transcriptomes; YKL-40.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers, Tumor / genetics*
Biomarkers, Tumor / metabolism
Brain Neoplasms / genetics*
Brain Neoplasms / metabolism
Brain Neoplasms / pathology
Cell Line, Tumor
Chitinase-3-Like Protein 1 / genetics*
Chitinase-3-Like Protein 1 / metabolism
Gene Expression Profiling*
Gene Expression Regulation, Neoplastic / drug effects
Glioblastoma / genetics*
Glioblastoma / metabolism
Glioblastoma / pathology
Heterocyclic Compounds, 3-Ring / pharmacology
Humans
Janus Kinase 2 / genetics
Janus Kinase 2 / metabolism
PTEN Phosphohydrolase / genetics
PTEN Phosphohydrolase / metabolism
Phosphatidylinositol 3-Kinase / genetics
Phosphatidylinositol 3-Kinase / metabolism
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors / pharmacology
STAT3 Transcription Factor / genetics
STAT3 Transcription Factor / metabolism
Signal Transduction / drug effects
Signal Transduction / genetics*

Substances

Biomarkers, Tumor
CHI3L1 protein, human
Chitinase-3-Like Protein 1
Heterocyclic Compounds, 3-Ring
MK 2206
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
STAT3 Transcription Factor
Phosphatidylinositol 3-Kinase
JAK2 protein, human
Janus Kinase 2
PTEN Phosphohydrolase
PTEN protein, human