Hypoxia‐induced CXC chemokine ligand 14 expression drives protumorigenic effects through activation of insulin‐like growth factor‐1 receptor signaling in glioblastoma

Abstract

Hypoxic tumor microenvironment (HTM) promotes a more aggressive and malignant state in glioblastoma. However, little is known about the role and mechanism of CXC chemokine ligand 14 (CXCL14) in HTM‐mediated glioblastoma progression. In this study, we report that CXCL14 expression correlated with poor outcomes, tumor grade, and hypoxia‐inducible factor (HIF) expression in patients with glioblastoma. CXCL14 was upregulated in tumor cells within the hypoxic areas of glioblastoma. Hypoxia induced HIF‐dependent expression of CXCL14, which promoted glioblastoma tumorigenicity and invasiveness in vitro and in vivo. Moreover, CXCL14 gain‐of‐function in glioblastoma cells activated insulin‐like growth factor‐1 receptor (IGF‐1R) signal transduction to regulate the growth, invasiveness, and neurosphere formation of glioblastoma. Finally, systemic delivery of CXCL14 siRNA nanoparticles (NPs) with polysorbate 80 coating significantly suppressed tumor growth in vivo and extended the survival time in patient‐derived glioblastoma xenografts. Together, these findings suggest that HIF‐dependent CXCL14 expression contributes to HTM‐promoted glioblastoma tumorigenicity and invasiveness through activation of the IGF‐1R signaling pathway. CXCL14 siRNA NPs as an oligonucleotide drug can inhibit glioblastoma progression and constitute a translational path for the clinical treatment of glioblastoma patients.

Cellular and exosomal GPx1 are essential for controlling hydrogen peroxide balance and alleviating oxidative stress in hypoxic glioblastoma

“…The GBM8401 cells were maintained in RPMI 1640 (Invitrogen) supplemented with 10% FBS, 10 mM HEPES, and 1% P/S. Primary glioblastoma cells, GBM04T and GBM09T, derived from our previous study [ 22 ], were propagated as tumor spheres in serum-free DMEM-F12 supplemented with 2% B27, 20 ng/mL bFGF, and 20 ng/mL EGF. The human umbilical vein endothelial cells (HUVECs) were procured from Sciencell Company and cultured with endothelial cell medium (ECM) (Sigma-Aldrich) containing 5% FBS, 1% endothelial cell growth supplement (ECGS), and 1% P/S.…”

The Chemokine CXCL14 as a Potential Immunotherapeutic Agent for Cancer Therapy

“…High levels of CXCL14 expression are correlated with overall patient survival in colorectal, breast, endometrial, intraepithelial, and head and neck cancers [30] and suppress tumor progression [31][32][33][34][35]. In contrast, other studies have shown protumor effects of CXCL14 in nasopharyngeal carcinoma, prostate cancer, glioblastoma, non-small-cell lung cancer, and microsatellite-stable colorectal tumors [25,[36][37][38][39].…”

The Role of CXCR1, CXCR2, CXCR3, CXCR5, and CXCR6 Ligands in Molecular Cancer Processes and Clinical Aspects of Acute Myeloid Leukemia (AML)

“…Its previous name is breast- and kidney-expressed chemokine (BRAK). The receptor for CXCL14 is not well defined, but it seems that CXCL14 can activate CXCR4, ACKR2 [ 101 ], IGF-1R [ 102 ], and GPR85 [ 103 ]. CXCL14 can also bind to CXCR4 [ 104 ].…”