Suppression of CLC-3 chloride channel reduces the aggressiveness of glioma through inhibiting nuclear factor-κB pathway

Abstract

CLC-3 chloride channel plays important roles on cell volume regulation, proliferation and migration in normal and cancer cells. Recent growing evidence supports a critical role of CLC-3 in glioma metastasis, however, the mechanism underlying is unclear. This study finds that CLC-3 is upregulated in glioma tissues and positively correlated with WHO histological grade. Patients with high CLC-3 expression had an overall shorter survival time, whereas patients with low expression of CLC-3 had a better survival time. Silencing endogenous CLC-3 with ShCLC-3 adenovirus significantly decreases volume-regulated chloride currents, inhibits the nuclear translocation of p65 subunit of Nuclear Factor-κB (NF-κB), decreases transcriptional activity of NF-κB, reduces MMP-3 and MMP-9 expression and decreases glioma cell migration and invasion. Taken together, these results suggest CLC-3 promotes the aggressiveness of glioma at least in part through nuclear factor-κB pathway, and might be a novel prognostic biomarker and therapeutic target for glioma.

ClC-3 chloride channel protein induces G1�arrest in hepatocellular carcinoma Hep3B cells

“…Blocking chloride channels can lead to the inhibition of cell proliferation and the arrest of cell cycle progression in human laryngeal cancer cells (28). It was reported that ClC-3, the inhibition of which was shown to decrease the aggressiveness of neuroglioma cells by inhibiting the NF-κB pathway, may be a novel therapeutic target and prognostic biomarker in neuroglioma (29). ClC-3 is a potential target for cancer therapy, and we found that it was highly expressed in Hep3B cells.…”

Molecular Determinants of Malignant Brain Cancers: From Intracellular Alterations to Invasion Mediated by Extracellular Vesicles

“…These modifications are part of the so called “epithelial-mesenchymal transition” (EMT) (see Section 2.2 ), which, although its role in glioma is still controversial, seems to be determinant for the degree of malignancy [ 27 ]. In addition, movement of cells throughout the brain tissue requires cell shape changes and protrusion of invadopodia, probably based on both modifications of the cytoskeleton [ 28 , 29 ] and movements of ions [ 30 , 31 ] and water [ 32 , 33 , 34 ] between the two sides of the plasma membrane. In this Section, we discuss these molecular modifications, while in Section 3 we will discuss possible involvement of EVs in them.…”

“…Taken together, these observations suggest that modifications of volume are critical for invasion and that they depend, at least in part, on ion fluxes and in turn on the expression of ion channels. It has been, for example, reported that CLC-3, one member of CLC voltage-gated chloride channel family, is upregulated in gliomas and correlates with a shorter survival of patients [ 31 ]. Similarly, the chloride intracellular channel 1 (CLIC1) is overexpressed in glioblastoma, with the highest expression in patients with worse prognosis [ 156 ].…”

Injectable Thermo-Sensitive Chitosan Hydrogel Containing CPT-11-Loaded EGFR-Targeted Graphene Oxide and SLP2 shRNA for Localized Drug/Gene Delivery in Glioblastoma Therapy

“…Specifically, SLP2 was fond to be markedly upregulated in glioma cells and glioma specimens. The up-regulation of SLP2 was shown to be significantly correlated with the World Health Organization (WHO) histological grade of gliomas, while patients with higher SLP2 expression levels had an overall shorter survival time compared to patients with a lower expression of SLP2 [ 24 ]. It was also demonstrated that the silencing of SLP 2 gene expression could drastically reduce the migration and invasive ability of glioma cells by inhibiting the transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and repressing the expression levels of NF-κB target genes, including matrix metallopeptidase 9 [ 25 ].…”