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.
Highlights
Glioma is the most common and a highly aggressive primary malignant tumor in the central nervous system [1]
The results showed that CLC-3 expression was up regulated in glioma and its overexpression was positively correlated with WHO histological grade (Figure 1A, 1B, Supplementary Table 2)
This study provides the first evidence to our knowledge that CLC-3 is overexpressed in glioma tissues and positively correlated with WHO histological www.impactjournals.com/oncotarget grade
Summary
Glioma is the most common and a highly aggressive primary malignant tumor in the central nervous system [1]. Even with aggressive treatment with surgery, radiation and chemotherapy, the prognosis for patients with malignant gliomas remains poor. The cumulative 1-year survival rate of glioma patients is less than 30%, and median reported survival of glioblastoma is 12-15 month [2]. The dismal prognosis of glioma patients is largely attributed to the highly invasive nature of glioma cells, which makes complete surgical resection of gliomas extremely difficult. The molecular determinants of disease aggressiveness are not well understood. A better understanding of the molecular pathogenesis of glioma may identify new targets for treatment of this typically incurable brain cancer
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