SLC12A5 as a novel potential biomarker of glioblastoma multiforme

Chen, Jiakai; Handong, Wang; Deng, Cong; Fei, Maoxing

doi:10.1007/s11033-023-08371-y

Cited by 6 publications

(6 citation statements)

References 53 publications

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“…All in all, the role of KCC2 in the physiological setting is surprisingly extensive and not even restricted to the function of the brain. For example, the downregulation of KCC2 and the resulting dysfunctionality of the inhibitory system in the spinal cord may influence the genesis of neuropathic pain (Kitayama, 2018 ), and, interestingly, KCC2 is a viable potential biomarker for certain cancers (Wei et al, 2011 ; Chen et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

A novel pathogenic SLC12A5 missense variant in epilepsy of infancy with migrating focal seizures causes impaired KCC2 chloride extrusion

Järvelä,

Hamze,

Komulainen-Ebrahim

et al. 2024

Front. Mol. Neurosci.

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The potassium-chloride co-transporter 2, KCC2, is a neuron-specific ion transporter that plays a multifunctional role in neuronal development. In mature neurons, KCC2 maintains a low enough intracellular chloride concentration essential for inhibitory neurotransmission. During recent years, pathogenic variants in the KCC2 encoding gene SLC12A5 affecting the functionality or expression of the transporter protein have been described in several patients with epilepsy of infancy with migrating focal seizures (EIMFS), a devastating early-onset developmental and epileptic encephalopathy. In this study, we identified a novel recessively inherited SLC12A5 c.692G>A, p. (R231H) variant in a patient diagnosed with severe and drug-resistant EIMFS and profound intellectual disability. The functionality of the variant was assessed in vitro by means of gramicidin-perforated patch-clamp experiments and ammonium flux assay, both of which indicated a significant reduction in chloride extrusion. Based on surface immunolabeling, the variant showed a reduction in membrane expression. These findings implicate pathogenicity of the SLC12A5 variant that leads to impaired inhibitory neurotransmission, increasing probability for hyperexcitability and epileptogenesis.

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Section: Discussionmentioning

confidence: 99%

A novel pathogenic SLC12A5 missense variant in epilepsy of infancy with migrating focal seizures causes impaired KCC2 chloride extrusion

Järvelä,

Hamze,

Komulainen-Ebrahim

et al. 2024

Front. Mol. Neurosci.

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“…The different effects of VPA on KCC2 gene expression in GBM cells that we have identified may be significant in several respects. Cell volume reduction is an early sign of apoptosis associated with the loss of intracellular K + and Cl − anions [29,57], which is associated with caspase activation and caspase cascade-related apoptotic mechanisms [58]. KCC2 positively correlated with the levels of tumor-infiltrating macrophages and CD4 + T cells [22].…”

Section: Discussionmentioning

confidence: 99%

“…K-Cl co-transporter (SLC12A5; KCC2), whose expression is reduced in GBM cells, is associated with intracellular ions' balance. Increased expression of SLC12A5 inhibits GBM cell proliferation [29]. VPA significantly increases the expression of the SLC12A5 gene (SLC12A5) in GBM cells; i.e., it promotes the efflux of K + and Clions from the cell, but this effect depends on different GBM cells [21] and does not have an association with DNA methylation [29].…”

Section: Introductionmentioning

confidence: 99%

“…Increased expression of SLC12A5 inhibits GBM cell proliferation [29]. VPA significantly increases the expression of the SLC12A5 gene (SLC12A5) in GBM cells; i.e., it promotes the efflux of K + and Clions from the cell, but this effect depends on different GBM cells [21] and does not have an association with DNA methylation [29]. Thus, SLC12A5 may become an important new GBM biomarker of prognostic significance.…”

Section: Introductionmentioning

confidence: 99%

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Differential Impact of Valproic Acid on SLC5A8, SLC12A2, SLC12A5, CDH1, and CDH2 Expression in Adult Glioblastoma Cells

Juknevičienė,

Balnytė,

Valančiūtė

et al. 2024

Biomedicines

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Valproic acid (VPA) has anticancer, anti-inflammatory, and epigenetic effects. The study aimed to determine the expression of carcinogenesis-related SLC5A8, SLC12A2, SLC12A5, CDH1, and CDH2 in adult glioblastoma U87 MG and T98G cells and the effects of 0.5 mM, 0.75 mM, and 1.5 mM doses of VPA. RNA gene expression was determined by RT-PCR. GAPDH was used as a control. U87 and T98G control cells do not express SLC5A8 or CDH1. SLC12A5 was expressed in U87 control but not in T98G control cells. The SLC12A2 expression in the U87 control was significantly lower than in the T98G control. T98G control cells showed significantly higher CDH2 expression than U87 control cells. VPA treatment did not affect SLC12A2 expression in U87 cells, whereas treatment dose-dependently increased SLC12A2 expression in T98G cells. Treatment with 1.5 mM VPA induced SLC5A8 expression in U87 cells, while treatment of T98G cells with VPA did not affect SLC5A8 expression. Treatment of U87 cells with VPA significantly increased SLC12A5 expression. VPA increases CDH1 expression depending on the VPA dose. CDH2 expression was significantly increased only in the U87 1.5 mM VPA group. Tested VPA doses significantly increased CDH2 expression in T98G cells. When approaching treatment tactics, assessing the cell’s sensitivity to the agent is essential.

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“…In recent years, studies have revealed that mutations or abnormal SLC12A5 expression contribute to the development of certain solid tumors (Kursan et al 2017 ). SLC12A5 expression promotes prostate and liver cancer progression (Yuan et al 2023 ; Tong et al 2023 ) while inhibiting glioma cell proliferation (Chen et al 2023 ). Although few studies have reported its potential role in glioma progression, further research is warranted (Tang et al 2020 ; Yang et al 2020a ).…”

Section: Introductionmentioning

confidence: 99%

Unveiling the therapeutic potential of IHMT-337 in glioma treatment: targeting the EZH2-SLC12A5 axis

Zhang,

Wang,

Qiao

et al. 2024

Mol Med

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Glioma is the most common malignant tumor of the central nervous system, with EZH2 playing a crucial regulatory role. This study further explores the abnormal expression of EZH2 and its mechanisms in regulating glioma progression. Additionally, it was found that IHMT-337 can potentially be a therapeutic agent for glioma. The prognosis, expression, and localization of EZH2 were determined using bioinformatics, IHC staining, Western blot (WB) analysis, and immunofluorescence (IF) localization. The effects of EZH2 on cell function were assessed using CCK-8 assays, Transwell assays, and wound healing assays. Public databases and RT-qPCR were utilized to identify downstream targets. The mechanisms regulating these downstream targets were elucidated using MS-PCR and WB analysis. The efficacy of IHMT-337 was demonstrated through IC50 measurements, WB analysis, and RT-qPCR. The effects of IHMT-337 on glioma cells in vitro were evaluated using Transwell assays, EdU incorporation assays, and flow cytometry. The potential of IHMT-337 as a treatment for glioma was assessed using a blood–brain barrier (BBB) model and an orthotopic glioma model. Our research confirms significantly elevated EZH2 expression in gliomas, correlating with patient prognosis. EZH2 facilitates glioma proliferation, migration, and invasion alongside promoting SLC12A5 DNA methylation. By regulating SLC12A5 expression, EZH2 activates the WNK1-OSR1-NKCC1 pathway, enhancing its interaction with ERM to promote glioma migration. IHMT-337 targets EZH2 in vitro to inhibit WNK1 activation, thereby suppressing glioma cell migration. Additionally, it inhibits cell proliferation and arrests the cell cycle. IHMT-337 has the potential to cross the BBB and has successfully inhibited glioma progression in vivo. This study expands our understanding of the EZH2-SLC12A5 axis in gliomas, laying a new foundation for the clinical translation of IHMT-337 and offering new insights for precision glioma therapy.

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SLC12A5 as a novel potential biomarker of glioblastoma multiforme

Cited by 6 publications

References 53 publications

A novel pathogenic SLC12A5 missense variant in epilepsy of infancy with migrating focal seizures causes impaired KCC2 chloride extrusion

A novel pathogenic SLC12A5 missense variant in epilepsy of infancy with migrating focal seizures causes impaired KCC2 chloride extrusion

Differential Impact of Valproic Acid on SLC5A8, SLC12A2, SLC12A5, CDH1, and CDH2 Expression in Adult Glioblastoma Cells

Unveiling the therapeutic potential of IHMT-337 in glioma treatment: targeting the EZH2-SLC12A5 axis

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