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bioRxiv · 10.1101/2025.09.19.677289

NKCC1 a Regulator of Glioblastoma Progression

Thomsen, A.·Freitag, D.·Haase, M.·Senft, C.·Schwarz, F.·Keiner, S.
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Abstract

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, with poor prognosis despite multimodal therapy. Chloride cotransporters NKCC1 and KCC2 are key regulators of intracellular chloride levels and thereby determine whether GABA acts inhibitory or excitatory. In GBM, disrupted chloride homeostasis promotes proliferation, migration, and stem-like properties, but its clinical relevance is not fully understood. We analysed NKCC1 and KCC2 expression in glioblastoma samples, considering clinical parameters such as age, gender, and MGMT promoter methylation. Statistical analyses included ROC-based cutoff determination, Kaplan-Meier survival analysis and subgroup. Immunohistochemistry was performed to identify cell types expressing NKCC1. NKCC1 expression was significantly higher in older patients and emerged as a prognostic marker for recurrence-free survival, with lower levels correlating with delayed recurrence, although overall survival was unaffected. NKCC1 was expressed in stem-like, astrocytic, and progenitor cells, but not in mature neurons. These findings identify NKCC1 as a regulator of GBM progression and recurrence, linking chloride transporter imbalance to GABAergic signalling. Targeting NKCC1 and restoring chloride homeostasis may provide promising new treatment strategies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=89 SRC="FIGDIR/small/677289v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@a964f1org.highwire.dtl.DTLVardef@1224400org.highwire.dtl.DTLVardef@9e5c94org.highwire.dtl.DTLVardef@d0324f_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Thomsen, A., Freitag, D., Haase, M., Senft, C., Schwarz, F., Keiner, S.. 2025-09-19. NKCC1 a Regulator of Glioblastoma Progression. https://doi.org/10.1101/2025.09.19.677289

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