G protein-coupled receptors (GPCRs) play a pivotal role in maintaining the stemness of both normal and cancer stem cells. However, the function of the regulator of G protein signaling (RGS) family, particularly in tumor stem cells, remains poorly under-stood. Through bioinformatics analysis of clinical data, we identified RGS20 as a potential regulator of glioma stemness and temozolomide (TMZ) resistance, which may significantly influence patient prognosis. Subsequent in vitro and in vivo experiments demonstrated that RGS20 inhibition markedly enhanced tumor sphere formation and upregulated stem cell markers by intrinsically activating the WNT/beta-catenin signaling pathway, thereby promoting tumorigenesis and ultimately leading to TMZ resistance. Furthermore, in human glioblastoma specimens, beta-catenin signaling associated with low RGS20 expression was significantly enriched in hypoxic regions, suggesting that this mechanism may support the maintenance of glioma stem cells (GSCs) and drive TMZ resistance within the hypoxic niche. Our findings reveal that low RGS20 expression sustains WNT/beta-catenin signaling in a ligand-reduced manner within hypoxic niches, unveiling a novel intracellular mechanism that drives glioma progression. Targeting this mechanism could provide new therapeutic strategies for glioma treatment.
[1]Tianjin Med Univ, Key Lab Canc Prevent & Therapy, Natl Clin Res Ctr Canc,Tianjins Clin Res Ctr Canc, Dept Biochem & Mol Biol,Canc Inst & Hosp, Tianjin 300060, Peoples R China.
[2]Tianjin Med Univ, Tianjin 300060, Peoples R China.
[3]Tianjin Med Univ, Affiliated Hosp 2, Dept Urol, Tianjin 300060, Peoples R China.
[4]Tsinghua Univ, Beijing Tsinghua Changgung Hosp, Dept Neurosurg, Beijing 100000, Peoples R China.
[5]Tianjin Med Univ, Gen Hosp, Dept Neurosurg, Tianjin 300052, Peoples R China.
[6]Tianjin Med Univ, Key Lab Canc Prevent & Therapy, Dept Neurooncol & Neurosurg, Natl Clin Res Ctr Canc,Canc Inst & Hosp, Tianjin 300060, Peoples R China.
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