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PER2 inhibits proliferation and stemness of glioma stem cells via the Wnt/??catenin signaling pathway.

ABSTRACT: Glioblastoma is a highly malignant tumor that contains stem?like cells known as glioma stem cells (GSCs), which lare associated with an increased risk of glioma occurrence, recurrence and poor prognosis. Circadian clock gene, period circadian clock 2 (PER2) expression has been revealed to be inhibited in various types of cancer. However, the precise role and potential mechanisms of PER2 in GSCs remains unclear. The present study demonstrated that PER2 mRNA and protein expression was downregulated in GSCs compared with non?stem glioma cells, which indicated that PER2 could be involved in the malignant process of glioma. Furthermore, functional studies revealed that PER2 overexpression could induce GSC arrest at the G0/G1 phase and suppress their proliferation, stemness and invasion ability in vitro and in vivo. Subsequently, the Wnt/??catenin signaling pathway was identified as the target of PER2 in GSCs. These results indicated that PER2 plays a critical role in regulating the stemness of GSCs and provides a novel therapeutic target to overcome the effects of GSCs.

SUBMITTER: Ma D

PROVIDER: S-EPMC7336516 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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PER2 inhibits proliferation and stemness of glioma stem cells via the Wnt/β‑catenin signaling pathway.

Ma Dede D Hou Li L Xia Hechun H Li Hailiang H Fan Heng H Jia Xiaoxiong X Niu Zhanfeng Z

Oncology reports 20200527 2

Glioblastoma is a highly malignant tumor that contains stem‑like cells known as glioma stem cells (GSCs), which lare associated with an increased risk of glioma occurrence, recurrence and poor prognosis. Circadian clock gene, period circadian clock 2 (PER2) expression has been revealed to be inhibited in various types of cancer. However, the precise role and potential mechanisms of PER2 in GSCs remains unclear. The present study demonstrated that PER2 mRNA and protein expression was downregulate ...[more]

PMID: 32468039

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Project description:Posaconazole (POS) has been reported to present potential antitumor activity for glioblastoma (GBM). However, its molecular mechanisms remain unclear. In this study, we found that POS has potent cytotoxicity and inhibits cell viability and proliferation in GBM. In addition, we adopted a sphere formation assay to detect the self-renewal capacity, performed western blotting to measure cancer stem-like cells (CSCs) marker proteins (CD133, SOX2, Nanog and Oct4) and applied flow cytometry to monitor the subpopulation of CD144+/CD33+ cells, and the results all demonstrated that POS can remarkably weaken CSCs stemness. Furthermore, western blotting, immunoflurescence, transmission electron microscopy and acridine orange staining were performed to detect autophagy-related proteins (LC3, SQSTM1, Beclin 1 and Atg5), count the numbers of endogenous LC3 puncta, visually observe the ultrastructural morphology of autophagosomes and judge the formation of acidic vesicular organelles, respectively, and the results validated that POS promotes autophagy induction. Importantly, the suppressive effect of POS on CSCs stemness was partially relieved when autophagy was blocked by the autophagy inhibitor chloroquine (CQ) or Atg5 shRNA. Bioinformatic techniques, including weighted gene coexpression network analysis (WGCNA), gene set difference analysis (GSVA) and KEGG pathway analysis, combined with experimental validations showed that survivin, which is implicated in both autophagy and the stem cell index, is one of the target proteins of POS and that POS weakens CSCs stemness via suppressing the Wnt/β-catenin signaling pathway in GBM. Besides, POS-induced autophagy and the Wnt/β-catenin signaling pathway are negative regulators for each other. Finally, the antitumor activity of POS was confirmed in GBM xenograft models in vivo. Consistent with the in vitro conclusions, POS upregulated the expression of LC3 and decreased the expression of CD133, survivin and β-catenin, as shown by the immunohistochemistry analysis. In summary, this work provides an experimental foundation for exploiting POS as a CSCs-targeting antitumor drug for GBM treatment.

Dataset Information

PER2 inhibits proliferation and stemness of glioma stem cells via the Wnt/??catenin signaling pathway.

Publications

PER2 inhibits proliferation and stemness of glioma stem cells via the Wnt/β‑catenin signaling pathway.

Similar Datasets

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