SOX9-PDK1 axis is essential for glioma stem cell self-renewal and temozolomide resistance

Abstract (Pro)renin receptor((P)RR) is a part of the Wnt receptor complex. Wnt/β-catenin signaling pathway (Wnt signaling) plays important role in pathogenesis and self-renewal of glioblastoma (GBM), or differentiation of glioma stem cell. We previously reported that (P)RR activated Wnt signaling, (P)RR expression correlated with malignancy of glioma, and treatment with (P)RR siRNA reduced the proliferative capacity. This time, we have searched for over 2632 microRNAs by microRNA microarray that its expression is affected by (P)RR whether overexpressed or suppressed and examined their effects in GBM cell lines or its glioma stem cells.

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circPTN sponges miR-145-5p/miR-330-5p to promote proliferation and stemness in glioma

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-019-1376-8 ◽

2019 ◽

Vol 38 (1) ◽

Cited By ~ 33

Author(s):

Jiansheng Chen ◽

Taoliang Chen ◽

Yubo Zhu ◽

Yan Li ◽

Yuxuan Zhang ◽

...

Keyword(s):

Stem Cell ◽

Cell Counting ◽

Biological Behavior ◽

Luciferase Reporter ◽

Glioma Stem Cell ◽

Self Renewal ◽

Inhibition Of Proliferation ◽

Tumor Sphere ◽

Sphere Formation

Abstract Background Growing evidences indicate that circular RNAs (circRNAs) play an important role in the regulation of biological behavior of tumor. We aim to explore the role of circRNA in glioma and elucidate how circRNA acts. Methods Real-time PCR was used to examine the expression of circPTN in glioma tissues and normal brain tissues (NBT). Assays of dual- luciferase reporter system, biotin label RNA pull-down and FISH were used to determine that circPTN could sponge miR-145-5p and miR-330-5p. Tumor sphere formation assay was performed to determine self- renewal of glioma stem cell (GSCs). Cell counting Kit-8 (CCK8), EdU assay and flow cytometry were used to investigate proliferation and cell cycle. Intracranial xenograft was established to determine how circPTN impacts in vivo. Tumor sphere formation assay was performed to determine self- renewal of glioma stem cell (GSCs). Results We demonstrated circPTN was significantly higher expression in glioma tissues and glioma cell lines, compared with NBT and HEB (human astrocyte). In gain- and loss-of-function experiments, circPTN significantly promoted glioma growth in vitro and in vivo. Furthermore, we performed dual-luciferase reporter assays and RNA pull-down assays to verify that circPTN acts through sponging miR-145-5p and miR-330-5p. Increasing expression of circPTN rescued the inhibition of proliferation and downregulation of SOX9/ITGA5 in glioma cells by miR-145-5p/miR-330-5p. In addition, we found that circPTN promoted self-renewal and increased the expression of stemness markers (Nestin, CD133, SOX9, and SOX2) via sponging miR-145-5p. Moreover, this regulation was disappeared when circPTN binding sites in miR-145-5p were mutated. Conclusions Our results suggest that circPTN is an oncogenic factor that acts by sponging miR-145-5p/miR-330-5p in glioma.

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CSIG-22. REGULATION OF GLIOMA STEM CELL SELF-RENEWAL AND TUMORIGENESIS BY CARBOHYDRATE BINDING PROTEINS

Neuro-Oncology ◽

10.1093/neuonc/noz175.192 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi48-vi49

Author(s):

Ahmad Sharanek ◽

Idris Fatakdawala ◽

Arezu Jahani-Asl

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Tumor Growth ◽

Binding Proteins ◽

Adult Brain ◽

Carbohydrate Binding ◽

Glioma Stem Cell ◽

Self Renewal ◽

Stat3 Signaling ◽

Carbohydrate Binding Proteins

Abstract Glioma Stem Cells (GSC) are a population of malignant self-renewing stem cells in glioblastoma (GBM) tumors, the most common and aggressive primary brain tumor in the adult brain. GSC promote tumor growth and recurrence and acquire resistance to therapy. Strategies to target GSC in the tumor bulk are urgently needed in order to develop more effective therapeutic strategies for GBM. EGFRvIII/STAT3 signaling is a major oncogenic pathway in GBM. Here, we report our discovery that Galectin1, a family member of carbohydrate-binding proteins with affinity for b-galactosides, promotes GSC self-renewal and tumor growth in EGFRvIII-expressing subset of tumors. Analysis of RNA-Seq data shows that LGALS1, the gene encoding Galectin1, is highly expressed in human EGFRvIII-expressing GSC and its expression correlates with the expression of transcription factor STAT3. Importantly, STAT3 directly binds the promoter of LGALS1 to upregulate its expression and knockdown of STAT3 significantly attenuates LGALS1 mRNA levels. Genetic knockdown of LGALS1 impairs the ability of GSC to form spheres, as assayed in limiting dilution assay, suggesting that LGALS1-STAT3 signaling regulates glioma stem cell fate in EGFRvIII tumor subset. Strikingly, we employed genetic and pharmacological approaches in patient derived xenografts and found that LGALS1/Galectin1 impairs gliomas stem cell growth and tumorigenesis. Subcutaneous and stereotactic intracranial implantation of CRISPR knockout LGALS1 EGFRvIII-expressing GSC into SCID mice showed significantly reduced in vivo tumor xenografts growth and increased survival rate compared with controls. Treatment of GSC with OTX008, a specific inhibitor of galectin-1, significantly attenuates the self-renewal ability of these cells and impairs tumorigenesis. Together, our findings suggest that targeting LGALS1/Galectin1 in combination with current standards of care may provide an effective strategy for the future treatment of these deadly brain tumors.

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