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HIF-1? is critical for hypoxia-mediated maintenance of glioblastoma stem cells by activating Notch signaling pathway.

ABSTRACT: Hypoxia induces the expansion of glioblastoma stem cells (GSCs), but the mechanism underlying it is still unclear. Here, we supply evidence that hypoxia-inducible factor-1? (HIF-1?) induced activation of Notch pathway is essential for hypoxia-mediated maintenance of GSC. Either depletion of HIF-1? or inactivation of Notch signaling partly inhibits the hypoxia-mediated maintenance of GSC. Further data suggest a role for HIF-1? in the interaction and stabilization of intracellular domain of Notch (NICD), and activation of Notch signaling. The mRNA level of HIF-1? and Notch target gene FABP7 was elevated in GSC. And the STAT3 pathway responsible for the HIF-1? gene transcription, the phosphatidylinositol 3-kinase-Akt and ERK1/2, both of which are contributed to HIF-1? protein translation, are also preferentially activated in GSC. Inhibition of these pathways partly reduces the hypoxia-induced activation of the Notch pathway and subsequent GSC maintenance. Taken together, our findings suggest that HIF-1? requires Notch pathway to drive the maintenance of GSC. The activated regulation of HIF-1? makes GSC more sensitive to hypoxia-mediated maintenance. These findings enhance our understanding of mechanism of hypoxia-mediated GSC expansion and provide HIF-1? as an attractive target for glioblastoma therapy.

SUBMITTER: Qiang L

PROVIDER: S-EPMC3263503 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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HIF-1α is critical for hypoxia-mediated maintenance of glioblastoma stem cells by activating Notch signaling pathway.

Qiang L L Wu T T Zhang H-W HW Lu N N Hu R R Wang Y-J YJ Zhao L L Chen F-H FH Wang X-T XT You Q-D QD Guo Q-L QL

Cell death and differentiation 20110805 2

Hypoxia induces the expansion of glioblastoma stem cells (GSCs), but the mechanism underlying it is still unclear. Here, we supply evidence that hypoxia-inducible factor-1α (HIF-1α) induced activation of Notch pathway is essential for hypoxia-mediated maintenance of GSC. Either depletion of HIF-1α or inactivation of Notch signaling partly inhibits the hypoxia-mediated maintenance of GSC. Further data suggest a role for HIF-1α in the interaction and stabilization of intracellular domain of Notch ...[more]

PMID: 21818118

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Project description:BackgroundNon-small cell lung cancer (NSCLC) is the most common type of human lung cancers, which has diverse pathological features. Although many signaling pathways and therapeutic targets have been defined to play important roles in NSCLC, limiting efficacies have been achieved.MethodsBioinformatics methods were used to identify differential long non-coding RNA expression in NSCLC. Real-time RT-PCR experiments were used to examine the expression pattern of lncRNA PKMYT1AR, miR-485-5p. Both in vitro and in vivo functional assays were performed to investigate the functional role of PKMYT1AR/miR-485-5p/PKMYT1 axis on regulating cell proliferation, migration and tumor growth. Dual luciferase reporter assay, fluorescent in situ hybridization (FISH), immunoblot, co-immunoprecipitation experiments were used to verify the molecular mechanism.ResultHere, we identify a human-specific long non-coding RNA (lncRNA, ENST00000595422), termed PKMYT1AR (PKMYT1 associated lncRNA), that is induced in NSCLC by Yin Yang 1 (YY1) factor, especially in cancerous cell lines (H358, H1975, H1299, H1650, A549 and SPC-A1) compared to that in normal human bronchial epithelium cell line (BEAS-2B). We show that PKMYT1AR high expression correlates with worse clinical outcome, and knockdown of PKMYT1AR inhibits tumor cell proliferation, migration and xenograft tumor formation abilities. Bioinformatic analysis and a luciferase assay demonstrate that PKMYT1AR directly interacts with miR-485-5p to attenuate the inhibitory role on its downstream oncogenic factor PKMYT1 (the protein kinase, membrane-associated tyrosine/threonine 1) in NSCLC. Furthermore, we uncover that miR-485-5p is downregulated in both cancerous cell lines and peripheral blood serum isolated from NSCLC patients compared to reciprocal control groups. Consistently, forced expression of miR-485-5p inhibits the proliferation and migration abilities of tumor cells. Moreover, we provide evidence showing that PKMYT1AR targeting antisense oligonucleotide (ASO) dramatically inhibit tumor growth in vivo. Mechanistic study shows that PKMYT1AR/ miR-485-5p /PKMYT1 axis promotes cancer stem cells (CSCs) maintenance in NSCLC via inhibiting β-TrCP1 mediated ubiquitin degradation of β-catenin proteins, which in turn causes enhanced tumorigenesis.ConclusionsOur findings reveal the critical role of PKMYT1AR/miR-485-5p /PKMYT1 axis during NSCLC progression, which could be used as novel therapeutic targets in the future.

Dataset Information

HIF-1? is critical for hypoxia-mediated maintenance of glioblastoma stem cells by activating Notch signaling pathway.

Publications

HIF-1α is critical for hypoxia-mediated maintenance of glioblastoma stem cells by activating Notch signaling pathway.

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