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HIF1α/HIF2α–Sox2/Klf4 promotes the malignant progression of glioblastoma via the EGFR–PI3K/AKT signalling pathway with positive feedback under hypoxia

Previous studies have suggested that hypoxic responses are regulated by hypoxia-inducible factors (HIFs), which in turn promote the malignant progression of glioblastoma (GBM) by inhibiting apoptosis and increasing proliferation; these events lead to a poor prognosis of GBM patients. However, there...

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Autores principales: Wang, Pan, Zhao, Lu, Gong, Sheng, Xiong, Shuanglong, Wang, Junwei, Zou, Dewei, Pan, Jinyu, Deng, Yangmin, Yan, Qian, Wu, Nan, Liao, Bin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990922/
https://www.ncbi.nlm.nih.gov/pubmed/33762574
http://dx.doi.org/10.1038/s41419-021-03598-8
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author Wang, Pan
Zhao, Lu
Gong, Sheng
Xiong, Shuanglong
Wang, Junwei
Zou, Dewei
Pan, Jinyu
Deng, Yangmin
Yan, Qian
Wu, Nan
Liao, Bin
author_facet Wang, Pan
Zhao, Lu
Gong, Sheng
Xiong, Shuanglong
Wang, Junwei
Zou, Dewei
Pan, Jinyu
Deng, Yangmin
Yan, Qian
Wu, Nan
Liao, Bin
author_sort Wang, Pan
collection PubMed
description Previous studies have suggested that hypoxic responses are regulated by hypoxia-inducible factors (HIFs), which in turn promote the malignant progression of glioblastoma (GBM) by inhibiting apoptosis and increasing proliferation; these events lead to a poor prognosis of GBM patients. However, there are still no HIF-targeted therapies for the treatment of GBM. We have conducted series of experiments and discovered that GBM cells exhibit features indicative of malignant progression and are present in a hypoxic environment. Knocking out HIF1α or HIF2α alone resulted in no significant change in cell proliferation and cell cycle progression in response to acute hypoxia, but cells showed inhibition of stemness expression and chemosensitization to temozolomide (TMZ) treatment. However, simultaneously knocking out HIF1α and HIF2α inhibited cell cycle arrest and promoted proliferation with decreased stemness, making GBM cells more sensitive to chemotherapy, which could improve patient prognosis. Thus, HIF1α and HIF2α regulate each other with negative feedback. In addition, HIF1α and HIF2α are upstream regulators of epidermal growth factor (EGF), which controls the malignant development of GBM through the EGFR–PI3K/AKT–mTOR–HIF1α signalling pathway. In brief, the HIF1α/HIF2α–EGF/EGFR–PI3K/AKT–mTOR–HIF1α signalling axis contributes to the growth of GBM through a positive feedback mechanism. Finally, HIF1α and HIF2α regulate Sox2 and Klf4, contributing to stemness expression and inducing cell cycle arrest, thus increasing malignancy in GBM. In summary, HIF1α and HIF2α regulate glioblastoma malignant progression through the EGFR–PI3K/AKT pathway via a positive feedback mechanism under the effects of Sox2 and Klf4, which provides a new tumour development model and strategy for glioblastoma treatment.
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spelling pubmed-79909222021-04-16 HIF1α/HIF2α–Sox2/Klf4 promotes the malignant progression of glioblastoma via the EGFR–PI3K/AKT signalling pathway with positive feedback under hypoxia Wang, Pan Zhao, Lu Gong, Sheng Xiong, Shuanglong Wang, Junwei Zou, Dewei Pan, Jinyu Deng, Yangmin Yan, Qian Wu, Nan Liao, Bin Cell Death Dis Article Previous studies have suggested that hypoxic responses are regulated by hypoxia-inducible factors (HIFs), which in turn promote the malignant progression of glioblastoma (GBM) by inhibiting apoptosis and increasing proliferation; these events lead to a poor prognosis of GBM patients. However, there are still no HIF-targeted therapies for the treatment of GBM. We have conducted series of experiments and discovered that GBM cells exhibit features indicative of malignant progression and are present in a hypoxic environment. Knocking out HIF1α or HIF2α alone resulted in no significant change in cell proliferation and cell cycle progression in response to acute hypoxia, but cells showed inhibition of stemness expression and chemosensitization to temozolomide (TMZ) treatment. However, simultaneously knocking out HIF1α and HIF2α inhibited cell cycle arrest and promoted proliferation with decreased stemness, making GBM cells more sensitive to chemotherapy, which could improve patient prognosis. Thus, HIF1α and HIF2α regulate each other with negative feedback. In addition, HIF1α and HIF2α are upstream regulators of epidermal growth factor (EGF), which controls the malignant development of GBM through the EGFR–PI3K/AKT–mTOR–HIF1α signalling pathway. In brief, the HIF1α/HIF2α–EGF/EGFR–PI3K/AKT–mTOR–HIF1α signalling axis contributes to the growth of GBM through a positive feedback mechanism. Finally, HIF1α and HIF2α regulate Sox2 and Klf4, contributing to stemness expression and inducing cell cycle arrest, thus increasing malignancy in GBM. In summary, HIF1α and HIF2α regulate glioblastoma malignant progression through the EGFR–PI3K/AKT pathway via a positive feedback mechanism under the effects of Sox2 and Klf4, which provides a new tumour development model and strategy for glioblastoma treatment. Nature Publishing Group UK 2021-03-24 /pmc/articles/PMC7990922/ /pubmed/33762574 http://dx.doi.org/10.1038/s41419-021-03598-8 Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Wang, Pan
Zhao, Lu
Gong, Sheng
Xiong, Shuanglong
Wang, Junwei
Zou, Dewei
Pan, Jinyu
Deng, Yangmin
Yan, Qian
Wu, Nan
Liao, Bin
HIF1α/HIF2α–Sox2/Klf4 promotes the malignant progression of glioblastoma via the EGFR–PI3K/AKT signalling pathway with positive feedback under hypoxia
title HIF1α/HIF2α–Sox2/Klf4 promotes the malignant progression of glioblastoma via the EGFR–PI3K/AKT signalling pathway with positive feedback under hypoxia
title_full HIF1α/HIF2α–Sox2/Klf4 promotes the malignant progression of glioblastoma via the EGFR–PI3K/AKT signalling pathway with positive feedback under hypoxia
title_fullStr HIF1α/HIF2α–Sox2/Klf4 promotes the malignant progression of glioblastoma via the EGFR–PI3K/AKT signalling pathway with positive feedback under hypoxia
title_full_unstemmed HIF1α/HIF2α–Sox2/Klf4 promotes the malignant progression of glioblastoma via the EGFR–PI3K/AKT signalling pathway with positive feedback under hypoxia
title_short HIF1α/HIF2α–Sox2/Klf4 promotes the malignant progression of glioblastoma via the EGFR–PI3K/AKT signalling pathway with positive feedback under hypoxia
title_sort hif1α/hif2α–sox2/klf4 promotes the malignant progression of glioblastoma via the egfr–pi3k/akt signalling pathway with positive feedback under hypoxia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990922/
https://www.ncbi.nlm.nih.gov/pubmed/33762574
http://dx.doi.org/10.1038/s41419-021-03598-8
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