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The HIF1?/HIF2?-miR210-3p network regulates glioblastoma cell proliferation, dedifferentiation and chemoresistance through EGF under hypoxic conditions.

ABSTRACT: Hypoxia-inducible factor 1? (HIF1?) promotes the malignant progression of glioblastoma under hypoxic conditions, leading to a poor prognosis for patients with glioblastoma; however, none of the therapies targeting HIF1? in glioblastoma have successfully eradicated the tumour. Therefore, we focused on the reason and found that treatments targeting HIF1? and HIF2? simultaneously increased tumour volume, but the combination of HIF1?/HIF2?-targeted therapies with temozolomide (TMZ) reduced tumourigenesis and significantly improved chemosensitization. Moreover, miR-210-3p induced HIF1? expression but inhibited HIF2? expression, suggesting that miR-210-3p regulates HIF1?/HIF2? expression. Epidermal growth factor (EGF) has been shown to upregulate HIF1? expression under hypoxic conditions. However, in the present study, in addition to the signalling pathways mentioned above, the upstream proteins HIF1? and HIF2? have been shown to induce EGF expression by binding to the sequences AGGCGTGG and GGGCGTGG. Briefly, in a hypoxic microenvironment the HIF1?/HIF2?-miR210-3p network promotes the malignant progression of glioblastoma through a positive feedback loop with EGF. Additionally, differentiated glioblastoma cells underwent dedifferentiation to produce glioma stem cells under hypoxic conditions, and simultaneous knockout of HIF1? and HIF2? inhibited cell cycle arrest but promoted proliferation with decreased stemness, promoting glioblastoma cell chemosensitization. In summary, both HIF1? and HIF2? regulate glioblastoma cell proliferation, dedifferentiation and chemoresistance through a specific pathway, which is important for glioblastoma treatments.

SUBMITTER: Wang P

PROVIDER: S-EPMC7674439 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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The HIF1α/HIF2α-miR210-3p network regulates glioblastoma cell proliferation, dedifferentiation and chemoresistance through EGF under hypoxic conditions.

Wang Pan P Yan Qian Q Liao Bin B Zhao Lu L Xiong Shuanglong S Wang Junwei J Zou Dewei D Pan Jinyu J Wu Liangqi L Deng Yangmin Y Wu Nan N Gong Sheng S

Cell death & disease 20201118 11

Hypoxia-inducible factor 1α (HIF1α) promotes the malignant progression of glioblastoma under hypoxic conditions, leading to a poor prognosis for patients with glioblastoma; however, none of the therapies targeting HIF1α in glioblastoma have successfully eradicated the tumour. Therefore, we focused on the reason and found that treatments targeting HIF1α and HIF2α simultaneously increased tumour volume, but the combination of HIF1α/HIF2α-targeted therapies with temozolomide (TMZ) reduced tumourige ...[more]

PMID: 33208727

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Project description:Objective: Our previous study showed that glioma stem-like cells could be induced to undergo dedifferentiation under hypoxic conditions, but the mechanism requires further study. HIF1α and HIF2α are the main molecules involved in the response to hypoxia, and Sox2, as a retroelement, plays an important role in the formation of induced pluripotent stem cells, especially in hypoxic microenvironments. Therefore, we performed a series of experiments to verify whether HIF1α, HIF2α and Sox2 regulated glioma cell dedifferentiation under hypoxic conditions. Materials and methods: Sphere formation by single glioma cells was observed, and CD133 and CD15 expression was compared between the normoxic and hypoxic groups. HIF1α, HIF2α, and Sox2 expression was detected using the CGGA database, and the correlation among HIF1α, HIF2α and Sox2 levels was analyzed. We knocked out HIF1α, HIF2α and Sox2 in glioma cells and cultured them under hypoxic conditions to detect CD133 and CD15 expression. The above cells were implanted into mouse brains to analyze tumor volume and survival time. Results: New spheres were formed from single glioma cells in 1% O2, but no spheres were formed in 21% O2. The cells cultured in 1% O2 highly expressed CD133 and CD15 and had a lower apoptosis rate. The CGGA database showed HIF1α and HIF2α expression in glioma. Knocking out HIF1α or HIF2α led to a decrease in CD133 and CD15 expression and inhibited sphere formation under hypoxic conditions. Moreover, tumor volume and weight decreased after HIF1α or HIF2α knockout with the same temozolomide treatment. Sox2 was also highly expressed in glioma, and there was a positive correlation between the HIF1α/HIF2α and Sox2 expression levels. Sox2 was expressed at lower levels after HIF1α or HIF2α was knocked out. Then, Sox2 was knocked out, and we found that CD133 and CD15 expression was decreased. Moreover, a lower sphere formation rate, higher apoptosis rate, lower tumor formation rate and longer survival time after temozolomide treatment were detected in the Sox2 knockout cells. Conclusion: In a hypoxic microenvironment, the HIF1α/HIF2α-Sox2 network induced the formation of glioma stem cells through the dedifferentiation of differentiated glioma cells, thus promoting glioma cell chemoresistance. This study demonstrates that both HIF1α and HIF2α, as genes upstream of Sox2, regulate the malignant progression of glioma through dedifferentiation.

Dataset Information

The HIF1?/HIF2?-miR210-3p network regulates glioblastoma cell proliferation, dedifferentiation and chemoresistance through EGF under hypoxic conditions.

Publications

The HIF1α/HIF2α-miR210-3p network regulates glioblastoma cell proliferation, dedifferentiation and chemoresistance through EGF under hypoxic conditions.

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