HIF1α/HIF2α-Sox2/Klf4 promotes the malignant progression of glioblastoma via the EGFR-PI3K/AKT signalling pathway with positive feedback under hypoxia.
HIF1α/HIF2α-Sox2/Klf4 promotes the malignant progression of glioblastoma via the EGFR-PI3K/AKT signalling pathway with positive feedback under hypoxia.
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在缺氧条件下，HIF1α/HIF2α - Sox2/Klf4通过具有正反馈的EGFR - PI3K/AKT信号通路促进胶质母细胞瘤的恶性进展。
DOI：
10.1038/s41419-021-03598-8
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发表时间：
2021-03-24
影响因子：
9
通讯作者：
Liao B
中科院分区：
文献类型：
--
作者：
Wang P;Zhao L;Gong S;Xiong S;Wang J;Zou D;Pan J;Deng Y;Yan Q;Wu N;Liao B
先前的研究表明，缺氧反应受缺氧诱导因子（HIFs）调控，而缺氧诱导因子通过抑制细胞凋亡和增加增殖反过来促进胶质母细胞瘤（GBM）的恶性进展；这些情况导致GBM患者预后不良。然而，目前仍然没有针对HIF的疗法用于治疗GBM。我们进行了一系列实验，发现GBM细胞呈现出恶性进展的特征，并且处于缺氧环境中。单独敲除HIF1α或HIF2α时，在急性缺氧情况下，细胞增殖和细胞周期进程没有显著变化，但细胞表现出干性表达受抑制以及对替莫唑胺（TMZ）治疗增敏。然而，同时敲除HIF1α和HIF2α抑制了细胞周期停滞，促进了增殖，同时干性降低，使得GBM细胞对化疗更敏感，这可能改善患者预后。因此，HIF1α和HIF2α之间存在负反馈调节。此外，HIF1α和HIF2α是表皮生长因子（EGF）的上游调节因子，表皮生长因子通过EGFR - PI3K/AKT - mTOR - HIF1α信号通路控制GBM的恶性发展。简而言之，HIF1α/HIF2α - EGF/EGFR - PI3K/AKT - mTOR - HIF1α信号轴通过正反馈机制促进GBM的生长。最后，HIF1α和HIF2α调节Sox2和Klf4，有助于干性表达并诱导细胞周期停滞，从而增加GBM的恶性程度。总之，在Sox2和Klf4的作用下，HIF1α和HIF2α通过正反馈机制经由EGFR - PI3K/AKT通路调节胶质母细胞瘤的恶性进展，这为胶质母细胞瘤的治疗提供了一种新的肿瘤发展模型和策略。
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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