The HIF1α/HIF2α-miR210-3p network regulates glioblastoma cell proliferation, dedifferentiation and chemoresistance through EGF under hypoxic conditions.
The HIF1α/HIF2α-miR210-3p network regulates glioblastoma cell proliferation, dedifferentiation and chemoresistance through EGF under hypoxic conditions.
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HIF1α/HIF2α-miR210-3p 网络在缺氧条件下通过 EGF 调节胶质母细胞瘤细胞增殖、去分化和化疗耐药
DOI：
10.1038/s41419-020-03150-0
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发表时间：
2020-11-18
影响因子：
9
通讯作者：
Gong S
中科院分区：
文献类型：
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作者：
Wang P;Yan Q;Liao B;Zhao L;Xiong S;Wang J;Zou D;Pan J;Wu L;Deng Y;Wu N;Gong S
缺氧诱导因子1α（HIF 1 α）在缺氧条件下促进胶质母细胞瘤的恶性进展，导致胶质母细胞瘤患者的预后不良;然而，在胶质母细胞瘤中靶向HIF 1 α的疗法均未成功根除肿瘤。因此，我们专注于原因，发现靶向HIF 1 α和HIF 2 α的治疗同时增加了肿瘤体积，但HIF 1 α/HIF 2 α靶向治疗与替莫唑胺（TMZ）联合使用减少了肿瘤发生，并显著提高了化疗增敏作用。此外，miR-210- 3 p诱导HIF 1 α表达，但抑制HIF 2 α表达，提示miR-210- 3 p调控HIF 1 α/HIF 2 α表达。表皮生长因子（EGF）已被证明在缺氧条件下上调HIF 1 α的表达。然而，在本研究中，除了上述信号通路外，上游蛋白HIF 1 α和HIF 2 α已被证明通过与序列AGGCGTGG和GGGCGTGG结合来诱导EGF表达。简而言之，在缺氧微环境中，HIF 1 α/HIF 2 α-miR 210 - 3 p网络通过与EGF的正反馈回路促进胶质母细胞瘤的恶性进展。此外，分化的胶质母细胞瘤细胞在缺氧条件下经历去分化以产生胶质瘤干细胞，并且HIF 1 α和HIF 2 α的同时敲除抑制细胞周期停滞，但促进增殖并降低干性，从而促进胶质母细胞瘤细胞的化学增敏。综上所述，HIF 1 α和HIF 2 α均通过特异性途径调节胶质母细胞瘤细胞的增殖、去分化和化疗耐药性，这对胶质母细胞瘤的治疗具有重要意义。
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 tumourigenesis and significantly improved chemosensitization. Moreover, miR-210-3p induced HIF1α expression but inhibited HIF2α expression, suggesting that miR-210-3p regulates HIF1α/HIF2α expression. Epidermal growth factor (EGF) has been shown to upregulate HIF1α expression under hypoxic conditions. However, in the present study, in addition to the signalling pathways mentioned above, the upstream proteins HIF1α and HIF2α have been shown to induce EGF expression by binding to the sequences AGGCGTGG and GGGCGTGG. Briefly, in a hypoxic microenvironment the HIF1α/HIF2α-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 HIF1α and HIF2α inhibited cell cycle arrest but promoted proliferation with decreased stemness, promoting glioblastoma cell chemosensitization. In summary, both HIF1α and HIF2α regulate glioblastoma cell proliferation, dedifferentiation and chemoresistance through a specific pathway, which is important for glioblastoma treatments.
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影响因子：
5.7
作者：
Lee G;Auffinger B;Guo D;Hasan T;Deheeger M;Tobias AL;Kim JY;Atashi F;Zhang L;Lesniak MS;James CD;Ahmed AU
通讯作者：
Ahmed AU
影响因子：
5.8
作者：
Jana, Anirban;Narula, Pankhuri;Kulshreshtha, Ritu
通讯作者：
Kulshreshtha, Ritu
DOI：
10.1007/s00259-019-04621-z
发表时间：
2019-11-28
影响因子：
9.1
作者：
Hu, Man;Zhu, Yufang;Yu, Jinming
通讯作者：
Yu, Jinming
影响因子：
64.8
作者：
Lee SB;Frattini V;Bansal M;Castano AM;Sherman D;Hutchinson K;Bruce JN;Califano A;Liu G;Cardozo T;Iavarone A;Lasorella A
通讯作者：
Lasorella A
影响因子：
9
作者：
通讯作者：
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