A Novel Role of BIRC3 in Stemness Reprogramming of Glioblastoma.
A Novel Role of BIRC3 in Stemness Reprogramming of Glioblastoma.
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DOI：
10.3390/ijms23010297
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发表时间：
2021-12-28
影响因子：
5.6
通讯作者：
Etame AB
中科院分区：
文献类型：
--
作者：
Wu Q;Berglund AE;MacAulay RJ;Etame AB
干细胞重编程仍然是胶质母细胞瘤（GBM）的主要致死原因。因此，确定和瞄准对GBM的生长和自我更新至关重要的机制至关重要。之前，我们认为BIRC3是GBM治疗耐药和生存适应的重要媒介。在这项研究中，我们提出了新的证据，证明BIRC3在GBM自我更新和茎干重编程中具有重要的非规范作用。我们证明BIRC3通过调控BMP4信号轴驱动人GBM细胞系、小鼠GBM细胞系和患者源性GBM干细胞（GSCs）的干细胞重编程。具体来说，BIRC3通过BMP4信号的下游失活诱导GBM的干性重编程。对GBM患者组织中干性重编程缺氧（假性脓样坏死和会阴坏死）生态位的RNA-Seq分析进一步证实了BIRC3高表达与BMP4低表达的相关性。BIRC3敲除上调BMP4表达，阻止GBM模型的干性重编程。此外，BMP4的siRNA沉默恢复了GBM模型中BIRC3敲除的干性重编程。体内沉默BIRC3抑制GBM原位颅内异种移植物肿瘤的发生和进展。GSCs和非GSCs群体的干细胞重编程强调了BIRC3对肿瘤内细胞异质性的影响。我们的研究已经确定了BIRC3的一种新功能，可以靶向逆转GBM的干性编程。
Stemness reprogramming remains a largely unaddressed principal cause of lethality in glioblastoma (GBM). It is therefore of utmost importance to identify and target mechanisms that are essential for GBM stemness and self-renewal. Previously, we implicated BIRC3 as an essential mediator of therapeutic resistance and survival adaptation in GBM. In this study, we present novel evidence that BIRC3 has an essential noncanonical role in GBM self-renewal and stemness reprogramming. We demonstrate that BIRC3 drives stemness reprogramming of human GBM cell lines, mouse GBM cell lines and patient-derived GBM stem cells (GSCs) through regulation of BMP4 signaling axis. Specifically, BIRC3 induces stemness reprogramming in GBM through downstream inactivation of BMP4 signaling. RNA-Seq interrogation of the stemness reprogramming hypoxic (pseudopalisading necrosis and perinecrosis) niche in GBM patient tissues further validated the high BIRC3/low BMP4 expression correlation. BIRC3 knockout upregulated BMP4 expression and prevented stemness reprogramming of GBM models. Furthermore, siRNA silencing of BMP4 restored stemness reprogramming of BIRC3 knockout in GBM models. In vivo silencing of BIRC3 suppressed tumor initiation and progression in GBM orthotopic intracranial xenografts. The stemness reprograming of both GSCs and non-GSCs populations highlights the impact of BIRC3 on intra-tumoral cellular heterogeneity GBM. Our study has identified a novel function of BIRC3 that can be targeted to reverse stemness programming of GBM.
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影响因子：
8
作者：
Semenza, G. L.
通讯作者：
Semenza, G. L.
影响因子：
158.5
作者：
Stupp, R;Mason, WP;Ryan, G
通讯作者：
Ryan, G
影响因子：
12.8
作者：
Ciechomska IA;Gielniewski B;Wojtas B;Kaminska B;Mieczkowski J
通讯作者：
Mieczkowski J
影响因子：
--
作者：
Sullivan KE;Rojas K;Cerione RA;Nakano I;Wilson KF
通讯作者：
Wilson KF
影响因子：
11.2
作者：
Galli, R;Binda, E;Vescovi, A
通讯作者：
Vescovi, A