Prrx1 promotes stemness and angiogenesis via activating TGF-β/smad pathway and upregulating proangiogenic factors in glioma.
Prrx1 promotes stemness and angiogenesis via activating TGF-β/smad pathway and upregulating proangiogenic factors in glioma.
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Prrx1 通过激活 TGF-β/smad 通路和上调胶质瘤中的促血管生成因子来促进干性和血管生成
DOI：
10.1038/s41419-021-03882-7
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发表时间：
2021-06-15
影响因子：
9
通讯作者：
Ke Y
中科院分区：
文献类型：
--
作者：
Chen Z;Chen Y;Li Y;Lian W;Zheng K;Zhang Y;Zhang Y;Lin C;Liu C;Sun F;Sun X;Wang J;Zhao L;Ke Y
胶质瘤是最致命的肿瘤之一，具有高度血管化的网络，越来越多的证据表明胶质瘤干细胞(GSCs)是胶质瘤过度血管生成的原因。配对相关同源异型盒1(Prrx1)的异常表达与包括GSCs在内的肿瘤干细胞的功能相关。在这项研究中，Prrx1在胶质瘤标本中显著上调，并且Prrx1表达上调与胶质瘤患者的预后呈负相关。Prrx1增强了非干细胞肿瘤细胞(NSTCs)的干性获取和GSCs的干性维持，同时增加了SOX2等干性标记的表达。Prrx1还通过上调促血管生成因子，如血管内皮生长因子，促进胶质瘤血管生成。一直以来，沉默Prrx1显著抑制了体内胶质瘤的增殖、干化和血管生成。结合亚细胞蛋白质组学和体外分析，我们发现Prrx1直接与转化生长因子-β-1基因的启动子区域结合，上调转化生长因子-β-1的表达，最终激活转化生长因子-β/Smad通路。沉默转化生长因子-β-1可减轻Prrx1诱导的恶性行为。该途径的激活与Prrx1协同上调茎干相关基因和促血管生成因子的表达。综上所述，我们的研究结果表明Prrx1/转化生长因子-β/Smad信号轴在胶质瘤干细胞分化和血管生成中起重要作用。破坏这一信号轴的功能可能代表着胶质瘤患者的一种新的治疗策略。
Glioma is one of the most lethal cancers with highly vascularized networks and growing evidences have identified glioma stem cells (GSCs) to account for excessive angiogenesis in glioma. Aberrant expression of paired-related homeobox1 (Prrx1) has been functionally associated with cancer stem cells including GSCs. In this study, Prrx1 was found to be markedly upregulated in glioma specimens and elevated Prrx1 expression was inversely correlated with prognosis of glioma patients. Prrx1 potentiated stemness acquisition in non-stem tumor cells (NSTCs) and stemness maintenance in GSCs, accompanied with increased expression of stemness markers such as SOX2. Prrx1 also promoted glioma angiogenesis by upregulating proangiogenic factors such as VEGF. Consistently, silencing Prrx1 markedly inhibited glioma proliferation, stemness, and angiogenesis in vivo. Using a combination of subcellular proteomics and in vitro analyses, we revealed that Prrx1 directly bound to the promoter regions of TGF-β1 gene, upregulated TGF-β1 expression, and ultimately activated the TGF-β/smad pathway. Silencing TGF-β1 mitigated the malignant behaviors induced by Prrx1. Activation of this pathway cooperates with Prrx1 to upregulate the expression of stemness-related genes and proangiogenic factors. In summary, our findings revealed that Prrx1/TGF-β/smad signal axis exerted a critical role in glioma stemness and angiogeneis. Disrupting the function of this signal axis might represent a new therapeutic strategy in glioma patients.
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影响因子：
11.2
作者：
Folkins C;Shaked Y;Man S;Tang T;Lee CR;Zhu Z;Hoffman RM;Kerbel RS
通讯作者：
Kerbel RS
影响因子：
10.8
作者：
Jiang, Mengshi;Li, Wei;You, Jian
通讯作者：
You, Jian
影响因子：
23.9
作者：
Lathia, Justin D.;Heddleston, John M.;Venere, Monica;Rich, Jeremy N.
通讯作者：
Rich, Jeremy N.
影响因子：
11.4
作者：
Goumans, MJ;Valdimarsdottir, G;ten Dijke, P
通讯作者：
ten Dijke, P
影响因子：
20.1
作者：
Ihida-Stansbury, K;McKean, DM;Jones, PL
通讯作者：
Jones, PL