The semaphorin 3A/neuropilin-1 pathway promotes clonogenic growth of glioblastoma via activation of TGF-β signaling.
The semaphorin 3A/neuropilin-1 pathway promotes clonogenic growth of glioblastoma via activation of TGF-β signaling.
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semaphorin 3A/neuropilin-1通路通过激活TGF-β信号通路促进胶质母细胞瘤的克隆生长
DOI：
10.1172/jci.insight.167049
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发表时间：
2023-11-08
期刊：
影响因子：
8
通讯作者：
Lee, Jeongwu
中科院分区：
文献类型：
--
作者：
Jeon, Hye-Min;Shin, Yong Jae;Lee, Jaehyun;Chang, Nakho;Woo, Dong-Hun;Lee, Won Jun;Nguyen, Dayna;Kang, Wonyoung;Cho, Hee Jin;Yang, Heekyoung;Lee, Jin-Ku;Sa, Jason K.;Lee, Yeri;Kim, Dong Geon;Purow, Benjamin W.;Yoon, Yeup;Nam, Do-Hyun;Lee, Jeongwu
胶质母细胞瘤(GBM)是最致命的脑癌，预后很差。干细胞样GBM细胞(GSCs)是GBM增殖和复发的主要驱动力；因此，了解促进GSCs的分子机制可能会导致有效的治疗方法。通过体外克隆生长实验，我们确定了与神经发育有关的配体分子的有丝分裂活性。我们发现，信号素3A(Sema3A)最初是中枢神经系统中的轴突引导分子，它能促进GBM细胞的克隆生长，但不能促进正常神经前体细胞(NC)的克隆生长。在机制上，Sema3A与其受体Nrp1结合，促进Nrp1和转化生长因子-β受体1(转化生长因子-β受体1)之间的相互作用，进而导致GSC和NPC中规范的转化生长因子-β信号的激活。转化生长因子-β信号通过诱导关键干细胞因子促进基底膜肿瘤的自我更新和存活，但它在鼻咽癌中引起细胞抑制反应。通过shRNA介导的Sema3A或Nrp1基因敲除Sema3A/Nrp1轴可以抑制GSC的克隆生长和转化生长因子-β途径的活性，从而抑制体内肿瘤的生长。综上所述，这些发现表明，Sema3A/Nrp1/转化生长因子-βR1信号轴是GSC增殖的关键调节因子，也是治疗基底膜的潜在靶点。
Glioblastoma (GBM) is the most lethal brain cancer with a dismal prognosis. Stem-like GBM cells (GSCs) are a major driver of GBM propagation and recurrence; thus, understanding the molecular mechanisms that promote GSCs may lead to effective therapeutic approaches. Through in vitro clonogenic growth-based assays, we determined mitogenic activities of the ligand molecules that are implicated in neural development. We have identified that semaphorin 3A (Sema3A), originally known as an axon guidance molecule in the CNS, promotes clonogenic growth of GBM cells but not normal neural progenitor cells (NPCs). Mechanistically, Sema3A binds to its receptor neuropilin-1 (NRP1) and facilitates an interaction between NRP1 and TGF-β receptor 1 (TGF-βR1), which in turn leads to activation of canonical TGF-β signaling in both GSCs and NPCs. TGF-β signaling enhances self-renewal and survival of GBM tumors through induction of key stem cell factors, but it evokes cytostatic responses in NPCs. Blockage of the Sema3A/NRP1 axis via shRNA-mediated knockdown of Sema3A or NRP1 impeded clonogenic growth and TGF-β pathway activity in GSCs and inhibited tumor growth in vivo. Taken together, these findings suggest that the Sema3A/NRP1/TGF-βR1 signaling axis is a critical regulator of GSC propagation and a potential therapeutic target for GBM.
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影响因子：
5.2
作者：
Madhavan, Subha;Zenklusen, Jean-Claude;Kotliarov, Yuri;Sahni, Himanso;Fine, Howard A.;Buetow, Kenneth
通讯作者：
Buetow, Kenneth
影响因子：
50.3
作者：
Kim E;Kim M;Woo DH;Shin Y;Shin J;Chang N;Oh YT;Kim H;Rheey J;Nakano I;Lee C;Joo KM;Rich JN;Nam DH;Lee J
通讯作者：
Lee J
DOI：
10.1084/jem.20111424
发表时间：
2012-03-12
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hamerlik P;Lathia JD;Rasmussen R;Wu Q;Bartkova J;Lee M;Moudry P;Bartek J Jr;Fischer W;Lukas J;Rich JN;Bartek J
通讯作者：
Bartek J
影响因子：
64.5
作者：
He, ZG;TessierLavigne, M
通讯作者：
TessierLavigne, M
影响因子：
64.5
作者：
Jacob F;Salinas RD;Zhang DY;Nguyen PTT;Schnoll JG;Wong SZH;Thokala R;Sheikh S;Saxena D;Prokop S;Liu DA;Qian X;Petrov D;Lucas T;Chen HI;Dorsey JF;Christian KM;Binder ZA;Nasrallah M;Brem S;O'Rourke DM;Ming GL;Song H
通讯作者：
Song H