Adenovirus infection promotes the formation of glioma stem cells from glioblastoma cells through the TLR9/NEAT1/STAT3 pathway
Adenovirus infection promotes the formation of glioma stem cells from glioblastoma cells through the TLR9/NEAT1/STAT3 pathway
复制标题
腺病毒感染通过TLR9/NEAT1/STAT3途径促进胶质母细胞瘤细胞形成胶质瘤干细胞
DOI：
10.1186/s12964-020-00598-7
复制
发表时间：
2020-03
影响因子：
8.4
通讯作者：
Liang Liang
中科院分区：
文献类型：
--
作者：
Zang Jian;Zheng Min-Hua;Cao Xiu-Li;Zhang Yi-Zhe;Zhang Yu-Fei;Gao Xiang-Yu;Cao Yuan;Shi Mei;Han Hua;Liang Liang
胶质瘤干细胞（Glioma stem cells，GSCs）是具有干细胞特性的胶质瘤细胞，参与胶质瘤的多种恶性行为。有证据表明，来自肿瘤微环境（TME）的信号增强胶质瘤细胞的干细胞性。然而，识别的信号分子和潜在的mechanisms还没有完全阐明。MethodsHuman样品和胶质瘤细胞系体外培养，以确定腺病毒（ADV）感染的球体形成，RT-qPCR，Western印迹，流式细胞仪和免疫荧光的影响。对于体内分析，应用小鼠颅内肿瘤模型。生物信息学分析，基因敲低siRNA，RT-qPCR和蛋白质印迹法被应用于进一步的mechanism.ResultsInfection患者源性胶质瘤细胞与ADV增加肿瘤球的形成。ADV感染可上调肿瘤细胞的干细胞标志物，进而促进肿瘤细胞自我更新和多向分化的能力。这些ADV感染的肿瘤球在免疫受损小鼠中形成异种移植肿瘤的潜力更强。ADV感染可以通过TLR 9促进GSC的形成，因为ADV感染后TLR 9上调，而TLR 9的敲低减少了ADV诱导的GSC。一致地，MYD 88以及总STAT 3和磷酸化（p-）STAT 3也在ADV诱导的GSC中上调。MYD 88的敲低或STAT 3的药物抑制减弱了ADV诱导的GSC的干性。此外，我们发现ADV感染上调lncRNA NEAT 1。NEAT 1的敲低损害了ADV诱导的GSC的干性。最后，HMGB 1，一种触发TLR信号的损伤相关分子模式（DAMP），也上调胶质瘤细胞中的干细胞标志物。结论ADV，已被开发作为基因治疗和溶瘤病毒的载体，通过TLR 9/NEAT 1/STAT 3信号促进GSCs的形成。
BackgroundGlioma stem cells (GSCs) are glioma cells with stemness and are responsible for a variety of malignant behaviors of glioma. Evidence has shown that signals from tumor microenvironment (TME) enhance stemness of glioma cells. However, identification of the signaling molecules and underlying mechanisms has not been completely elucidated.MethodsHuman samples and glioma cell lines were cultured in vitro to determine the effects of adenovirus (ADV) infection by sphere formation, RT-qPCR, western blotting, FACS and immunofluorescence. For in vivo analysis, mouse intracranial tumor model was applied. Bioinformatics analysis, gene knockdown by siRNA, RT-qPCR and western blotting were applied for further mechanistic studies.ResultsInfection of patient-derived glioma cells with ADV increases the formation of tumor spheres. ADV infection upregulated stem cell markers and in turn promoted the capacities of self-renewal and multi-lineage differentiation of the infected tumor spheres. These ADV infected tumor spheres had stronger potential to form xenograft tumors in immune-compromised mice. GSCs formation could be promoted by ADV infection via TLR9, because TLR9 was upregulated after ADV infection, and knockdown of TLR9 reduced ADV-induced GSCs. Consistently, MYD88, as well as total STAT3 and phosphorylated (p-)STAT3, were also upregulated in ADV-induced GSCs. Knockdown of MYD88 or pharmaceutical inhibition of STAT3 attenuated stemness of ADV-induced GSCs. Moreover, we found that ADV infection upregulated lncRNA NEAT1. Knockdown of NEAT1 impaired stemness of ADV-induced GSCs. Lastly, HMGB1, a damage associated molecular pattern (DAMP) that triggers TLR signaling, also upregulated stemness markers in glioma cells.ConclusionADV, which has been developed as vectors for gene therapy and oncolytic virus, promotes the formation of GSCs via TLR9/NEAT1/STAT3 signaling.Video abstract
登录
查看更多内容
影响因子：
5.3
作者：
通讯作者：
--
Notch激活促进人胶质瘤细胞中的细胞增殖和神经干细胞样集落的形成
影响因子：
4.3
作者：
Liang, Liang;Yang, An-Gang;Feng, Lei;Zou, Lian;Zhang, Xue-Ping;Yin, Dan-Dan;Yao, Li-Bo;Zhang, Su-Zhen;Chen, Jing-Yuan;Zhou, Peng;Zheng, Gang;Hou, Li-Hong;Zheng, Qi-Jun;Liu, Hui-Ling;Han, Hua
通讯作者：
Han, Hua
影响因子：
37.3
作者：
Toh TB;Lim JJ;Chow EK
通讯作者：
Chow EK
影响因子：
5.8
作者：
Nakagawa S;Yamazaki T;Hirose T
通讯作者：
Hirose T
影响因子：
5.7
作者：
Yamamoto Y;Nagasato M;Yoshida T;Aoki K
通讯作者：
Aoki K