B7-H3 Regulates Glioma Growth and Cell Invasion Through a JAK2/STAT3/Slug-Dependent Signaling Pathway
B7-H3 Regulates Glioma Growth and Cell Invasion Through a JAK2/STAT3/Slug-Dependent Signaling Pathway
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DOI：
10.2147/ott.s237841
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发表时间：
2020-01-01
影响因子：
4
通讯作者：
Chen, Ligang
中科院分区：
文献类型：
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作者：
Zhong, Chuanhong;Tao, Bei;Chen, Ligang
目的：本研究旨在探讨B7-H3在恶性胶质瘤进展中的潜在作用，为临床胶质瘤治疗提供新的思路。方法：采用免疫组化方法检测B7-H3在高、低级别胶质瘤组织中的表达。分别采用CCK-8法和原位小鼠胶质瘤模型，在体外和体内分析B7-H3过表达或敲除胶质瘤细胞的增殖和侵袭能力。JAK 2/STAT 3/Slug信号通路的激活和上皮-间充质转化（EMT）通过Western印迹和免疫荧光检查。结果：B7-H3在高级别胶质瘤组织中的表达高于低级别胶质瘤组织。与此一致，B7-H3的过表达增强了胶质瘤细胞的增殖，诱导了胶质瘤的持续生长，并促进了胶质瘤细胞在体外和体内的侵袭。此外，这些作用是通过激活B7-H3过表达胶质瘤细胞中的JAK 2/STAT 3/Slug信号通路介导的。我们还发现B7-H3通过下调E-cadherin和上调MMP-2/-9的表达诱导EMT过程，导致胶质瘤细胞的侵袭增强。最后，我们表明，NAP和TMZ的组合显着抑制胶质瘤的生长和胶质瘤细胞的侵袭，在体外和invivo.Conclusion：B7-H3过表达促进持续胶质瘤生长，并通过JAK 2/STAT 3/Slug依赖的信号通路促进胶质瘤细胞的侵袭。应用STAT 3抑制剂NAP可显著抑制胶质瘤的生长和侵袭，并有可能作为治疗胶质瘤的治疗策略。
Purpose: The aim of this study was to explore the potential role of B7-H3 in malignant glioma progression and identify an innovative approach in clinical glioma therapy.Methods: The protein expression of B7-H3 in high- and low-grade tumor tissues from glioma patients was assessed by immunohistochemistry. The proliferative and invasive ability of B7-H3-overexpressing or knockout glioma cells was analyzed in vitro and in vivo by CCK-8 assay and an orthotopic mouse glioma model, respectively. Activation of the JAK2/STAT3/Slug signaling pathway and epithelial-mesenchymal transition (EMT) was examined by Western blotting and immunofluorescence. The anticancer effects of napabucasin (NAP) and temozolomide (TMZ) were analyzed in an orthotopic mouse glioma model.Results: The expression of B7-H3 was higher in high-grade than in low-grade tumor tissues from glioma patients. In line with this, overexpression of B7-H3 enhanced glioma cell proliferation, induced sustained glioma growth, and promoted glioma cell invasion in vitro and in vivo. Moreover, these effects were mediated through the activation of the JAK2/ STAT3/Slug signaling pathway in B7-H3 overexpression glioma cells. We also found that B7-H3 induced EMT processes through downregulation of E-cadherin and upregulation of MMP-2/-9 expression, resulting in enhanced invasion of glioma cells. Finally, we show that the combination of NAP and TMZ significantly suppressed glioma growth and glioma cell invasion, both in vitro and in vivo.Conclusion: B7-H3 overexpression facilitated sustained glioma growth and promoted glioma cell invasion through a JAK2/STAT3/Slug-dependent signaling pathway. Application of the STAT3 inhibitor NAP significantly suppressed glioma growth and invasion, and has potential as a therapeutic strategy for the treatment of glioma.