OncoTargets and Therapy (Mar 2020)
B7-H3 Regulates Glioma Growth and Cell Invasion Through a JAK2/STAT3/Slug-Dependent Signaling Pathway
Abstract
Chuanhong Zhong,1,2 Bei Tao,3 Yitian Chen,4 Zhangchao Guo,1 Xiaobo Yang,1,2 Lilei Peng,1,2 Xiangguo Xia,1,2 Ligang Chen1,2 1Neurosurgery Department, Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China; 2Neurosurgical Clinical Medical Research Center of Sichuan Province, Luzhou, People’s Republic of China; 3Rheumatism Department, Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China; 4Department of Clinical Medicine, Medical College of Soochow University, Suzhou, People’s Republic of ChinaCorrespondence: Ligang ChenNeurosurgery Department, Affiliated Hospital of Southwest Medical University, Luzhou 646000, People’s Republic of ChinaTel/Fax +86 18113556657Email [email protected]: 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.Keywords: B7-H3, glioma, JAK2/STAT3/Slug, temozolomide
