Wnt5a and CCL25 promote adult T-cell acute lymphoblastic leukemia cell migration, invasion and metastasis
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Xinzhou Deng1,2,*, Zhenbo Tu1,*, Meng Xiong1,*, Kingsley Tembo1, Lu Zhou3, Pan Liu1, Shan Pan1, Jie Xiong1, Xiangyong Yang4, Jun Leng1, Qian Zhang5, Ruijing Xiao1 and Qiuping Zhang1,6
1Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China
2Department of Clinical Oncology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
3Department of Hematology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
4Department of Biochemical Engineering, Hubei University of Technology Engineering and Technology College, Wuhan, Hubei, China
5Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
6Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, Hubei, China
*These authors have contributed equally to this work
Qiuping Zhang, email: [email protected]
Ruijing Xiao, email: [email protected]
Keywords: Wnt5a, CCL25/CCR9, T-cell acute lymphoblastic leukemia, PI3K, RhoA
Received: July 20, 2016 Accepted: February 27, 2017 Published: March 25, 2017
Adult T-cell acute lymphoblastic leukemia (T-ALL) is a refractory leukemia. We previously showed that CCL25/CCR9 promotes T-ALL metastasis. In the present study, we assessed the effects of CCL25 on Wnt expression and the effects of Wnt5a and CCL25 on PI3K/Akt and RhoA activation. Transwell assays and mouse xenograft experiments were utilized to assess the effects of Wnt5a and CCL25 on MOLT4 cell invasion, migration and metastasis. The effects of Wnt5a on MOLT4 cell actin polarization and pseudopodium formation were examined using laser scanning confocal microscopy and scanning electron microscopy. CCL25 induced Wnt5a expression in MOLT4 cells by promoting protein kinase C (PKC) expression and activation. Wnt5a promoted MOLT4 cell migration, invasion, actin polarization, and lamellipodium and filopodia formation via PI3K/Akt-RhoA pathway activation. These effects were rescued by PI3K/Akt or RhoA knockdown or inhibition. Additionally, Wnt5a in cooperation with CCL25 promoted MOLT4 cell mouse liver metastasis and stimulated RhoA activation. These results show that CCL25/CCR9 upregulates Wnt5a by promoting PKC expression and activation in MOLT4 cells. This in turn promotes cell migration and invasion via PI3K/Akt-RhoA signaling, enhancing cell polarization and pseudopodium formation. These findings indicate that the PI3K/Akt-RhoA pathway is likely responsible for Wnt5a-induced adult T-ALL cell migration and invasion.
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