Reelin promotes the adhesion and drug resistance of multiple myeloma cells via integrin β1 signaling and STAT3
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Liang Lin1,*, Fan Yan3,*, Dandan Zhao4,*, Meng Lv2, Xiaodong Liang5, Hui Dai1, Xiaodan Qin1, Yan Zhang1, Jie Hao1, Xiuyuan Sun1, Yanhui Yin1, Xiaojun Huang2, Jun Zhang1, Jin Lu2, Qing Ge1
1Key Laboratory of Medical Immunology, Ministry of Health, Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
2Peking University Institute of Hematology, People’s Hospital, Beijing 100044, China
3Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China
4Jining No.1 People’s Hospital, Jining, Shandong 272011, China
5Hangzhou Cancer Hospital, Hang Zhou 310002, China
*These authors have contributed equally to this work
Qing Ge, e-mail: [email protected]
Jin Lu, e-mail: [email protected]
Jun Zhang, e-mail: [email protected]
Keywords: multiple myeloma, reelin, adhesion, integrin, STAT3
Received: September 02, 2015 Accepted: January 23, 2016 Published: February 03, 2016
Reelin is an extracellular matrix (ECM) protein that is essential for neuron migration and positioning. The expression of reelin in multiple myeloma (MM) cells and its association with cell adhesion and survival were investigated. Overexpression, siRNA knockdown, and the addition of recombinant protein of reelin were used to examine the function of reelin in MM cells. Clinically, high expression of reelin was negatively associated with progression-free survival and overall survival. Functionally, reelin promoted the adhesion of MM cells to fibronectin via activation of α5β1 integrin. The resulting phosphorylation of Focal Adhesion Kinase (FAK) led to the activation of Src/Syk/STAT3 and Akt, crucial signaling molecules involved in enhancing cell adhesion and protecting cells from drug-induced cell apoptosis. These findings indicate reelin’s important role in the activation of integrin-β1 and STAT3/Akt pathways in multiple myeloma and highlight the therapeutic potential of targeting reelin/integrin/FAK axis.
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