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Abstract
Cancer stem cells (CSCs) play an important role in osteosarcoma (OS) metastasis and recurrence, and both Wnt/β-catenin and Notch signaling are essential for the development of the biological traits of CSCs. However, the mechanism that underlies the simultaneous hyperactivation of both Wnt/β-catenin and Notch signaling in OS remains unclear. Here, we report that expression of miR-135b correlates with the overall and recurrence-free survival of OS patients, and that miR-135b has an activating effect on both Wnt/β-catenin and Notch signaling. The overexpression of miR-135b simultaneously targets multiple negative regulators of the Wnt/β-catenin and Notch signaling pathways, including glycogen synthase kinase-3 beta (GSK3β), casein kinase 1a (CK1α), and ten-eleven translocation 3 (TET3). Therefore, upregulated miR-135b promotes CSC traits, lung metastasis, and tumor recurrence in OS. Notably, antagonizing miR-135b potently inhibits OS lung metastasis, cancer cell stemness, CSC-induced tumor formation, and recurrence in xenograft animal models. These findings suggest that miR-135b mediates the constitutive activation of Wnt/β-catenin and Notch signaling, and that the inhibition of miR-135b is a novel strategy to inhibit tumor metastasis and prevent CSC-induced recurrence in OS.
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1 Department of Thoracic Surgery, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, China
2 Department of Orthopaedics, The General Hospital of Chinese People’s Liberation Army, Beijing 100853, China
3 Department of Pathology, The General Hospital of Chinese People’s Liberation Army, Beijing 100853, China
4 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Jilin University, Changchun 130021, China
5 Department of Basic Medical Science, School of Medicine, Hangzhou Normal University, Hangzhou 310036, China
6 Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, China