miR-135b Stimulates Osteosarcoma Recurrence and Lung Metastasis via Notch and Wnt/β-Catenin Signaling

• Published in: Molecular therapy. Nucleic acids Vol. 8; pp. 111 - 122
• Main Authors: Jin, Hua, Luo, Song, Wang, Yun, Liu, Chang, Piao, Zhenghao, Xu, Meng, Guan, Wei, Li, Qing, Zou, Hua, Tan, Qun-You, Yang, Zhen-Zhou, Wang, Yan, Wang, Dong, Xu, Cheng-Xiong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.09.2017; Elsevier Limited; American Society of Gene & Cell Therapy; Elsevier
• Subjects: Animal models; Bone cancer; Casein; Cell adhesion & migration; Glycogen; Glycogen synthase kinase 3; Immunoglobulins; Lung cancer; Metastases; Metastasis; MicroRNAs; miR-135b; Original; Osteosarcoma; recurrence; Sarcoma; Software; Stem cell transplantation; Stem cells; Tumors; Wnt protein; Wnt/β-catenin; Xenografts; β-Catenin; recurrence; miR-135b; metastasis; Wnt/β-catenin; osteosarcoma
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2017.06.008

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.