MAFB Promotes Cancer Stemness and Tumorigenesis in Osteosarcoma through a Sox9-Mediated Positive Feedback Loop

作者：Yanyan Chen, Tao Wang, Mengxi Huang, Qin Liu, Chao Hu, Bin Wang, Dong Han, Cheng Chen, Junliang Zhang, Zhiping Li, Chao Liu, Wenbin Lei, Yue Chang, Meijuan Wu, Dan Xiang, Yitian Chen, Rui Wang, Weiqian Huang, Zengjie Lei, Xiaoyuan Chu · 发表于：Cancer Research · 年份：2020 · DOI：10.1158/0008-5472.can-19-1764 · 被引用次数：55 · 研究领域：Cancer Cells and Metastasis、Sarcoma Diagnosis and Treatment、MicroRNA in disease regulation

Abstract Despite the fact that osteosarcoma is one of the most common primary bone malignancies with poor prognosis, the mechanism behind the pathogenesis of osteosarcoma is only partially known. Here we characterized differentially expressed genes by extensive analysis of several publicly available gene expression profile datasets and identified musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) as a key transcriptional regulator in osteosarcoma progression. MAFB was highly expressed in tumor tissues and required for proliferation and tumorigenicity of osteosarcoma cells. MAFB expression was elevated in osteosarcoma stem cells to maintain their self-renewal potential in vitro and in vivo through upregulation of stem cell regulator Sox9 at the transcriptional level. Sox9 in turn activated MAFB expression via direct recognition of its sequence binding enrichment motif on the MAFB locus, thereby forming a positive feedback regulatory loop. Sox9-mediated feedback activation of MAFB was pivotal to tumorsphere-forming and tumor-initiating capacities of osteosarcoma stem cells. Moreover, expression of MAFB and Sox9 was highly correlated in osteosarcoma and associated with disease progression. Combined detection of both MAFB and Sox9 represented a promising prognostic biomarker that stratified a subset of patients with osteosarcoma with shortest overall survival. Taken together, these findings reveal a MAFB–Sox9 reciprocal regulatory axis driving cancer stemness and malignanc...