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 malignancy in osteosarcoma and identify novel molecular targets that might be therapeutically applicable in clinical settings. Significance: Transcription factors MAFB and Sox9 form a positive feedback loop to maintain cell stemness and tumor growth in vitro and in vivo , revealing a potential target pathway for therapeutic intervention in osteosarcoma.

中文翻译：

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MAFB通过Sox9介导的正反馈回路促进骨肉瘤的癌变和肿瘤发生。

尽管事实上骨肉瘤是最常见的预后不良的原发性骨恶性肿瘤之一，但骨肉瘤发病机理的机制仅是部分已知的。在这里，我们通过广泛分析几个公共可用的基因表达谱数据集来表征差异表达的基因，并确定了肌肉腱膜纤维肉瘤癌基因同源物B（MAFB）作为骨肉瘤进展中的关键转录调节因子。MAFB在肿瘤组织中高表达，是骨肉瘤细胞增殖和致瘤性所必需的。通过在转录水平上调干细胞调节剂Sox9，MAFB在骨肉瘤干细胞中表达升高，从而在体外和体内维持其自我更新的潜力。Sox9通过直接识别MAFB基因座上的序列结合富集基序，进而激活了MAFB表达，从而形成正反馈调节环。Sox9介导的MAFB反馈激活对骨肉瘤干细胞的肿瘤形成能力和肿瘤启动能力至关重要。而且，MAFB和Sox9的表达在骨肉瘤中高度相关并与疾病进展相关。MAFB和Sox9的联合检测代表了有前途的预后生物标志物，该标志物将部分骨肉瘤患者的总体生存期最短。综上所述，这些发现揭示了一个MAFB–Sox9互作调控轴驱动骨肉瘤中的癌症干和恶性肿瘤，并确定了可能在临床上可用于治疗的新型分子靶标。意义：