MAFB Promotes Cancer Stemness and Tumorigenesis in Osteosarcoma through a Sox9-Mediated Positive Feedback Loop
MAFB Promotes Cancer Stemness and Tumorigenesis in Osteosarcoma through a Sox9-Mediated Positive Feedback Loop
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MAFB 通过 Sox9 介导的正反馈环促进骨肉瘤的癌症干细胞和肿瘤发生
DOI：
10.1158/0008-5472.can-19-1764
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发表时间：
2020-06-15
期刊：
影响因子：
11.2
通讯作者：
Chu, Xiaoyuan
中科院分区：
文献类型：
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作者：
Chen, Yanyan;Wang, Tao;Chu, Xiaoyuan
尽管骨肉瘤是最常见的原发性骨恶性肿瘤之一，预后不良，但骨肉瘤发病机理背后的机制仅部分知道。在这里，我们通过对几个公共基因表达谱数据集的广泛分析来表征差异表达的基因，并确定了肌肉核酸纤维纤维肉瘤癌基因癌基因同源物B（MAFB）是骨肉瘤进展中的关键转录调节剂。 MAFB在肿瘤组织中高度表达，需要骨肉瘤细胞的增殖和肿瘤性。 MAFB表达在骨肉瘤干细胞中升高，以通过在转录水平上上调干细胞调节剂SOX9在体外和体内保持自我更新潜力。 Sox9反过来通过直接识别其序列结合富集基序在MAFB基因座上激活了MAFB表达，从而形成了正反馈调节环。 Sox9介导的MAFB的喂养激活对于骨肉肉瘤干细胞的肿瘤形成和肿瘤发射能力至关重要。此外，MAFB和SOX9的表达在骨肉瘤中高度相关，并且与疾病进展有关。 MAFB和SOX9的联合检测代表了一种有希望的预后生物标志物，该标志物对整体生存期最短的骨肉瘤患者进行了分层。综上所述，这些发现揭示了MAFB-SOX9相互调控轴驱动癌症的骨骼和恶性肿瘤，并确定可能适用于临床环境中的治疗性的新型分子靶标。体外和体内肿瘤生长，揭示了治疗干预的潜在靶标途径骨肉瘤。
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. 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.