Oncogenic role of SFRP2 in p53-mutant osteosarcoma development via autocrine and paracrine mechanism
Oncogenic role of SFRP2 in p53-mutant osteosarcoma development via autocrine and paracrine mechanism
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DOI：
10.1073/pnas.1814044115
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发表时间：
2018-11-20
影响因子：
11.1
通讯作者：
Schaniel, Christoph
中科院分区：
文献类型：
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作者：
Kim, Huensuk;Yoo, Seungyeul;Schaniel, Christoph
骨肉瘤(OS)是最常见的原发骨肿瘤，具有高转移性、高化疗耐药性、低生存率等特点。利用Li-Fraumeni综合征(LFS)患者的诱导多能干细胞(IPSCs)，我们研究了分泌型卷曲相关蛋白2(SFRP2)在P53突变相关OS发生中的致癌作用。有趣的是，我们发现在OS患者样本中SFRP2的高表达与较差的存活率相关。系统水平的分析表明，SFRP2的表达在LFS OS发育过程中增加，并能诱导血管生成。在正常成骨细胞前体细胞中异位过表达SFRP2足以抑制正常成骨细胞的分化，并通过以β-连环蛋白非依赖性的方式诱导FOXM1和CYR61等致癌分子促进OS表型。相反，抑制SFRP2、FOXM1或CyR61会抑制致瘤潜力。综上所述，这些发现证明了SFRP2在P53突变相关OS的发生中的致癌作用，并且抑制SFRP2是一种潜在的治疗策略。
Osteosarcoma (OS), the most common primary bone tumor, is highly metastatic with high chemotherapeutic resistance and poor survival rates. Using induced pluripotent stem cells (iPSCs) generated from Li-Fraumeni syndrome (LFS) patients, we investigate an oncogenic role of secreted frizzled-related protein 2 (SFRP2) in p53 mutation-associated OS development. Interestingly, we find that high SFRP2 expression in OS patient samples correlates with poor survival. Systems-level analyses identified that expression of SFRP2 increases during LFS OS development and can induce angiogenesis. Ectopic SFRP2 overexpression in normal osteoblast precursors is sufficient to suppress normal osteoblast differentiation and to promote OS phenotypes through induction of oncogenic molecules such as FOXM1 and CYR61 in a beta-catenin-independent manner. Conversely, inhibition of SFRP2, FOXM1, or CYR61 represses the tumorigenic potential. In summary, these findings demonstrate the oncogenic role of SFRP2 in the development of p53 mutation-associated OS and that inhibition of SFRP2 is a potential therapeutic strategy.