ONZIN Upregulation by Mutant p53 Contributes to Osteosarcoma Metastasis Through the CXCL5-MAPK Signaling Pathway
ONZIN Upregulation by Mutant p53 Contributes to Osteosarcoma Metastasis Through the CXCL5-MAPK Signaling Pathway
复制标题
突变体 p53 上调 ONZIN 通过 CXCL5-MAPK 信号通路促进骨肉瘤转移
DOI：
10.1159/000491976
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发表时间：
2018-01-01
影响因子：
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通讯作者：
Xiong, Shunbin
中科院分区：
文献类型：
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作者：
Zhang, Yanqin;Hu, Qianghua;Xiong, Shunbin
背景/目的：突变型p53的功能获得与骨肉瘤肺转移的高发生率相关。为了研究突变型p53诱导骨肉瘤转移的机制，进行表达阵列分析，比较来自p53（+/-）小鼠的非转移性骨肉瘤和来自p53（R172 H/+）小鼠的转移性骨肉瘤。Onzin（Plac 8）被鉴定为p53（R172 H/+）小鼠转移性骨肉瘤中上调的基因之一。因此，我们研究ONZIN在人骨肉瘤转移中的作用。方法：在骨肉瘤细胞系中检测ONZIN功能及其下游靶点。在骨肉瘤细胞中进行与肿瘤发生和转移相关的测定，包括细胞迁移、侵袭、克隆形成存活和软琼脂集落形成。此外，使用小鼠异种移植模型来检查ONZIN过表达在体内肿瘤发生中的作用。最后，招募了87名骨肉瘤患者，以研究ONZIN过表达在转移和预后中的临床相关性。结果：ONZIN过表达增强骨肉瘤细胞增殖、克隆形成存活、迁移和侵袭，与p53状态无关。此外，ONZIN过表达诱导CXCL 5上调，导致ERK磷酸化增加，这有助于更积极的骨肉瘤转移表型。更重要的是，ONZIN在人骨肉瘤患者中的过表达与肺转移、低生存率和生存率密切相关。结论：ONZIN的过表达促进骨肉瘤的进展和转移，并可作为骨肉瘤转移和预后的临床生物标志物。(C)2018作者（S）由S发布。Karger AG，巴塞尔
Background/Aims: Gain-of-function of mutant p53 is associated with a high rate of lung metastasisinosteosarcoma. To investigate the mechanism of mutant p53-induced osteosarcoma metastasis, expression array analysis was performed, comparing non-metastatic osteosarcomas from p53(+/-) mice with metastatic osteosarcomas from p53(R172H/+) mice. Onzin (Plac8) was identified as one of the genes upregulated in p 53(R172H/+) mouse metastatic osteosarcomas. Accordingly, we investigated the role of ONZIN in human osteosarcoma metastasis. Methods: ONZIN function and its downstream targets were examined in osteosarcoma cell lines. Assays related to tumorigenesis and metastasis, including cell migration, invasion, clonogenic survival, and soft agar colony formation, were performed in osteosarcoma cells. Additionally, mouse xenograft models were used to examine the role of ONZIN overpression in tumorigenesis in vivo. Lastly, 87 osteosarcoma patients were recruited to investigate the clinical relevance of ONZIN overexpression in metastasis and prognosis. Results: ONZIN overexpression enhanced osteosarcoma cell proliferation, clonogenic survival, migration, and invasion independent of p53 status. Furthermore, ONZIN overexpression induced CXCL5 upregulation and resulted in increased ERK phosphorylation, which contributed to more aggressive osteosarcoma metastatic phenotypes. More importantly, overexpression of ONZIN in human osteosarcoma patients was closely associated with lung metastasis, poor prognoses, and survival. Conclusions: Overexpression of ONZIN promotes osteosarcoma progression and metastasis, and can serve as a clinical biomarker for osteosarcoma metastasis and prognosis. (C) 2018 The Author(s) Published by S. Karger AG, Basel