p27 Is a Candidate Prognostic Biomarker and Metastatic Promoter in Osteosarcoma.
p27 Is a Candidate Prognostic Biomarker and Metastatic Promoter in Osteosarcoma.
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DOI：
10.1158/0008-5472.can-15-3189
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发表时间：
2016-07-01
期刊：
影响因子：
11.2
通讯作者：
Man TK
中科院分区：
文献类型：
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作者：
Li Y;Nakka M;Kelly AJ;Lau CC;Krailo M;Barkauskas DA;Hicks JM;Man TK
转移进展是骨肉瘤死亡的主要原因，骨肉瘤是儿童和年轻人最常见的骨恶性肿瘤。然而，转移性疾病的预后生物标志物和有效的靶向治疗仍然缺乏。利用免疫蛋白质组学方法，我们发现高危骨肉瘤患者血浆中抗细胞周期蛋白激酶抑制物p27(KIP1，CDKN1B)的自身抗体升高。使用来自骨肉瘤患者(n=233)的大量血清样本，我们验证了p27自身抗体水平较高与较差的总体和无事件生存率显著相关(p<；0.05)。免疫组织化学分析还显示，在大多数骨肉瘤病例和高转移骨肉瘤细胞系中，p27错误定位于细胞质。我们发现胞浆p27的异位表达促进了骨肉瘤细胞的迁移和侵袭，而shRNA介导的基因沉默抑制了这些作用。此外，p27磷酸化位点S10或T198的突变，而不是T157，取消了迁移和侵袭性表型。此外，与空载体对照相比，注射表达细胞质p27的细胞的小鼠肺转移的发生增加。总而言之，我们的发现支持进一步研究p27作为一个潜在的预后生物标志物和治疗靶点在表现出p27亚细胞定位异常的骨肉瘤病例中的作用。
Metastatic progression is the major cause of death in osteosarcoma, the most common bone malignancy in children and young adults. However, prognostic biomarkers and efficacious targeted treatments for metastatic disease remain lacking. Using an immunoproteomic approach, we discovered that autoantibodies against the cell cycle kinase inhibitor p27 (KIP1, CDKN1B) were elevated in plasma of high-risk osteosarcoma patients. Using a large cohort of serum samples from osteosarcoma patients (n=233), we validated that a higher level of the p27 autoantibody significantly correlated with poor overall and event-free survival (p < 0.05). Immunohistochemical analysis also showed that p27 was mislocalized to the cytoplasm in the majority of osteosarcoma cases and in highly metastatic osteosarcoma cell lines. We demonstrated that ectopic expression of cytoplasmic p27 promoted migration and invasion of osteosarcoma cells, whereas shRNA-mediated gene silencing suppressed these effects. Additionally, mutations at the p27 phosphorylation sites S10 or T198, but not T157, abolished the migratory and invasive phenotypes. Furthermore, the development of pulmonary metastases increased in mice injected with cells expressing cytoplasmic p27 compared with an empty vector control. Collectively, our findings support further investigation of p27 as a potential prognostic biomarker and therapeutic target in osteosarcoma cases exhibiting aberrant p27 subcellular localization.