IRX1 hypomethylation promotes osteosarcoma metastasis via induction of CXCL14/NF-κB signaling
IRX1 hypomethylation promotes osteosarcoma metastasis via induction of CXCL14/NF-κB signaling
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DOI：
10.1172/jci78437
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发表时间：
2015-05-01
影响因子：
15.9
通讯作者：
Wang, Jin
中科院分区：
文献类型：
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作者：
Lu, Jinchang;Song, Guohui;Wang, Jin
骨肉瘤是一种常见的恶性骨肿瘤，有向肺部转移的倾向。表观遗传学异常已被证明是骨肉瘤发生的基础，然而，表观遗传学机制，参与转移还不清楚。在这里，我们分析了2个同基因的原代人骨肉瘤细胞系，表现出不同的表观遗传修饰和表达的差异转移潜力。利用甲基化DNA免疫沉淀（MeDIP）和微阵列表达分析筛选转移相关基因，我们确定了易洛魁同源框1（IRX 1）。在人骨肉瘤细胞系和临床骨肉瘤组织中，IRX 1过表达与其自身启动子的低甲基化密切相关。此外，IRX 1在骨肉瘤细胞系中的实验调节深刻地改变了转移活性，包括迁移、侵袭和体外抗失巢凋亡，并影响了小鼠模型中的肺转移。IRX 1的这些促转移作用是通过上调CXCL 14/NF-κ B信号传导介导的。在骨肉瘤患者的血清中，循环肿瘤DNA中IRX 1低甲基化的存在降低了无肺转移生存率。总之，这些结果确定IRX 1作为促转移基因，暗示IRX 1低甲基化作为肺转移的潜在分子标记，并表明IRX 1活化的表观遗传逆转可能有利于控制骨肉瘤转移。
Osteosarcoma is a common malignant bone tumor with a propensity to metastasize to the lungs. Epigenetic abnormalities have been demonstrated to underlie osteosarcoma development; however, the epigenetic mechanisms that are involved in metastasis are not yet clear. Here, we analyzed 2 syngeneic primary human osteosarcoma cell lines that exhibit disparate metastatic potential for differences in epigenetic modifications and expression. Using methylated DNA immunoprecipitation (MeDIP) and microarray expression analysis to screen for metastasis-associated genes, we identified Iroquois homeobox 1 (IRX1). In both human osteosarcoma cell lines and clinical osteosarcoma tissues, IRX1 overexpression was strongly associated with hypomethylation of its own promoter. Furthermore, experimental modulation of IRX1 in osteosarcoma cell lines profoundly altered metastatic activity, including migration, invasion, and resistance to anoikis in vitro, and influenced lung metastasis in murine models. These prometastatic effects of IRX1 were mediated by upregulation of CXCL14/NF-kappa B signaling. In serum from osteosarcoma patients, the presence of IRX1 hypomethylation in circulating tumor DNA reduced lung metastasis free survival. Together, these results identify IRX1 as a prometastatic gene, implicate IRX1 hypomethylation as a potential molecular marker for lung metastasis, and suggest that epigenetic reversion of IRX1 activation may be beneficial for controlling osteosarcoma metastasis.