CIZ/NMP4 is expressed in B16 melanoma and forms a positive feedback loop with RANKL to promote migration of the melanoma cells
CIZ/NMP4 is expressed in B16 melanoma and forms a positive feedback loop with RANKL to promote migration of the melanoma cells
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DOI：
10.1002/jcp.24066
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发表时间：
2012-07-01
影响因子：
5.6
通讯作者：
Noda, Masaki
中科院分区：
文献类型：
--
作者：
Sakuma, Tomomi;Nakamoto, Tetsuya;Noda, Masaki
肿瘤转移到骨是一种严重的病理情况，会导致剧烈疼痛和排尿功能恶化。然而，肿瘤转移的机制仍不完全清楚。CIZ/NMP 4是一种核质穿梭蛋白，其在肿瘤细胞中的作用尚不清楚。因此，我们假设CIZ/NMP 4在转移到骨的B16黑色素瘤细胞中的作用。CIZ/NMP 4在B16细胞中表达。CIZ/NMP 4表达水平与不同类型黑素瘤细胞的转移活性相关。在Trans-well实验中，CIZ/NMP 4的过表达增加了B16细胞的迁移。相反，基于siRNA的CIZ/NMP 4敲低抑制了这些细胞的迁移活性。由于RANKL促进骨中肿瘤细胞的转移，我们测试了其对黑色素瘤细胞中CIZ的影响。RANKL处理增强CIZ/NMP 4表达。RANKL导致的CIZ增加促进了迁移。相反，我们在RANKL的启动子中鉴定了CIZ/NMP 4结合位点。此外，荧光素酶分析表明，CIZ/NMP 4过表达增强RANKL启动子活性，揭示了CIZ/NMP 4和RANKL在黑色素瘤中的正反馈环。这些观察结果表明CIZ/NMP 4是黑素瘤细胞转移的关键调节剂。J.细胞。227：28072812，2012。(C)2012 Wiley Periodicals，Inc.
Tumor metastasis to bone is a serious pathological situation that causes severe pain, and deterioration in locomoter function. However, the mechanisms underlying tumor metastasis is still incompletely understood. CIZ/NMP4 is a nucleocytoplasmic shuttling protein and its roles in tumor cells have not been known. We, therefore, hypothesized the role of CIZ/NMP4 in B16 melanoma cells that metastasize to bone. CIZ/NMP4 is expressed in B16 cells. The CIZ/NMP4 expression levels are correlated to the metastatic activity in divergent types of melanoma cells. Overexpression of CIZ/NMP4 increased B16 cell migration in Trans-well assay. Conversely, siRNA-based knockdown of CIZ/NMP4 suppressed migratory activity of these cells. As RANKL promotes metastasis of tumor cells in bone, we tested its effect on CIZ in melanoma cells. RANKL treatment enhanced CIZ/NMP4 expression. This increase of CIZ by RANKL promoted migration. Conversely, we identified CIZ/NMP4 binding site in the promoter of RANKL. Furthermore, luciferase assay indicated that CIZ/NMP4 overexpression enhanced RANKL promoter activities, revealing a positive feedback loop of CIZ/NMP4 and RANKL in melanoma. These observations indicate that CIZ/NMP4 is critical regulator of metastasis of melanoma cells. J. Cell. Physiol. 227: 28072812, 2012. (C) 2012 Wiley Periodicals, Inc.