Prognostic significance of nuclear factor-kB p105/p50 in human melanoma and its role in cell migration
Prognostic significance of nuclear factor-kB p105/p50 in human melanoma and its role in cell migration
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DOI：
10.1158/0008-5472.can-05-4402
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发表时间：
2006-09-01
期刊：
影响因子：
11.2
通讯作者：
Li, Gang
中科院分区：
文献类型：
--
作者：
Gao, Kai;Dai, Derek L.;Li, Gang
转录因子核因子-κ B（NF-κ B B）家族在肿瘤的发病机制中起重要作用，是肿瘤治疗的潜在靶点。然而，有必要阐明NF-κ B成员的特异性功能，这将为选择性阻断和减少因非特异性抑制NF-κ B成员而导致的治疗副作用提供基础。本研究旨在探讨NF-κ B B p105/p50在黑色素瘤发病机制中的作用。我们发现，与正常痣相比，发育不良痣、原发性黑素瘤和转移性黑素瘤中NF-κ B p105/p50的表达显著增加（P = 0.0004，卡方检验）。此外，NF-κ B p105/p50核染色随着黑色素瘤进展而增加，并且强NF-κ B p105/p50核染色与肿瘤厚度> 2.0 min的患者的疾病特异性5年生存率呈负相关（P = 0.014，对数秩检验）。多因素考克斯回归分析显示NF-κ B B p105/p50的核表达是该亚组的独立预后因素。此外，我们发现NF-κ B B p50的上调增强了黑色素瘤细胞的迁移，而小干扰RNA敲低抑制了细胞迁移。此外，NF-κ B p50的过表达诱导RhoA活性和Rock介导的黑色素瘤细胞中应激纤维的形成。综上所述，我们的数据表明NF-κ B p105/p50可能是人类黑色素瘤进展和预后的重要标志物，以及潜在的选择性治疗靶点。
Transcriptional factor nuclear factor-kappa B (NF-kappa B) family has been shown to play an important role in tumor pathogenesis and serve as a potential target in cancer therapy. However, it is necessary to clarify the specific functions of NF-kappa B members, which would provide the basis for the selective blockade and reduction of therapeutic side effects resulting from unspecific inhibition of NF-kappa B members. In this study, we explored the role of NF-kappa B p105/p50 in melanoma pathogenesis in vitro and in vivo. We found that the expression of NF-kappa B p105/p50 significantly increased in dysplastic nevi, primary melanoma, and metastatic melanoma compared with normal nevi (P = 0.0004, chi(2) test). Furthermore, NF-kappa B p105/p50 nuclear staining increased with melanoma progression and strong NF-kappa B p105/p50 nuclear staining was inversely correlated with disease-specific 5-year survival of patients with tumor thickness > 2.0 min (P = 0.014, log-rank test). Multivariate Cox regression analysis revealed that nuclear expression of NF-kappa B p105/p50 is an independent prognostic factor in this subgroup. Moreover, we found that upregulation of NF-kappa B p50 enhanced melanoma cell migration, whereas small interfering RNA knockdown inhibited cell migration. In addition, overexpression of NF-kappa B p50 induced RhoA activity and Rock-mediated formation of stress fiber in melanoma cells. Taken together, our data indicate that NF-kappa B p105/p50 may be an important marker for human melanoma progression and prognosis as well as a potentially selective therapeutic target.