Role of Tip60 in Human Melanoma Cell Migration, Metastasis, and Patient Survival
Role of Tip60 in Human Melanoma Cell Migration, Metastasis, and Patient Survival
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Tip60 在人黑色素瘤细胞迁移、转移和患者生存中的作用
DOI：
10.1038/jid.2012.193
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发表时间：
2012-11-01
影响因子：
6.5
通讯作者：
Li, Gang
中科院分区：
文献类型：
--
作者：
Chen, Guangdi;Cheng, Yabin;Li, Gang
肿瘤抑制因子 Tip60 调节基因转录、DNA 损伤反应、细胞凋亡和癌症发展，但其在黑色素瘤中的作用尚不清楚。在本研究中，我们研究了 Tip60 在黑色素瘤中的表达模式并评估了其预后价值。使用由 448 例黑色素瘤（201 例为训练集，247 例为验证集）和 105 例痣组成的组织微阵列，我们发现与普通痣（P = 0.045）、发育不良痣（P = 0.047）和原发性黑色素瘤（P = 0.001）相比，转移性黑色素瘤中 Tip60 的表达显着降低。 Kaplan-Meier 生存曲线和单变量 Cox 回归分析表明，Tip60 表达减少与原发性黑色素瘤 (P = 0.016) 和转移性黑色素瘤患者 (P = 0.027) 较差的 5 年疾病特异性生存率相关。多变量 Cox 回归分析表明，Tip60 表达是原发性黑色素瘤 (P = 0.024) 和转移性黑色素瘤 (P = 0.035) 的独立预后标志物。体外伤口愈合测定表明，Tip60 的强制表达会受到抑制，但 Tip60 敲低会增强黑色素瘤细胞的迁移，表明 Tip60 可能调节黑色素瘤的转移。最后，我们发现黑色素瘤细胞中 Tip60 的过度表达导致化疗敏感性显着增加。我们的数据表明 Tip60 可以作为黑色素瘤患者预后的潜在生物标志物以及潜在的治疗靶点。
The tumor suppressor Tip60 regulates gene transcription, DNA damage response, apoptosis, and cancer development, but its role in melanoma is unknown. In this study, we investigated the expression pattern of Tip60 in melanoma and assessed its prognostic value. Using tissue microarrays consisting of 448 cases of melanomas (201 for the training set and 247 for the validation set) and 105 cases of nevi, we found that Tip60 expression was significantly reduced in metastatic melanoma compared to common nevi (P = 0.045), dysplastic nevi (P = 0.047), and primary melanoma (P = 0.001). Kaplan-Meier survival curve and univariate Cox regression analyses showed that reduced Tip60 expression was associated with a poorer 5-year disease-specific survival in primary melanoma (P = 0.016) and metastatic melanoma patients (P = 0.027). Multivariate Cox regression analyses indicated that Tip60 expression was an independent prognostic marker for primary (P = 0.024) and metastatic melanomas (P = 0.035). In vitro wound healing assay showed that enforced Tip60 expression inhibited but Tip60 knockdown enhanced melanoma cell migration, suggesting that Tip60 might regulate melanoma metastasis. Finally, we showed that overexpression of Tip60 in melanoma cells resulted in significantly increased chemosensitivity. Our data indicate that Tip60 may serve as a potential biomarker for melanoma patient outcome as well as a potential therapeutic target.