Hmgb1 inhibits Klotho expression and malignant phenotype in melanoma cells by activating NF-κB.
Hmgb1 inhibits Klotho expression and malignant phenotype in melanoma cells by activating NF-κB.
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Hmgb1 通过激活 NF-κB 抑制黑色素瘤细胞中 Klotho 表达和恶性表型
DOI：
10.18632/oncotarget.12623
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发表时间：
2016-12-06
期刊：
影响因子：
--
通讯作者：
Xie H
中科院分区：
文献类型：
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作者：
Xie B;Cao K;Li J;Chen J;Tang J;Chen X;Xia K;Zhou X;Cheng Y;Zhou J;Xie H
黑色素瘤中炎症参与的分子和细胞机制尚未完全阐明。在本研究中，敲低Hmgb 1表达增加了黑色素瘤细胞的凋亡，降低了侵袭和p-NF-κB表达，但增加了Klotho蛋白水平。Hmgb 1敲低的影响被LPS克服。外源性Hmgb 1可显著降低黑色素瘤细胞的凋亡率，增加细胞侵袭力，增加p-NF-κB表达，降低Klotho蛋白水平。NF-κB抑制剂CAPE可拮抗外源性Hmgb 1的作用。Hmgb 1敲低激活了p-IGF 1 R/p-PI 3 K p-85/p-Akt/p-mTOR信号传导，但外源性Hmgb 1使其失活。Klotho基因表达的敲低显著降低了细胞凋亡，增加了黑色素瘤细胞的侵袭，并抑制了异种移植物A375肿瘤的生长。与正常和良性皮肤组织相比，黑素瘤组织中p-NF-κB染色阳性但Klotho染色阴性的细胞百分比显著较高。p-NF-κB蛋白阳性表达和Klotho蛋白阴性表达与黑色素瘤患者预后不良相关。多因素分析显示p-NF-κB / Klotho蛋白水平与总生存期之间存在独立相关性。结论：Hmgb 1可通过激活NF-κB信号通路抑制Klotho基因的表达，从而抑制黑素瘤细胞的恶性表型。
The molecular and cellular mechanisms behind the involvement of inflammation in melanoma have not been fully elucidated. In this study, knockdown of Hmgb1 expression increased apoptosis, reduced invasion and p-NF-κB expression, but increased Klotho protein level in melanoma tumor cells. The effect of Hmgb1 knockdown was overcome by LPS. Introduction of exogenous Hmgb1 significantly decreased apoptosis, increased invasion, elevated p-NF-κB, but lowered Klotho protein level in melanoma cells. The effect of exogenous Hmgb1 was agonized by NF-κB inhibitor CAPE. Hmgb1 knockdown activated, but exogenous Hmgb1 inactivated, p-IGF1R/p-PI3K p-85/p-Akt/p-mTOR signaling. Knockdown of Klotho gene expression significantly decreased apoptosis, increased invasion in melanoma cells, and inhibited xenograft A375 tumor growth. A significantly high percentage of cells stained positive for p-NF-κB, but negative for Klotho, in melanoma tissues compared to normal and benign skin tissues. The positive p-NF-κB and negative Klotho protein expression correlated with poor prognosis in melanoma patients. Multivariate analysis revealed an independent association between p-NF-κB / Klotho protein level and overall survival. In conclusion, Hmgb1 can inhibit Klotho gene expression and malignant phenotype in melanoma cells through activation of NF-κB signaling.