Lipocalin 2 Enhances Migration and Resistance against Cisplatin in Endometrial Carcinoma Cells.
Lipocalin 2 Enhances Migration and Resistance against Cisplatin in Endometrial Carcinoma Cells.
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DOI：
10.1371/journal.pone.0155220
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Shiozawa T
中科院分区：
文献类型：
--
作者：
Miyamoto T;Kashima H;Yamada Y;Kobara H;Asaka R;Ando H;Higuchi S;Ida K;Mvunta DH;Shiozawa T
Lipocalin 2(Lcn2)是一种分泌型蛋白，参与包括铁转运在内的多种生理过程。我们先前发现Lcn2基因在子宫内膜癌中上调，并发现Lcn2及其受体SLC22A17的过度表达与不良预后有关。然而，目前Lcn2的功能和作用机制尚不清楚。Lcn2高表达的子宫内膜癌细胞株HHUA和RL95-2，以及Lcn2低表达的细胞株HEC1B。分别采用划痕愈合实验、WST-1实验和Apostrand实验检测Lcn2在不同应激条件下对细胞迁移、细胞活力和细胞凋亡的影响。利用shRNA方法沉默Lcn2可显著降低细胞的迁移能力(p<；0.05)。与对照细胞相比，细胞毒性应激显著降低LCN2沉默细胞的存活率。相反，Lcn2过表达显著增加了顺铂的耐药性。这些影响可以通过添加铁络合剂去铁胺来消除。紫外线照射后，Lcn2沉默细胞中磷酸化Akt的表达降低，PI3K抑制剂可抵消Lcn2诱导的细胞对紫外线敏感性的差异。Lcn2对顺铂诱导的PAKT基因表达无明显影响，而Lcn2基因沉默可上调P53和p21的表达。这些结果表明，Lcn2以铁依赖的方式参与了子宫内膜癌细胞在不同应激状态下的迁移和存活。Lcn2的生存功能可能通过PI3K途径和抑制P53-p21途径发挥作用。Lcn2的这些功能可能会增加子宫内膜癌细胞的恶性潜能。
Lipocalin 2 (LCN2) is a secretory protein that is involved in various physiological processes including iron transport. We previously identified LCN2 as an up-regulated gene in endometrial carcinoma, and found that the overexpression of LCN2 and its receptor, SLC22A17, was associated with a poor prognosis. However, the functions and mechanism of action of LCN2 currently remain unclear. The LCN2-overexpressing endometrial carcinoma cell lines, HHUA and RL95-2, and LCN2-low-expressing one, HEC1B, were used. The effects of LCN2 on cell migration, cell viability, and apoptosis under various stresses, including ultraviolet (UV) irradiation and cisplatin treatment, were examined using the scratch wound healing assay, WST-1 assay, and Apostrand assay, respectively. LCN2-silencing using shRNA method significantly reduced the migration ability of cells (p<0.05). Cytotoxic stresses significantly decreased the viability of LCN2-silenced cells more than that of control cells. In contrast, LCN2 overexpression was significantly increased cisplatin resistance. These effects were canceled by the addition of the iron chelator, deferoxamine. After UV irradiation, the expression of phosphorylated Akt (pAkt) was decreased in LCN2-silenced cells, and the PI3K inhibitor canceled the difference induced in UV sensitivity by LCN2. The cisplatin-induced expression of pAkt was not affected by LCN2; however, the expression of p53 and p21 was increased by LCN2-silencing. These results indicated that LCN2 was involved in the migration and survival of endometrial carcinoma cells under various stresses in an iron-dependent manner. The survival function of LCN2 may be exerted through the PI3K pathway and suppression of the p53-p21 pathway. These functions of LCN2 may increase the malignant potential of endometrial carcinoma cells.