EphB2 promotes cervical cancer progression by inducing epithelial-mesenchymal transition
EphB2 promotes cervical cancer progression by inducing epithelial-mesenchymal transition
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DOI：
10.1016/j.humpath.2013.10.001
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发表时间：
2014-02-01
期刊：
影响因子：
3.3
通讯作者：
Li, Zongfang
中科院分区：
文献类型：
--
作者：
Gao, Qing;Liu, Wei;Li, Zongfang
EphB2是一种肾上腺素配体的受体酪氨酸激酶，在多种癌症中过表达，在肿瘤进展中发挥重要作用。然而，EphB2在宫颈癌中的表达和功能尚不清楚。在本研究中，我们对临床宫颈标本进行了免疫组织化学染色，发现EphB2在宫颈癌标本中过表达，并且其表达与宫颈癌的进展有关。EphB2阳性细胞比例从正常宫颈的28%逐渐增加到高度鳞状上皮内病变的40%，最终在鳞状细胞癌中增加到69.8%(P<；0.05)。我们在HeLa细胞中过表达EphB2，在宫颈癌(C33A)细胞中沉默EphB2，分别表达低水平和高水平的EphB2。外源性EphB2促进细胞迁移、侵袭和上皮-间充质转化(EMT)特征，这是器官形成和癌症转移过程中发生的一个复杂过程，而EphB2沉默具有相反的效果(P<；0.05)。此外，含有外源性EphB2的HeLa细胞在体外表现出类似干细胞的状态，促进肿瘤球体的形成，并在体内显示出肿瘤形成的潜力(P<；0.05)，而在C33A细胞中沉默EphB2抑制了这些干细胞的特性(P<；0.05)。此外，我们还对宫颈癌的细胞内信号通路进行了研究，发现在临床标本中，R-RAS的表达与EphB2呈正相关，其活性受EphB2的调节。这些发现表明，EphB2通过激活R-RAS来协调EMT程序，从而在宫颈癌的进展中发挥重要作用。(C)2014 Elsevier Inc.保留所有权利。
EphB2, a receptor tyrosine kinase for ephrin ligands, is overexpressed in various cancers and plays an important role in tumor progression. However, the expression and functions of EphB2 in cervical cancer remain unknown. In this study, we performed immunohistochemistry in clinical cervical specimens and found that EphB2 was overexpressed in the cervical cancer specimens, and its expression correlated with cancer progression. The percentage of EphB2-positive cells increased gradually from 28% in the normal cervix to 40% in high-grade squamous intraepithelial lesions, and ultimately to 69.8% in squamous cell carcinomas (P < .05). We overexpressed EphB2 in HeLa cells and silenced EphB2 in cervical cancer (C33A) cells, which expressed low and high levels of EphB2, respectively. Exogenous EphB2 promoted cell migration, invasion, and an epithelial-mesenchymal transition (EMT) signature, which is a complex process that occurs during organogenesis and cancer metastasis, whereas EphB2 silencing had the opposite effect (P < .05). Furthermore, HeLa cells with exogenous EphB2 exhibited a stem cell like state that promoted tumorsphere formation in vitro and exhibited tumorigenesis potential in vivo (P < .05), whereas EphB2 silencing in C33A cells inhibited these stem cell properties (P < .05). In addition, we investigated the intracellular signaling pathways in cervical cancer and found that R-Ras expression correlated positively with EphB2 in clinical samples, and its activity was regulated by EphB2 in cervical cancer. These findings demonstrate that EphB2 plays an important role in cervical cancer progression by orchestrating an EMT program through R-Ras activation. (C) 2014 Elsevier Inc. All rights reserved.