WNT5A promotes stemness characteristics in nasopharyngeal carcinoma cells leading to metastasis and tumorigenesis.
WNT5A promotes stemness characteristics in nasopharyngeal carcinoma cells leading to metastasis and tumorigenesis.
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WNT5A促进鼻咽癌细胞的干性特征，导致转移和肿瘤发生
DOI：
10.18632/oncotarget.3518
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发表时间：
2015-04-30
期刊：
影响因子：
--
通讯作者：
Qian CN
中科院分区：
文献类型：
--
作者：
Qin L;Yin YT;Zheng FJ;Peng LX;Yang CF;Bao YN;Liang YY;Li XJ;Xiang YQ;Sun R;Li AH;Zou RH;Pei XQ;Huang BJ;Kang TB;Liao DF;Zeng YX;Williams BO;Qian CN
鼻咽癌是头颈部肿瘤中转移率最高的肿瘤，其发生机制尚不清楚。WNT5A属于WNT家族富含半胱氨酸的分泌型糖蛋白。我们之前的高通量基因表达谱显示Wnt5A在高转移细胞中上调。在本研究中，我们首先证实了Wnt5A在转移性鼻咽癌组织中的表达在mRNA和蛋白水平上的升高。我们发现Wnt5A促进鼻咽癌细胞上皮-间充质转化(EMT)，诱导CD24-CD44+细胞聚集和侧集，这被认为是肿瘤干细胞的特征。此外，Wnt5A在体外促进了鼻咽癌细胞的迁移和侵袭，而体内重组Wnt5A治疗则促进了肺转移。敲除Wnt5A基因可降低鼻咽癌的体内致瘤性。当Wnt5A的高表达与Vimentin的高表达在鼻咽癌中的表达一致时，患者的预后较差。在鼻咽癌细胞的主要信号通路中，蛋白激酶C(PKC)信号是由Wnt5A激活的。Wnt5A与磷酸化PKC之间存在促进EMT的正反馈环。综上所述，这些数据表明，Wnt5A是促进鼻咽癌干细胞特性、导致肿瘤发生和转移的重要分子。
Nasopharyngeal carcinoma (NPC) has the highest metastasis rate among head and neck cancers with unclear mechanism. WNT5A belongs to the WNT family of cysteine-rich secreted glycoproteins. Our previous high-throughput gene expression profiling revealed that WNT5A was up-regulated in highly metastatic cells. In the present study, we first confirmed the elevated expression of WNT5A in metastatic NPC tissues at both the mRNA and protein levels. We then found that WNT5A promoted epithelial-mesenchymal transition (EMT) in NPC cells, induced the accumulation of CD24-CD44+ cells and side population, which are believed to be cancer stem cell characteristics. Moreover, WNT5A promoted the migration and invasion of NPC cells in vitro, while in vivo treatment with recombinant WNT5A promoted lung metastasis. Knocking down WNT5A diminished NPC tumorigenesis in vivo. When elevated expression of WNT5A coincided with the elevated expression of vimentin in the primary NPC, the patients had a poorer prognosis. Among major signaling pathways, protein kinase C (PKC) signaling was activated by WNT5A in NPC cells. A positive feedback loop between WNT5A and phospho-PKC to promote EMT was also revealed. Taken together, these data suggest that WNT5A is an important molecule in promoting stem cell characteristics in NPC, leading to tumorigenesis and metastasis.
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