Loss of VHL expression contributes to epithelial-mesenchymal transition in oral squamous cell carcinoma.
Loss of VHL expression contributes to epithelial-mesenchymal transition in oral squamous cell carcinoma.
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DOI：
10.1016/j.oraloncology.2014.06.007
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发表时间：
2014-09
期刊：
影响因子：
4.8
通讯作者：
Shu Zhang;Xuan Zhou;Bo Wang;Kailiang Zhang;Supriya K Liu;K. Yue;Lun Zhang;Xudong Wang
中科院分区：
文献类型：
--
作者：
Shu Zhang;Xuan Zhou;Bo Wang;Kailiang Zhang;Supriya K Liu;K. Yue;Lun Zhang;Xudong Wang
目的冯·希佩尔-林道(Von Hippel-Lindau，VHL)基因表达缺失与人类肿瘤的发生发展有关。然而，其在口腔鳞状细胞癌(OSCC)中的作用仍不明确。本研究的目的是明确口腔鳞癌组织中VHL的表达，探讨VHL在口腔鳞癌上皮-间充质转化过程中的作用机制。材料与方法应用免疫组织化学方法检测口腔鳞癌组织中VHL、HIF-1α和间质转化相关蛋白的表达。分析VHL与临床病理特征、预后及EMT相关蛋白的关系。以Tscca和Tca8113P160细胞为研究对象，通过四甲基偶氮唑盐比色试验、划痕实验和侵袭实验观察VHL对细胞形态、增殖、迁移和侵袭的影响。结果VHL表达缺失与口腔鳞癌的病理分级、淋巴结转移、预后不良及EMT密切相关。VHL重新表达后，细胞形态发生改变，细胞的动力、增殖、侵袭受到抑制。转染VHL后，Snail、N-钙粘蛋白和基质金属蛋白酶-2/9、缺氧诱导因子-1α和血管内皮生长因子的表达均下调，而E-钙粘附素的表达上调。免疫印迹和免疫荧光显示VHL可抑制β-catenin在细胞核内的积聚。结论VHL与口腔鳞癌的侵袭过程密切相关。β-catenin是口腔鳞癌中除HIF-1α外的重要下游基因，可诱导口腔鳞癌发生、发展过程。
ObjectiveLoss of Von Hippel–Lindau (VHL) gene expression has been implicated in the development of human cancers. However, its function in oral squamous cell carcinoma (OSCC) remains undefined. The aim of this study was to clarify the VHL expression in OSCC and to explore the underlying mechanisms of VHL in modulating the epithelial–mesenchymal transition (EMT) in OSCC.Materials and methodsThe expression of VHL, HIF-1α and EMT related proteins in OSCC tissues were evaluated by immunohistochemistry. The correlation of VHL with clinico-pathological characteristics, prognosis and EMT related proteins were analyzed. The roles of VHL on the cell morphology, proliferation, migration, and invasion were determined by MTT, scratch and transwell invasion assay in Tscca and Tca8113P160 cells. The EMT related proteins were determined by Western blot and immunofluorescence (IF) methods.ResultsLoss of VHL expression was closely associated with pathologic grading, lymph node metastasis, poor prognosis, and EMT in OSCC. After re-expression of VHL, there was a cell morphologic change and motivation, proliferation, invasion of the cells were inhibited. The expression of Snail, N-cadherin and MMP-2/9, HIF-1α and VEGF were down-regulated in both the cell lines after transfection with VHL plasmid, while E-cadherin was up-regulated. Moreover, the effect of VHL suppressing β-catenin accumulation in nucleus was proved by Western blot and IF.ConclusionVHL was significantly correlated with EMT process of OSCC. β-Catenin was an important downstream gene of VHL besides HIF-1α, which could induce the EMT process in OSCC.