Possible involvement of ΔNp63 downregulation in the invasion and metastasis of oral squamous cell carcinoma via induction of a mesenchymal phenotype
Possible involvement of ΔNp63 downregulation in the invasion and metastasis of oral squamous cell carcinoma via induction of a mesenchymal phenotype
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DOI：
10.1007/s10585-013-9628-z
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发表时间：
2014-03-01
影响因子：
4
通讯作者：
Nakamura, Seiji
中科院分区：
文献类型：
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作者：
Goto, Yuichi;Kawano, Shintaro;Nakamura, Seiji
上皮-间质转化（EMT）是一种重要的发育过程，参与肿瘤的进展。Delta Np 63是p53的同源物，与EMT程序有关，但详细的机制仍有待阐明。在这项研究中，我们研究了Delta Np 63在口腔鳞状细胞癌（OSCC）进展过程中EMT中的作用。使用了5种OSCC细胞系和78例OSCC患者的标本。在OSCC细胞中检测到Delta Np 63、p63 α、p63 β和上皮标志物（细胞角蛋白5和14）的表达，但在SQUU-B细胞（高转移潜能）中未检测到。上皮钙粘蛋白在所有口腔鳞癌细胞中均有表达。间充质标志物在SQUU-B细胞中强烈表达。敲低HSC-2细胞内源性Delta Np 63可诱导细胞形态学改变为梭形，上皮标记物表达减少，间充质标记物表达增加，迁移增加，增殖减少。相比之下，过表达Delta Np 63 β的SQUU-B细胞显示其形态从基质细胞样改变为上皮细胞。然而，E-cadherin的表达不受Delta Np 63敲低或过表达的影响。免疫组化染色显示，表达波形蛋白的癌细胞被发现在口腔鳞癌标本的浸润前沿。在这些细胞中Delta Np 63表达的强度也降低。有趣的是，波形蛋白阳性或Delta Np 63强度降低与OSCC患者的转移和预后不良呈正相关。这些结果表明，癌细胞中的Delta Np 63下调诱导与OSCC的肿瘤进展相关的间充质表型。
Epithelial-to-mesenchymal transition (EMT), an essential developmental program, is involved in tumor progression. Delta Np63, a homolog of p53, is associated with the EMT program, but the detailed mechanism remains to be elucidated. In this study, we investigated the role of Delta Np63 in EMT during progression of oral squamous cell carcinoma (OSCC). Five OSCC cell lines and specimens from 78 patients with OSCC were used. The expressions of Delta Np63, p63 alpha, p63 beta and epithelial markers (cytokeratins 5 and 14) was detected in the OSCC cells, but not in SQUU-B cells (high metastatic potential). E-cadherin was expressed in all OSCC cells. Mesenchymal markers were strongly expressed in the SQUU-B cells. Knockdown of endogenous Delta Np63 in HSC-2 cells induced morphological changes to the spindle shape, decreased the expression of epithelial markers, increased the expression of mesenchymal markers, increased migration and reduced proliferation. By contrast, SQUU-B cells overexpressing Delta Np63 beta showed changed their morphology from stromal cell-like to epithelial cells. However, E-cadherin expression was not affected by Delta Np63 knockdown or overexpression. Immunohistochemical staining revealed that cancer cells expressing vimentin were found at the invasive front in the OSCC specimens. The intensity of Delta Np63 expression was also decreased in these cells. Interestingly, the vimentin positivity or decreased intensity of Delta Np63 was positively associated with metastases and poor prognosis in the OSCC patients. These results indicated that Delta Np63 downregulation in cancer cells induces a mesenchymal phenotype that is related to tumor progression of OSCC.