Involvement of the Wnt-β-catenin pathway in invasion and migration of oral squamous carcinoma cells
Involvement of the Wnt-β-catenin pathway in invasion and migration of oral squamous carcinoma cells
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DOI：
10.3892/ijo_00000761
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发表时间：
2010-11-01
影响因子：
5.2
通讯作者：
Yura, Yoshiaki
中科院分区：
文献类型：
--
作者：
Iwai, Soichi;Yonekawa, Atsuko;Yura, Yoshiaki
Wnt/β-连环蛋白通路在细胞增殖和肿瘤发生中起关键作用。为了阐明β-连环蛋白在口腔鳞状细胞癌（SCC）中胞浆积聚的作用，我们将缺失糖原合成酶激酶-3 β的整个区域的β-连环蛋白突变体的cDNA，将GSK-3 β特异性磷酸化位点转染到β-连环蛋白主要在膜上表达的Ca 9 -22细胞中，并产生在细胞质和细胞核中表达异常β-连环蛋白的永久细胞系。这些转染子，C1和C5，以类似的速度，父母的Ca 9 -22细胞增殖，但细胞形态从多边形变成梭形和细胞间的密切相互作用丢失。这些突变体β-连环蛋白表达细胞表现出比野生型Ca 9 -22细胞显著更高的侵袭/迁移能力。这种突变的β-连环蛋白形式的转录活性在这些细胞中增强，这可以通过转录因子T细胞因子（Tcf）/淋巴增强因子（Lef）依赖性报告基因活性的升高水平以及Wnt/β-连环蛋白靶基因基质金属蛋白酶（MMP）-7的上调来证明。此外，我们还观察到E-cadherin的重新分布，肌动蛋白丝的重排和活性Rho家族成员的升高。Cdc 42和Rae.这些结果表明，β-连环蛋白的异常细胞质积累可以诱导Tcf/Lef介导的转录活性，上调MMP-7，并诱导上皮和间充质转化（EMT）。这将促进口腔SCC细胞的侵袭和迁移。
The Wnt/beta-catenin pathway plays a critical role in cell proliferation and oncogenesis. To clarify the role of cytoplasmic accumulation of beta-catenin in oral squamous cell carcinoma (SCC), the cDNA of a mutant form of beta-catenin that lacks the entire region with the glycogen synthase kinase-3 beta (GSK-3 beta)-specific phosphorylation site was transfected into Ca9-22 cells whose beta-catenin had been expressed predominantly at the membrane, and permanent cell lines expressing aberrant beta-catenin in the cytoplasm and nucleus were produced. These transfectants, C1 and C5, proliferated at similar rates to the parental Ca9-22 cells, but the cell morphology changed from polygonal to spindle-shaped and close cell-cell interaction was lost. These mutant beta-catenin-expressing cells exhibited a significantly higher invasion/migration capacity than wild-type Ca9-22 cells. The transcriptional activities of this mutant beta-catenin form was enhanced in these cells which could be demonstrated by an elevated level of the transcription factor T-cell factor (Tcf)/lymphoid enhancer factor (Lef)-dependent reporter gene activity as well as by the up-regulation of Wnt/beta-catenin target gene matrix metalloproteinase (MMP)-7. Moreover, we observed the redistribution of E-cadherin, the rearrangement of actin filaments, and the elevation of active Rho family members. Cdc42 and Rae. These results suggest that aberrant cytoplasmic accumulation of beta-catenin can induce Tcf/Lef-mediated transcriptional activity, up-regulate MMP-7, and induce epithelial and mesenchymal transition (EMT). This would enhance the invasion and migration of oral SCC cells.