Laminin γ2 Mediates Wnt5a-Induced Invasion of Gastric Cancer Cells
Laminin γ2 Mediates Wnt5a-Induced Invasion of Gastric Cancer Cells
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DOI：
10.1053/j.gastro.2009.02.003
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发表时间：
2009-07-01
期刊：
影响因子：
29.4
通讯作者：
Kikuchi, Akira
中科院分区：
文献类型：
--
作者：
Yamamoto, Hideki;Kitadai, Yasuhiko;Kikuchi, Akira
背景与目的：Wnt 5a的表达通过未知的机制刺激体外培养的胃癌细胞的迁移和侵袭，并且还与胃肿瘤的侵袭性相关。本研究的目的是证实Wnt 5a参与胃癌细胞的体内转移，并探讨Wnt 5a调控胃癌细胞迁移和侵袭的分子机制。方法：将Wnt 5a基因敲减的胃癌细胞接种于裸鼠脾内，建立裸鼠肝转移模型。微阵列分析用于比较稳定表达野生型和不稳定形式的Wnt 5a的小鼠成纤维细胞L细胞之间的表达模式，以研究Wnt 5a依赖性基因表达。在培养的胃癌细胞中研究了发现受p53 5a调控的基因的表达。免疫组化分析，以测量153例胃癌标本中Wnt调控基因产物的水平。结果：胃癌细胞中Wnt 5a的敲低减少了裸鼠中形成的肝转移的数量。微阵列分析表明，Wnt 5a活性诱导的基因编码层粘连蛋白γ 2，上皮基底膜蛋白层粘连蛋白-5的亚基的表达。Wnt 5a通过激活蛋白激酶C和c-Jun-N-末端激酶诱导层粘连蛋白γ 2的表达。胃癌细胞的侵袭活性依赖于层粘连蛋白γ 2;在弥漫-分散型胃癌患者的样本中，Wnt 5a表达水平与层粘连蛋白γ 2的表达水平相关。结论：Wnt 5a通过增加转移潜力促进胃癌进展。wnt 5a上调层粘连蛋白γ 2介导胃癌细胞侵袭性。
BACKGROUND & AIMS: Wnt5a expression stimulates in vitro migration and invasion of cultured gastric cancer cells by an unknown mechanism and is also correlated with aggressiveness of gastric tumors. The aim of this study was to show that Wnt5a is involved in metastasis of gastric cancer cells in vivo and to explore the molecular mechanism by which Wnt5a regulates migration and invasion. METHODS: In an experimental liver metastasis assay, Wnt5a-knockdown gastric cancer cells were injected into the spleens of nude mice. Microarray anatyses were used to compare expression patterns between mouse fibroblast L cells that stably express wild-type and a inurant form of Wnt5a to investigate Wnt5a-dependent gene expression. The expression of genes found to be regulated by Writ5a was investigated in cultured gastric cancer cells. Immunohistochemical analyses were performed to measure levels of Wnt-regulated gene products in 153 gastric cancer samples. RESULTS: Knockdown of Wnt5a in gastric cancer cells reduced the number of liver metastases that formed in nude mice. Microarray analyses indicated that Wnt5a activity induced expression of the gene encoding laminin gamma 2, a subunit of the epithelial basement membrane protein laminin-5. Wnt5a induced the expression of laminin gamma 2 through the activation of protein kinase C and c-Jun-N-terminal kinase. The invasive activity of gastric cancer cells depended on laminin gamma 2; Wnt5a expression levels correlated with those of laminin gamma 2 in diffuse-scattered type gastric tumor samples from patients. CONCLUSIONS: Wnt5a contributes to gastric cancer progression by increasing metastatic potential. Wnt5a up-regulates laminin gamma 2 to mediate gastric cancer cell aggressiveness.