Clinical implication of Frizzled 2 expression and its association with epithelial-to-mesenchymal transition in hepatocellular carcinoma
Clinical implication of Frizzled 2 expression and its association with epithelial-to-mesenchymal transition in hepatocellular carcinoma
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DOI：
10.3892/ijo.2017.3937
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发表时间：
2017-05-01
影响因子：
5.2
通讯作者：
Kodera, Yasuhiro
中科院分区：
文献类型：
--
作者：
Asano, Tomonari;Yamada, Suguru;Kodera, Yasuhiro
上皮细胞向间质细胞转化（EMT）是肝细胞癌（HCC）侵袭和转移的起始、关键步骤。Frizzled 2（Fzd 2）表达可能通过非经典Wnt途径（多种EMT信号传导途径之一）驱动EMT。在15个HCC细胞系中检测上皮（E-cadherin）和间质（vimentin）标记物以及Wnt 5 b、Stat 3、IL-6、Jak 2和Fzd 2的表达。采用免疫组化法检测100例HCC患者的EMT状态（vimentin/E-cadherin mRNA表达比值）、Fzd 2 mRNA表达和pSTAT 3蛋白表达，并分析其表达与临床病理因素及预后的关系。在Fzd 2敲低后评估细胞增殖、迁移和侵袭性。Fzd 2表达与HCC细胞系中的间充质表型显著相关。用Fzd 2 siRNA处理细胞系导致迁移和侵袭力显著降低，但不影响增殖。HCC患者EMT状态与Fzd 2表达之间存在显著相关性。多因素分析显示，Fzd 2表达是复发的独立预测因子（P=0.034）。Fzd 2高表达患者的无复发生存率显著低于低表达患者（P=0.03）。最后，pSTAT 3表达与EMT和Fzd 2状态显著相关（分别为P=0.0028和P=0.0066）。Fzd 2表达可诱导EMT，增强细胞迁移和侵袭能力，可能是HCC复发的一个新的预测因子。此外，Stat 3可能受Wnt 5/Fzd 2和IL-6/Jak 2信号通路的共同调控，在EMT中发挥重要作用。
The epithelial-to-mesenchymal transition (EMT) is an initial, critical step in hepatocellular carcinoma (HCC) tumor invasion and metastasis. Frizzled 2 (Fzd2) expression might drive EMT through the non-canonical Wnt pathway, one of the various EMT signaling pathways. The expression of epithelial (E-cadherin) and mesenchymal (vimentin) markers, as well as that of Wnt5b, Stat3, IL-6, Jak2 and Fzd2, were measured in 15 HCC cell lines. The EMT status (vimentin to E-cadherin mRNA expression ratio), Fzd2 mRNA expression, and pSTAT3 protein expression were assessed by immunostaining in 100 HCC patients, and correlations of their expression with clinicopathological factors and prognosis were analyzed. Cell proliferation, migration, and invasiveness were assessed after Fzd2 knockdown. Fzd2 expression was significantly correlated with a mesenchymal phenotype in the HCC cell lines. Treatment of the cell lines with Fzd2 siRNA resulted in significantly reduced migration and invasiveness but did not affect proliferation. A significant correlation was detected between the EMT status and Fzd2 expression in the HCC patients. Multivariate analysis revealed that Fzd2 expression was an independent predictor of recurrence (P=0.034). Patients with high Fzd2 expression had significantly poorer recurrence-free survival than those with low expression (P=0.03). Finally, pSTAT3 expression was significantly correlated with the EMT and Fzd2 status (P=0.0028, and P=0.0066, respectively). Fzd2 expression induced EMT and enhanced cell migration and invasiveness, and it might be a novel predictor of HCC recurrence. Furthermore, Stat3 might be controlled by both the Wnt5/Fzd2 and IL-6/Jak2 signaling pathways and play an important role in EMT.