卷曲蛋白2(Frizzled 2)表达在肝细胞癌中的临床意义及其与上皮-间质转化的关系

Clinical implication of Frizzled 2 expression and its association with epithelial-to-mesenchymal transition in hepatocellular carcinoma.

作者信息

Asano Tomonari, Yamada Suguru, Fuchs Bryan C, Takami Hideki, Hayashi Masamichi, Sugimoto Hiroyuki, Fujii Tsutomu, Tanabe Kenneth K, Kodera Yasuhiro

机构信息

Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.

Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.

出版信息

Int J Oncol. 2017 May;50(5):1647-1654. doi: 10.3892/ijo.2017.3937. Epub 2017 Mar 27.

Abstract

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.

摘要

上皮-间质转化(EMT)是肝细胞癌(HCC)肿瘤侵袭和转移的起始关键步骤。卷曲蛋白2(Fzd2)的表达可能通过非经典Wnt通路驱动EMT,非经典Wnt通路是众多EMT信号通路之一。在15种HCC细胞系中检测了上皮(E-钙黏蛋白)和间质(波形蛋白)标志物以及Wnt5b、Stat3、IL-6、Jak2和Fzd2的表达。通过免疫染色在100例HCC患者中评估EMT状态(波形蛋白与E-钙黏蛋白mRNA表达比值)、Fzd2 mRNA表达和pSTAT3蛋白表达,并分析它们的表达与临床病理因素及预后的相关性。在Fzd2基因敲低后评估细胞增殖、迁移和侵袭能力。Fzd2表达与HCC细胞系中的间质表型显著相关。用Fzd2 siRNA处理细胞系导致迁移和侵袭能力显著降低,但不影响增殖。在HCC患者中检测到EMT状态与Fzd2表达之间存在显著相关性。多因素分析显示Fzd2表达是复发的独立预测因子(P = 0.034)。Fzd2高表达患者的无复发生存期明显低于低表达患者(P = 0.03)。最后,pSTAT3表达与EMT和Fzd2状态显著相关(分别为P = 0.0028和P = 0.0066)。Fzd2表达诱导EMT并增强细胞迁移和侵袭能力,它可能是HCC复发的新预测因子。此外,Stat3可能受Wnt5/Fzd2和IL-6/Jak2信号通路共同调控,并在EMT中起重要作用。

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