Qi Lisha, Sun Baocun, Liu Zhiyong, Cheng Runfen, Li Yixian, Zhao Xiulan
Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.
The Key Laboratory of Tianjin Cancer Prevention and Treatment, Tianjin, 300060, China.
J Exp Clin Cancer Res. 2014 Dec 11;33(1):107. doi: 10.1186/s13046-014-0107-4.
Epithelial-mesenchymal transition (EMT) contributes to the progression and metastasis of cancer cells and is associated with a more invasive phenotype of cancer. The Wnt/β-catenin signaling pathway is one of the major pathways involved in EMT regulation. Many studies provide evidence that β-catenin, the key regulator of the canonical Wnt signaling pathway, is important in regulating EMT in cancer. However, the roles of Wnt3a, the representative canonical Wnt ligand, in EMT and colon cancer progression have not yet been fully explored.
The expression levels of Wnt3a and EMT-associated proteins (E-cadherin, vimentin, and β-catenin) were assessed by immunohistochemistry in human colon cancer tissues to evaluate the clinicopathological significance of Wnt3a, as well as the correlation between Wnt3a and EMT. We then upregulated Wnt3a expression in HCT116 colon cancer cells, established a nude mouse xenograft model, detected the expression of EMT and Wnt/β-catenin signaling-associated proteins, and observed invasion and clone-initiating abilities.
In 203 human colon cancer tissue samples, Wnt3a protein overexpression was related to colon cancer histological differentiation (P = 0.004), clinical stage (P = 0.008), presence of metastasis and recurrence (P = 0.036), and survival time (P = 0.007) of colon cancer patients. Wnt3a expression was notably concomitant with EMT immunohistochemical features, such as reduced expression of the epithelial marker E-cadherin (P = 0.012), increased expression of the mesenchymal marker vimentin (P = 0.002), and cytoplasmic distribution of β-catenin (P = 0.021). Results of in vitro and in vivo experiments showed that Wnt3a overexpression could alter cell morphology, regulate EMT-associated protein expression, and enhance clone-initiation and invasion. Dkk1 (antagonist of Wnt/β-catenin signaling) could also partially reverse the expression of EMT-associated proteins in Wnt3a-overexpressing cells.
Wnt3a expression was associated with EMT and promoted colon cancer progression. The EMT-inducing effect was partially due to the stimulative effect of Wnt3a on the Wnt/β-catenin pathway.
上皮-间质转化（EMT）促进癌细胞的进展和转移，并与癌症更具侵袭性的表型相关。Wnt/β-连环蛋白信号通路是参与EMT调节的主要通路之一。许多研究表明，经典Wnt信号通路的关键调节因子β-连环蛋白在调节癌症中的EMT方面很重要。然而，代表性的经典Wnt配体Wnt3a在EMT和结肠癌进展中的作用尚未得到充分探索。
通过免疫组织化学评估人结肠癌组织中Wnt3a和EMT相关蛋白（E-钙黏蛋白、波形蛋白和β-连环蛋白）的表达水平，以评估Wnt3a的临床病理意义以及Wnt3a与EMT之间的相关性。然后我们上调HCT116结肠癌细胞中Wnt3a的表达，建立裸鼠异种移植模型，检测EMT和Wnt/β-连环蛋白信号相关蛋白的表达，并观察侵袭和克隆起始能力。
在203份人结肠癌组织样本中，Wnt3a蛋白过表达与结肠癌组织学分化（P = 0.004）、临床分期（P = 0.008）、转移和复发情况（P = 0.036）以及结肠癌患者的生存时间（P = 0.007）相关。Wnt3a的表达明显与EMT免疫组织化学特征相关，如上皮标志物E-钙黏蛋白表达降低（P = 0.012）、间充质标志物波形蛋白表达增加（P = 0.002）以及β-连环蛋白的细胞质分布（P = 0.021）。体外和体内实验结果表明，Wnt3a过表达可改变细胞形态，调节EMT相关蛋白表达，并增强克隆起始和侵袭能力。Dkk1（Wnt/β-连环蛋白信号的拮抗剂）也可部分逆转Wnt3a过表达细胞中EMT相关蛋白的表达。
Wnt3a表达与EMT相关，并促进结肠癌进展。EMT诱导作用部分归因于Wnt3a对Wnt/β-连环蛋白通路的刺激作用。
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