Wnt is necessary for mesenchymal to epithelial transition in colorectal cancer cells
Wnt is necessary for mesenchymal to epithelial transition in colorectal cancer cells
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DOI：
10.1002/dvdy.24527
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发表时间：
2018-03-01
影响因子：
2.5
通讯作者：
Vincan, Elizabeth
中科院分区：
文献类型：
--
作者：
Schwab, Renate H. M.;Amin, Nancy;Vincan, Elizabeth
背景：转移是导致结直肠癌死亡的主要原因。癌细胞以单细胞或小细胞簇的形式在体内扩散，具有侵袭性、间充质、非增殖性表型。在继发部位，它们恢复为增殖性肿瘤，构建上皮表型以重建肿瘤。我们之前开发了一种独特的体外三维模型，称为LIM1863-Mph，它忠实地概括了这些支持结直肠癌转移的可逆转变。Wnt信号在这些转变中起着关键作用，并由细胞外Wnt与卷曲（FZD）的偶联启动。使用LIM1863-Mph模型系统，我们证明了Wnt受体FZD7是间充质向上皮转化（MET）所必需的。在这里，我们研究了Wnt在MET中的作用。结果：Wnt的分泌依赖于豪猪（PORC）的棕榈酰化。一种阻止Wnt分泌的PORC抑制剂（IWP2）阻断了间充质LIM1863-Mph细胞的上皮转化。Wnt基因阵列分析发现，与间充质LIM1863-Mph细胞相比，上皮细胞中有几种Wnt表达上调，表明这些配体存在于MET中。Wnt2B是差异表达量最大的Wnt基因。事实上，重组Wnt2B可以克服iwp2介导的间充质LIM1863-Mph细胞上皮转化的阻滞。结论：Wnt2B与Frizzled7协同介导MET在结直肠癌中的作用。科学通报，2018(7):521- 531。(c) 2017 Wiley期刊公司
Background: Metastasis underlies most colorectal cancer mortality. Cancer cells spread through the body as single cells or small clusters of cells that have an invasive, mesenchymal, nonproliferative phenotype. At the secondary site, they revert to a proliferative tumor constructing epithelial phenotype to rebuild a tumor. We previously developed a unique in vitro three-dimensional model, called LIM1863-Mph, which faithfully recapitulates these reversible transitions that underpin colorectal cancer metastasis. Wnt signaling plays a key role in these transitions and is initiated by the coupling of extracellular Wnt to Frizzled (FZD). Using the LIM1863-Mph model system we demonstrated that the Wnt receptor FZD7 is necessary for mesenchymal to epithelial transition (MET). Here we investigate the role of Wnt in MET. Results: Wnt secretion is dependent on palmitoylation by Porcupine (PORC). A PORC inhibitor (IWP2) that prevents Wnt secretion, blocked the epithelial transition of mesenchymal LIM1863-Mph cells. Wnt gene array analysis identified several Wnts that are upregulated in epithelial compared with mesenchymal LIM1863-Mph cells, suggesting these ligands in MET. Wnt2B was the most abundant differentially expressed Wnt gene. Indeed, recombinant Wnt2B could overcome the IWP2-mediated block in epithelial transition of mesenchymal LIM1863-Mph cells. Conclusions: Wnt2B co-operates with Frizzled7 to mediate MET in colorectal cancer. Developmental Dynamics 247:521-530, 2018. (c) 2017 Wiley Periodicals, Inc.