Schwab Renate H M, Amin Nancy, Flanagan Dustin J, Johanson Timothy M, Phesse Toby J, Vincan Elizabeth
Molecular Oncology Laboratory, University of Melbourne and the Victorian Infectious Diseases Reference Laboratory, Doherty Institute of Infection and Immunity, Melbourne, Victoria, Australia.
European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Cardiff, Wales, United Kingdom.
Dev Dyn. 2018 Mar;247(3):521-530. doi: 10.1002/dvdy.24527. Epub 2017 Jun 22.
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.
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.
Wnt2B co-operates with Frizzled7 to mediate MET in colorectal cancer. Developmental Dynamics 247:521-530, 2018. © 2017 Wiley Periodicals, Inc.
转移是大多数结直肠癌死亡的原因。癌细胞以单个细胞或小细胞簇的形式在体内扩散，这些细胞具有侵袭性、间充质、非增殖表型。在转移部位，它们会转变为增殖性的“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，它能忠实地重现这些支撑结直肠癌转移的可逆转变。Wnt信号通路在这些转变中起关键作用，由细胞外Wnt与卷曲蛋白（FZD）的偶联启动。利用LIM1863-Mph模型系统，我们证明Wnt受体FZD7对间充质向上皮转变（MET）是必需的。在此，我们研究Wnt在MET中的作用。
Wnt分泌依赖于刺猬蛋白（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细胞的上皮转变。Wnt基因阵列分析确定了几种在间充质LIM1863-Mph细胞与上皮细胞相比上调的Wnt，提示这些配体参与MET。Wnt2B是差异表达最丰富的Wnt基因。实际上，重组Wnt2B可以克服IWP2介导的间充质LIM1863-Mph细胞上皮转变阻滞。
Wnt2B与卷曲蛋白7协同作用介导结直肠癌中的MET。《发育动力学》247:521 - 530，2018年。©2017威利期刊公司。
