Transcription factors c-Myc and CDX2 mediate E-selectin ligand expression in colon cancer cells undergoing EGF/bFGF-induced epithelial-mesenchymal transition
Transcription factors c-Myc and CDX2 mediate E-selectin ligand expression in colon cancer cells undergoing EGF/bFGF-induced epithelial-mesenchymal transition
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DOI：
10.1073/pnas.1111135109
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发表时间：
2012-05-15
影响因子：
11.1
通讯作者：
Kannagi, Reiji
中科院分区：
文献类型：
--
作者：
Sakuma, Keiichiro;Aoki, Masahiro;Kannagi, Reiji
唾液酸刘易斯x（sLe（x））和唾液酸刘易斯a（sLe（a））聚糖在高转移性结肠癌细胞上表达。它们通过与内皮细胞上的E-选择素相互作用促进癌细胞外渗和肿瘤血管生成。最近，上皮间质转化（EMT）已被视为转移性癌细胞的关键表型改变。为了解决sLe（x/a）表达与EMT之间的关联，我们评估了sLe（x/a）是否在经历EMT的结肠癌细胞上高度表达。用EGF和/或碱性FGF（bFGF）处理HT 29和DLD-1细胞诱导EMT，并显著增加sLe（x/a）表达，导致E-选择素结合活性增强。糖基转移酶基因ST 3GAL 1/3/4和FUT 3的转录水平显著升高，而FUT 2的转录水平被治疗显著抑制。我们提供的证据表明，ST 3GAL 1/3/4和FUT 3是转录上调的c-Myc可能参与Ser 62磷酸化，和FUT 2是转录下调通过衰减CDX 2。通过敲低或强制表达实验证明c-Myc和CDX 2对sLe（x/a）诱导的贡献是显著的。有趣的是，经历EMT的细胞表现出显著增加的VEGF分泌，其可以与sLe（x/a）协同促进肿瘤血管生成。最后，免疫组织学研究表明，在体内经历EMT的癌细胞上高E-选择素配体表达，支持在体外观察到的它们的共存。这些结果表明sLe（x/a）表达与结肠癌细胞中的EMT之间存在显著联系，并且c-Myc和CDX 2在EMT期间调节sLe（x/a）表达中具有关键作用。
Sialyl Lewis x (sLe(x)) and sialyl Lewis a (sLe(a)) glycans are expressed on highly metastatic colon cancer cells. They promote extravasation of cancer cells and tumor angiogenesis via interacting with E-selectin on endothelial cells. Recently, epithelial-mesenchymal transition (EMT) has been noted as a critical phenotypic alteration in metastatic cancer cells. To address the association between sLe(x/a) expression and EMT, we assessed whether sLe(x/a) are highly expressed on colon cancer cells undergoing EMT. Treatment of HT29 and DLD-1 cells with EGF and/or basic FGF (bFGF) induced EMT and significantly increased sLe(x/a) expression resulting in enhanced E-selectin binding activity. The transcript levels of the glycosyltransferase genes ST3GAL1/3/4 and FUT3 were significantly elevated and that of FUT2 was significantly suppressed by the treatment. We provide evidence that ST3GAL1/3/4 and FUT3 are transcriptionally up-regulated by c-Myc with probable involvement of Ser62 phosphorylation, and that FUT2 is transcriptionally down-regulated through the attenuation of CDX2. The contribution of c-Myc and CDX2 to the sLe(x/a) induction was proved to be significant by knockdown or forced expression experiments. Interestingly, the cells undergoing EMT exhibited significantly increased VEGF secretion, which can promote tumor angiogenesis in cooperation with sLe(x/a). Finally, immunohistological study indicated high E-selectin ligand expression on cancer cells undergoing EMT in vivo, supporting their coexistence observed in vitro. These results suggest a significant link between sLe(x/a) expression and EMT in colon cancer cells and a pivotal role of c-Myc and CDX2 in regulating sLe(x/a) expression during EMT.