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Transcription factors c-Myc and CDX2 mediate E-selectin ligand expression in colon cancer cells undergoing EGF/bFGF-induced epithelial-mesenchymal transition

Division of Molecular Pathology, Aichi Cancer Center, Chikusa-ku, Nagoya, Aichi 464-8681, Japan.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 04/2012; 109(20):7776-81. DOI: 10.1073/pnas.1111135109
Source: PubMed

ABSTRACT 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.

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    • "TNF-α stimulates the expression of selectin ligands through different mechanisms: in lung cells through stimulation of ST3GAL4 [72] [81], in prostate cancer cells through up-regulation of ST3GAL3 and other glycosyltransferases [82]. Epithelial to mesenchymal transition (EMT), a crucial event in metastasis formation of epithelial tumors, induced by EGF or bFGF treatment of colon cancer cells, produced expression of sLe x /sLe a antigens [83] through the transcriptional activation of sialyltransferases ST3GAL1, -3-and -4 (and of FUT3), mediated by c-myc [83]. The transcription of ST3GAL6, also involved in sLe x biosynthesis , is increased by treatment with 5-aza-2′-deoxycytidine, a drug which inhibits DNA methylation [84]. "
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    ABSTRACT: Background: Glycosylation is increasingly recognized as one of the most relevant postranslational modifications. Sialic acids are negatively charged sugars which frequently terminate the carbohydrate chains of glycoproteins and glycolipids. The addition of sialic acids is mediated by sialyltransferases, a family of glycosyltransferases with a crucial role in cancer progression. Scope of the review: To describe the phenotypic and clinical implications of altered expression of sialyltransferases and of their cognate sialylated structures in cancer. To propose a unifying model of the role of sialyltransferases and sialylated structures on cancer progression. Major conclusions: We first discuss the biosynthesis and the role played by the major cancer-associated sialylated structures, including Thomsen-Friedenreich-associated antigens, sialyl Lewis antigens, alpha 2,6-sialylated lactosamine, polysialic acid and gangliosides. Then, we show that altered sialyltransferase expression in cancer, consequence of genetic and epigenetic alterations, generates a flow of information toward the membrane through the biosynthesis of aberrantly sialylated molecules (inside-out signaling). In turn, the presence of aberrantly sialylated structures on cell membrane receptors generates a flow of information toward the nucleus, which can exacerbate the neoplastic phenotype (outside-in signaling). We provide examples of self-fueling loops generated by these flows of information. General significance: Sialyltransferases have a wide impact on the biology of cancer and can be the target of innovative therapies. Our unified view provides a conceptual framework to understand the impact of altered glycosylation in cancer.
    Biochimica et Biophysica Acta (BBA) - General Subjects 06/2014; 1840(9). DOI:10.1016/j.bbagen.2014.06.006 · 3.83 Impact Factor
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    • "TNF-α stimulates the expression of selectin ligands through different mechanisms: in lung cells through stimulation of ST3GAL4 [72] [81], in prostate cancer cells through up-regulation of ST3GAL3 and other glycosyltransferases [82]. Epithelial to mesenchymal transition (EMT), a crucial event in metastasis formation of epithelial tumors, induced by EGF or bFGF treatment of colon cancer cells, produced expression of sLe x /sLe a antigens [83] through the transcriptional activation of sialyltransferases ST3GAL1, -3-and -4 (and of FUT3), mediated by c-myc [83]. The transcription of ST3GAL6, also involved in sLe x biosynthesis , is increased by treatment with 5-aza-2′-deoxycytidine, a drug which inhibits DNA methylation [84]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Glycosylation is increasingly recognized as one of the most relevant postranslational modifications. Sialic acids are negatively charged sugars which frequently terminate the carbohydrate chains of glycoproteins and glycolipids. The addition of sialic acids is mediated by sialyltransferases, a family of glycosyltransferases with a crucial role in cancer progression. Scope of the review To describe the phenotypic and clinical implications of altered expression of sialyltransferases and of their cognate sialylated structures in cancer. To propose a unifying model of the role of sialyltransferases and sialylated structures on cancer progression. Major conclusions We first discuss the biosynthesis and the role played by the major cancer-associated sialylated structures, including Thomsen-Friedenreich-associated antigens, sialyl Lewis antigens, α2,6-sialylated lactosamine, polysialic acid and gangliosides. Then, we show that altered sialyltransferase expression in cancer, consequence of genetic and epigenetic alterations, generates a flow of information toward the membrane through the biosynthesis of aberrantly sialylated molecules (inside-out signaling). In turn, the presence of aberrantly sialylated structures on cell membrane receptors generates a flow of information toward the nucleus, which can exacerbate the neoplastic phenotype (outside-in signaling). We provide examples of self-fueling loops generated by these flows of information. General significance Sialyltransferases have a wide impact on the biology of cancer and can be the target of innovative therapies. Our unified view provides a conceptual framework to understand the impact of altered glycosylation in cancer.
    Biochimica et Biophysica Acta (BBA) - General Subjects 01/2014; 2014. · 3.83 Impact Factor
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    • "Nevertheless, further investigation will be necessary to clarify the sites within TbRs that are fucosylated by FUT3 and FUT6, and the mechanism of crosstalk in growth factor signalling induced by other FUTs such as FUT1, 8. Overexpression of FUT3 and FUT6 might be predictive of a poor prognosis in patients with CRC not only because of the increased interaction between E-selectin and endothelial cells through sLe a /sLe x but also via activation of TGF-b signalling through EMT, leading to enhanced metastatic potential. It should be noted that EGF/bFGF signalling augments EMT by inducing sLe a /sLe x expression (Sakuma et al, 2012). In our preliminary examination, we observed that 80% of stage IV patients were positive for both FUT3 and FUT6 expressions (data not shown), although we could not show a significant correlation between the metastatic stage and FUT3/6 expression due to the small size of the study. "
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    ABSTRACT: Background: Transforming growth factor-β (TGF-β) is a major inducer of epithelial–mesenchymal transition (EMT) in different cell types. TGF-β-mediated EMT is thought to contribute to tumour cell spread and metastasis. Sialyl Lewis antigens synthesised by fucosyltransferase (FUT) 3 and FUT6 are highly expressed in patients with metastatic colorectal cancer (CRC) and are utilised as tumour markers for cancer detection and evaluation of treatment efficacy. However, the role of FUT3 and FUT6 in augmenting the malignant potential of CRC induced by TGF-β is unclear. Methods: Colorectal cancer cell lines were transfected with siRNAs for FUT3/6 and were examined by cell proliferation, invasion and migration assays. The expression and phosphorylation status of TGF-β downstream molecules were analysed by western blot. Fucosylation of TGF-β receptor (TβR) was examined by lectin blot analysis. Results: Inhibition of FUT3/6 expression by siRNAs suppressed the fucosylation of type I TβR and phosphorylation of the downstream molecules, thereby inhibiting the invasion and migration of CRC cells by EMT. Conclusion: Fucosyltransferase 3/6 has an essential role in cancer cell adhesion to endothelial cells by upregulation of sialyl Lewis antigens and also by enhancement of cancer cell migration through TGF-β-mediated EMT.
    British Journal of Cancer 11/2013; 110(1). DOI:10.1038/bjc.2013.699 · 4.82 Impact Factor
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