Article

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.

0 Bookmarks
 · 
86 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Tumor heterogeneity of adult high-grade glioma (HGG) is recognized in 3 major subtypes based on core gene signatures. However, the molecular signatures and clinical implications of glioma stem cells (GSCs) in individual HGG subtypes remain poorly characterized. Recently genome-wide transcriptional analysis identified two mutually exclusive GSC subtypes with distinct dysregulated signaling and metabolic pathways. Analysis of genetic profiles and phenotypic assays distinguished proneural (PN) from mesenchymal (MES) GSCs and revealed a striking correlation with the corresponding PN or MES HGGs. Similar to HGGs with a MES signature, MES GSCs display more aggressive phenotypes both in vitro and in vivo. Furthermore, MES GSCs are markedly resistant to radiation as compared with PN GSCs, consistent with the relative radiation resistance of MES GBM compared with other subtypes. A systems biology approach has identified a set of transcription factors as the master regulators for the MES signature. Metabolic reprogramming in MES GSCs has also been noticed with the prominent activation of the glycolytic pathway, comprising aldehyde dehydrogenase (ALDH) family genes. This review summarizes recent progress in the characterization of the molecular signature in distinct HGG and GSC subtypes and plasticity between different GSC subtypes as well as between GSCs and non-GSCs in HGG tumors. Clinical implications of the translational GSC research are also discussed.
    Journal of Neurosurgery 11/2014; 122(2):1-7. DOI:10.3171/2014.9.JNS132253 · 3.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The regulation of cardiac differentiation is critical for maintaining normal cardiac development and function. The precise mechanisms whereby cardiac differentiation is regulated remain uncertain. Here, we have identified a GATA-4 target, EGF, which is essential for cardiogenesis and regulates cardiac differentiation in a dose- and time-dependent manner. Moreover, EGF demonstrates functional interaction with GATA-4 in inducing the cardiac differentiation of P19CL6 cells in a time- and dose-dependent manner. Biochemically, GATA-4 forms a complex with STAT3 to bind to the EGF promoter in response to EGF stimulation and cooperatively activate the EGF promoter. Functionally, the cooperation during EGF activation results in the subsequent activation of cyclin D1 expression, which partly accounts for the lack of additional induction of cardiac differentiation by the GATA-4/STAT3 complex. Thus, we propose a model in which the regulatory cascade of cardiac differentiation involves GATA-4, EGF, and cyclin D1.
    Cellular and Molecular Life Sciences CMLS 12/2014; DOI:10.1007/s00018-014-1795-9 · 5.86 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Anterior gradient 2 (AGR2), a member of the protein disulfide isomerase family, has been implicated in various cancers including pancreatic ductal adenocarcinoma (PDAC) and is known to promote cancer progression. However, the prognostic value of AGR2 expression and the interaction with epithelial-mesenchymal transition (EMT) remain unclear. We investigated the clinical significance of AGR2 and EMT markers in PDAC patients by immunohistochemical analyses. Although AGR2 expression was not observed in normal pancreas, all pancreatic precursor neoplastic lesions were positive for AGR2, even at the earliest stages, including pancreatic intraepithelial neoplasia-1A, AGR2 expression was reduced in 27.7% (54/195 cases) of PDAC patients. AGR2 downregulation correlated with EMT markers (vimentin overexpression and reduced membranous E-cadherin expression), high Union for International Cancer Control stage (P<0.0001), high histological cellular grade (P<0.0001), and adverse outcome (P<0.0001). In vitro, targeted silencing of AGR2 in cancer cells using siRNA reduced cell proliferation, colony formation, cell invasiveness, and migration, but did not alter EMT markers. To confer a more aggressive phenotype and induce EMT in PDAC cells, we co-cultured PDAC cell lines with primary-cultured pancreatic stellate cells (PSCs) and found that AGR2 was downregulated in co-cultured PDAC cells compared with PDAC monocultures. Treatment with transforming growth factor beta-1 (TGF-β), secreted from PSCs, decreased AGR2 expression, whereas inhibition of TGF-β signaling using recombinant soluble human TGF-β receptor type II and TGF-β-neutralizing antibodies restored AGR2 expression. We conclude that AGR2 downregulation is a useful prognostic marker, induced by EMT, and that secreted TGF-β from PSCs may partially contribute to AGR2 downregulation in PDAC patients. AGR2 downregulation does not induce EMT or a more aggressive phenotype, but is a secondary effect of these processes in advanced PDAC.Laboratory Investigation advance online publication, 24 November 2014; doi:10.1038/labinvest.2014.138.
    Laboratory Investigation 11/2014; 95(2). DOI:10.1038/labinvest.2014.138 · 3.83 Impact Factor

Preview

Download
0 Downloads
Available from