1045

CDX2

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.

The epithelialtomesenchymal transition (EMT) has been noted as a critical event in the early step of cancer metastasis. Recent studies showed that nuclear transcription factor caudal type homeobox transcription factor 2 (CDX2) is a prognostic factor, which acts as a marker of good outcome in gastric cancer (GC) patients. However, the association between CDX2 expression and EMT has remained to be fully elucidated. The present study reported that forced overexpression of CDX2 in MKN45/CDX2 cells inhibited GCcell growth and proliferation, and attenuated migration and invasion in vitro. Furthermore, MKN45/CDX2 cells exhibited a significant upregulation of Ecadherin protein and a significant downregulation of vimentin protein expression. These results were further supported by in vivo tumorigenicity assays, which showed that CDX2 suppressed gastric tumor xenograft growth and inhibited EMT in nude mice. These results indicated that CDX2 is capable of inhibiting GCcell growth and invasion. CDX2 may participate in the process of EMT of GC cells by regulating the expression of the epithelial and mesenchymal proteins Ecadherin and vimentin.