Fucosylated TGF-β receptors transduces a signal for epithelial–mesenchymal transition in colorectal cancer cells

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.

Epithelial–mesenchymal transition in colorectal cancer metastasis: A system review

“…Taken together, these findings suggest that loss of Smad4 may underlie the functional shift of TGF-␤ and BMP from a tumor suppressor to a tumor promoter. In addition, fucosylated TGF-␤ receptors are able to transduce a signal for EMT in CRC cells [74].…”

Selectin Ligands Sialyl-Lewis a and Sialyl-Lewis x in Gastrointestinal Cancers

“…For instance, the expression of the metastasis-suppressive gene Nm23-H1 in a human hepatocarcinoma cell line induces down-regulation of both FUTs and ST3GALs, resulting in reduced sLe x expression [62]. On the other hand, sLe antigens expressed on the TGF-β receptor enhance colon cancer cell migration through promotion of the epithelial to mesenchymal transition [63], which instead was found associated to the activity of the ST6GAL1 gene in other cancer cell lines [64]. …”

Targeting Notch-1 positive acute leukemia cells by novel fucose-bound liposomes carrying daunorubicin

“…These observations indicate a high requirement for L-fucose by various cancer cells [15]. Indeed, we, together with others, have reported that enhanced FUT activity facilitated the metastatic potential of colorectal cancer cells, thus highlighting this as a therapeutic target for cancer therapy [16]. …”

“…Such findings demonstrated that Notch-1 signaling maintained tumor growth, antiapoptotic signaling, epithelial-mesenchymal transition for cancer cell metastasis, angiogenesis, and cancer stem cell survival [5]. Our strategy to target cancer cells, which actively take up L-fucose to produce fucosylated proteins such as sialylated antigens and growth factors in response to Notch-1 activation, can be utilized for killing Notch-1-expressing cancer cells in the same manner [16]. As described in this report, our drug delivery system has the potential to specifically target cancer cells with reduced toxicity and high efficacy.…”