Abstract
Simple SummaryThe major cause of death in cancer is that tumor cells metastasize (i.e., spread to vital organs such as the lungs and liver). Our knowledge of how metastasis occurs is incomplete and consequently, there is a lack of therapeutic strategies that target metastasis. Recent data show that inflammatory signals may influence tumor cells to undergo an identity switch, whereby they develop metastatic properties. Understanding how this identity switch is regulated is important to develop novel therapeutics. Recently, syndecan-1, a protein found on the surface of various cells, was shown to regulate the identity switch. In this study, we report that re-localization of syndecan-1 from the cell surface to the nucleus contributes to its capacity to regulate the identity switch in tumor cells. These results identify nuclear syndecan-1 as a regulator of the identity switch and open up to further studies to elucidate the mechanisms involved.Tumor cells undergoing epithelial-mesenchymal transition (EMT) lose cell surface adhesion molecules and gain invasive and metastatic properties. EMT is a plastic process and tumor cells may shift between different epithelial-mesenchymal states during metastasis. However, how this is regulated is not fully understood. Syndecan-1 (SDC1) is the major cell surface proteoglycan in epithelial cells and has been shown to regulate carcinoma progression and EMT. Recently, it was discovered that SDC1 translocates into the cell nucleus in certain tumor cells. Nuclear SDC1 inhibits cell proliferation, but whether nuclear SDC1 contributes to the regulation of EMT is not clear. Here, we report that loss of nuclear SDC1 is associated with cellular elongation and an E-cadherin-to-N-cadherin switch during TGF-β1-induced EMT in human A549 lung adenocarcinoma cells. Further studies showed that nuclear translocation of SDC1 contributed to the repression of mesenchymal and invasive properties of human B6FS fibrosarcoma cells. The results demonstrate that nuclear translocation contributes to the capacity of SDC1 to regulate epithelial-mesenchymal plasticity in human tumor cells and opens up to mechanistic studies to elucidate the mechanisms involved.
Highlights
The initial steps of the metastatic process involve induction of epithelial-to-mesenchymal transition (EMT), whereby tumor cells shift identity from a stationary, epithelial phenotype to a more motile, mesenchymal-like phenotype
An integral part of this phenotypic plasticity is shifting the repertoire of cell surface proteins that are expressed in tumor cells
SDC1, the major cell surface proteoglycan in epithelial cells is deregulated during the EMT process
Summary
The initial steps of the metastatic process involve induction of epithelial-to-mesenchymal transition (EMT), whereby tumor cells shift identity from a stationary, epithelial phenotype to a more motile, mesenchymal-like phenotype. EMT is not a binary switch but rather a dynamic process by which tumor cells adopt various states of epithelial/mesenchymal phenotypes. This plasticity is a prerequisite for changes in tumor cell morphology during invasion, intravasation, and extravasation along the metastatic route [1]. EMT is associated with a change in the repertoire of adhesion molecules that are expressed and localized at the cell surface. The cadherin switch is a hallmark of EMT and is associated with malignant progression of epithelial cancers into invasive and metastatic disease [8] Another example is the coxsackie- and adenovirus receptor (CXADR/CAR), a tight junction-based cell adhesion molecule, which is frequently lost during carcinoma progression. Some cell surface molecules are important to maintain epithelial characteristics and control cellular sensitivity to TGF-β1-induced EMT
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