Abstract
Genes involved in normal developmental processes attract attention as mediators of tumour progression as they facilitate migration of tumour cells. EMT (epithelial–mesenchymal transition), an essential part of embryonic development, tissue remodelling and wound repair, is crucial for tumour metastasis. Previously, zinc transporter ZIP6 [SLC39A6; solute carrier family 39 (zinc transporter), member 6; also known as LIV-1) was linked to EMT in zebrafish gastrulation through a STAT3 (signal transducer and activator of transcription 3) mechanism, resulting in nuclear localization of transcription factor Snail. In the present study, we show that zinc transporter ZIP6 is transcriptionally induced by STAT3 and unprecedented among zinc transporters, and is activated by N-terminal cleavage which triggers ZIP6 plasma membrane location and zinc influx. This zinc influx inactivates GSK-3β (glycogen synthase kinase 3β), either indirectly or directly via Akt or GSK-3β respectively, resulting in activation of Snail, which remains in the nucleus and acts as a transcriptional repressor of E-cadherin (epithelial cadherin), CDH1, causing cell rounding and detachment. This was mirrored by ZIP6-transfected cells which underwent EMT, detached from monolayers and exhibited resistance to anoikis by their ability to continue proliferating even after detachment. Our results indicate a causative role for ZIP6 in cell motility and migration, providing ZIP6 as a new target for prediction of clinical cancer spread and also suggesting a ZIP6-dependent mechanism of tumour metastasis.
Highlights
Genes involved in normal developmental processes are attracting attention as mediators of tumour progression as they facilitate migration and invasion of epithelial tumour cells
We did observe a significant increase in signal transducer and activator of transcription 3 (STAT3) mRNA in the presence of ZIP6 siRNA, suggesting that ZIP6 may have a role in inhibiting STAT3 mRNA expression, which was evident at the protein level (Figure 1D)
We demonstrate that the role of ZIP6 in controlling epithelial–mesenchymal transition (EMT) is conserved between fish and human and unravel details of the Zn2+ signalling pathway involved
Summary
Genes involved in normal developmental processes are attracting attention as mediators of tumour progression as they facilitate migration and invasion of epithelial tumour cells. During EMT, cellular adhesion is lost, the cytoskeleton is remodelled and mesenchymal indicative genes are expressed allowing cells to migrate and detach. The exact mechanism of ZIP7 channel gate opening has been shown recently to be regulated by phosphorylation by protein kinase CK2 [4]. This family of one subfamily of the SLC39A zinc transporters, termed the LIV-1 subfamily and defined by a highly conserved novel potential metalloprotease motif [7], contains nine human members, many of which are increasingly being implicated in a variety of disease states [8]. Using anti-ZIP6 antibodies, we have confirmed this in cell lines and clinical material [8]
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