A mechanism for epithelial-mesenchymal transition and anoikis resistance in breast cancer triggered by zinc channel ZIP6 and STAT3 (signal transducer and activator of transcription 3).
A mechanism for epithelial-mesenchymal transition and anoikis resistance in breast cancer triggered by zinc channel ZIP6 and STAT3 (signal transducer and activator of transcription 3).
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DOI：
10.1042/bj20130483
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发表时间：
2013-10-15
期刊：
影响因子：
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通讯作者：
Taylor KM
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文献类型：
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作者：
Hogstrand C;Kille P;Ackland ML;Hiscox S;Taylor KM
参与正常发育过程的基因作为肿瘤进展的介质引起了人们的注意，因为它们促进了肿瘤细胞的迁移。EMT（上皮-间质转化）是胚胎发育、组织重塑和创伤修复的重要组成部分，对肿瘤转移至关重要。先前，锌转运蛋白ZIP 6 [SLC 39 A6;溶质载体家族39（锌转运蛋白），成员6;也称为LIV-1）通过STAT 3（信号转导子和转录激活子3）机制与斑马鱼原肠胚形成中的EMT相关，导致转录因子Snail的核定位。在本研究中，我们发现锌转运蛋白ZIP 6是转录诱导STAT 3和前所未有的锌转运蛋白，并激活N-末端切割触发ZIP 6质膜定位和锌内流。这种锌流入分别间接或直接通过Akt或GSK-3β使GSK-3β（糖原合成酶激酶3β）失活，导致Snail激活，Snail保留在细胞核中并作为E-钙粘蛋白（上皮钙粘蛋白）CDH 1的转录抑制因子，导致细胞变圆和分离。这反映了ZIP 6转染的细胞经历EMT，从单层脱离，并表现出抗失巢凋亡的能力，即使在脱离后继续增殖。我们的研究结果表明ZIP 6在细胞运动和迁移中的致病作用，为ZIP 6作为预测临床癌症扩散的新靶点提供了依据，也表明了肿瘤转移的ZIP 6依赖性机制。我们证明了一种新的机制，细胞锌驱动细胞脱离和迁移的能力与乳腺癌扩散的影响。该机制涉及锌摄取通道ZIP 6（也称为SLC 39 A6）和转录因子STAT 3。
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. We demonstrate a novel mechanism for the ability of cellular zinc to drive cell detachment and migration with implications for breast cancer spread. This mechanism involves a zinc uptake channel ZIP6 (also known as SLC39A6) and a transcription factor, STAT3.