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首页> 外文期刊>Cellular Signalling >Clusterin silencing in human lung adenocarcinoma cells induces a mesenchymal-to-epithelial transition through modulating the ERK/Slug pathway
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Clusterin silencing in human lung adenocarcinoma cells induces a mesenchymal-to-epithelial transition through modulating the ERK/Slug pathway

机译：人肺腺癌细胞中的Clusterin沉默通过调节ERK / Slug途径诱导间充质向上皮的转化

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摘要

The ubiquitously expressed glycoprotein Clusterin (CLU) is implicated in diverse cellular processes, yet its genuine molecular function remains undefined. CLU expression has been associated with various human malignancies. yet the mechanisms by which CLU promotes cancer progression and metastasis are not elucidated. In this study, using human lung adenocarcinoma cell lines as a model, we explored the involvement of CLU in modulating invasiveness of cancer cells. We discovered that CLU levels positively correlated with the degree of invasiveness in human lung adenocarcinoma cell lines. The observation that CLU-rich cells displayed a spindle-shape morphology while those with low CLU levels were cuboidal in shape prompted us to investigate if CLU modulates epithelial-to-mesenchymal transitions (EMT). CLU silencing by siRNA in a highly invasive, CLU-rich lung adenocarcinoma cell line induced a mesenchymal-to-epithelial transition (MET) evidenced by the spindle-to-cuboidal morphological change, increased E-cadherin expression, and decreased fibronectin expression. Compared with the vector-transfected cells, CLU-knocked-down (CLUi) cells showed reduced migration and invasion in vitro, as well as decreased metastatic potential in experimental metastasis. Re-expression of CLU in CLUi cells reversed the MET and restored the mesenchymal and invasive phenotypes. We found that Slug, a zinc-finger-containing transcriptional repressor of E-cadherin, was downregulated in CLUi cells. We also discovered that levels of activated ERK correlated with those of CLU and Slug. Taken together, our data suggest that CLU may regulate EMT and aggressive behaviour of human lung adenocarcinoma cells through modulating ERK signalling and Slug expression.
机译：普遍表达的糖蛋白簇蛋白（CLU）与多种细胞过程有关，但其真正的分子功能仍不确定。 CLU表达已经与多种人类恶性肿瘤相关。然而，CLU促进癌症进展和转移的机制尚未阐明。在这项研究中，我们以人肺腺癌细胞系为模型，探讨了CLU在调节癌细胞侵袭性中的作用。我们发现，CLU水平与人肺腺癌细胞株的侵袭程度呈正相关。观察到富含CLU的细胞表现出纺锤形形态，而具有低CLU的细胞呈长方体形，这促使我们研究CLU是否调节上皮-间充质转变（EMT）。 siRNA在高度侵袭性的，富含CLU的肺腺癌细胞系中产生的CLU沉默诱导了间充质到上皮的转化（MET），这从纺锤体到立方体的形态变化，增加的E-钙黏着蛋白表达和降低的纤连蛋白表达得以证明。与载体转染的细胞相比，CLU敲除（CLUi）细胞在体外的迁移和侵袭减少，在实验转移中的转移潜力也降低。 CLUi细胞中CLU的重新表达逆转了MET，并恢复了间充质和侵袭性表型。我们发现Slug是E-cadherin的含锌指转录阻遏物，在CLUi细胞中被下调。我们还发现激活的ERK的水平与CLU和Slug的水平相关。两者合计，我们的数据表明CLU可能通过调节ERK信号传导和Slug表达来调节人肺腺癌细胞的EMT和侵袭行为。

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