E-cadherin bridges cell polarity and spindle orientation to ensure prostate epithelial integrity and prevent carcinogenesis in vivo.
E-cadherin bridges cell polarity and spindle orientation to ensure prostate epithelial integrity and prevent carcinogenesis in vivo.
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E-钙粘蛋白连接细胞极性和纺锤体方向，确保前列腺上皮完整性并预防体内癌变
DOI：
10.1371/journal.pgen.1007609
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发表时间：
2018-08
期刊：
影响因子：
4.5
通讯作者：
Zhu HH
中科院分区：
文献类型：
--
作者：
Wang X;Dong B;Zhang K;Ji Z;Cheng C;Zhao H;Sheng Y;Li X;Fan L;Xue W;Gao WQ;Zhu HH
细胞的极性和正确的有丝分裂纺锤体位置对于维持正常的前列腺上皮结构是至关重要的，而这两个生物学特性的破坏在前列腺肿瘤发生的早期就会发生。然而，这两种上皮属性在体内是否以及如何联系在一起在很大程度上是未知的。我们在此报道，在小鼠模型中，粘着连接的关键成分E-钙粘附素的条件性遗传缺失会导致前列腺腔细胞极性的丧失和纺锤体取向的随机化。关键是，E-钙粘素消融会导致前列腺增生，进而发展为浸润性腺癌。在机制上，E-钙粘蛋白和纺锤体定位决定子LGN与细胞极性蛋白Scrib的PDZ结构域相互作用，形成一个三元蛋白质复合体，连接细胞极性和细胞分裂方向。这些发现提供了一种新的机制，通过E-钙粘附素作为锚来维持前列腺上皮的完整性，并在体内防止癌症发生。腔细胞是前列腺上皮细胞中含量最丰富的一种。大多数前列腺癌也表现为管腔表型。管腔细胞的水平分裂允许分泌性前列腺腔的表面扩张，同时保持单层和极化的上皮结构。上皮完整性的破坏和多层上皮的出现是前列腺癌发生的早期事件。然而，确保腔细胞水平分裂的分子机制在很大程度上仍不清楚。在这里，我们建立了一个基因工程小鼠模型，在该模型中，E-钙粘附素在前列腺腔细胞中被敲除，E-钙粘附素是连接相邻上皮细胞侧质膜的粘连连接的关键成分。E-钙粘附素缺失会导致细胞极性丧失和细胞分裂方向混乱，从而导致细胞增殖失调，并极易导致小鼠前列腺癌的发生。重要的是，我们揭示了E-钙粘蛋白作为锚的作用，将细胞极性蛋白Scrib和纺锤体定位决定因素LGN募集到细胞膜的侧面，从而确保细胞分裂平面的正确排列。所有这些发现揭示了一种新的机制，通过E-钙粘蛋白将细胞极性和纺锤体方向联系起来，以保持前列腺上皮的完整性和预防癌症的发生。
Cell polarity and correct mitotic spindle positioning are essential for the maintenance of a proper prostate epithelial architecture, and disruption of the two biological features occurs at early stages in prostate tumorigenesis. However, whether and how these two epithelial attributes are connected in vivo is largely unknown. We herein report that conditional genetic deletion of E-cadherin, a key component of adherens junctions, in a mouse model results in loss of prostate luminal cell polarity and randomization of spindle orientations. Critically, E-cadherin ablation causes prostatic hyperplasia which progresses to invasive adenocarcinoma. Mechanistically, E-cadherin and the spindle positioning determinant LGN interacts with the PDZ domain of cell polarity protein SCRIB and form a ternary protein complex to bridge cell polarity and cell division orientation. These findings provide a novel mechanism by which E-cadherin acts an anchor to maintain prostate epithelial integrity and to prevent carcinogenesis in vivo. Luminal cells are the most abundant type of the prostate epithelial cells. Most prostate cancers also display a luminal phenotype. Horizontal cell division of luminal cells allows the surface expansion of the secretory prostate lumen and meanwhile maintains the monolayer and polarized epithelial architecture. Disruption of the epithelial integrity and appearance of multilayer epithelia are early events in prostate adenocarcinoma development. However, the molecular mechanism that ensures the horizontal division in luminal cells remains largely unknown. Here, we generated a genetically engineered mouse model in which E-cadherin, a key component of the adherens junction that serves to connect the lateral plasma membrane of neighboring epithelial cells, was knocked out in the prostate luminal cells. E-cadherin deletion leads to loss of cell polarity and disoriented cell division, which subsequently causes dysregulated cell proliferation and strongly predisposes mice for prostate tumorigenesis. Importantly, we revealed that E-cadherin acts as an anchor to recruit cell polarity protein SCRIB and spindle positioning determinant LGN to the lateral cell membrane, thereby ensure a proper alignment of the cell division plane. All these findings uncover a novel mechanism by which E-cadherin links cell polarity and spindle orientation to keep prostate epithelial integrity and prevent carcinogenesis.
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影响因子：
9.2
作者：
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