State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
PLoS Genet. 2018 Aug 17;14(8):e1007609. doi: 10.1371/journal.pgen.1007609. eCollection 2018 Aug.
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.
细胞极性和正确的有丝分裂纺锤体定位对于维持适当的前列腺上皮结构至关重要，而这两个生物学特征的破坏发生在前列腺肿瘤发生的早期。然而，这两种上皮特征在体内是如何联系的，在很大程度上尚不清楚。我们在此报告，在一种小鼠模型中，细胞黏附连接关键成分 E-钙黏蛋白的条件性基因缺失导致前列腺腔细胞极性丧失和纺锤体方向随机化。关键的是，E-钙黏蛋白缺失导致前列腺增生，进而发展为浸润性腺癌。从机制上讲，E-钙黏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，形成三元蛋白复合物，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，即 E-钙黏蛋白作为一种锚定物，维持前列腺上皮完整性，并防止体内致癌作用。
