Boylan Kristin L M, Buchanan Petra C, Manion Rory D, Shukla Dip M, Braumberger Kelly, Bruggemeyer Cody, Skubitz Amy P N
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
Oncotarget. 2017 Feb 7;8(6):9717-9738. doi: 10.18632/oncotarget.14206.
The cell adhesion molecule Nectin-4 is overexpressed in epithelial cancers, including ovarian cancer. The objective of this study was to determine the biological significance of Nectin-4 in the adhesion, aggregation, migration, and proliferation of ovarian cancer cells. Nectin-4 and its binding partner Nectin-1 were detected in patients' primary tumors, omental metastases, and ascites cells. The human cell lines NIH:OVCAR5 and CAOV3 were genetically modified to alter Nectin-4 expression. Cells that overexpressed Nectin-4 adhered to Nectin-1 in a concentration and time-dependent manner, and adhesion was inhibited by antibodies to Nectin-4 and Nectin-1, as well as synthetic Nectin peptides. In functional assays, CAOV3 cells with Nectin-4 knock-down were unable to form spheroids and migrated more slowly than CAOV3 parental cells expressing Nectin-4. NIH:OVCAR5 parental cells proliferated more rapidly, migrated faster, and formed larger spheroids than either the Nectin-4 knock-down or over-expressing cells. Parental cell lines expressed higher levels of epithelial markers and lower levels of mesenchymal markers compared to Nectin-4 knock-down cells, suggesting a role for Nectin-4 in epithelial-mesenchymal transition. Our results demonstrate that Nectin-4 promotes cell-cell adhesion, migration, and proliferation. Understanding the biology of Nectin-4 in ovarian cancer progression is critical to facilitate its development as a novel therapeutic target.
细胞黏附分子Nectin-4在包括卵巢癌在内的上皮癌中过表达。本研究的目的是确定Nectin-4在卵巢癌细胞黏附、聚集、迁移和增殖中的生物学意义。在患者的原发性肿瘤、网膜转移灶和腹水细胞中检测到了Nectin-4及其结合伴侣Nectin-1。对人细胞系NIH:OVCAR5和CAOV3进行基因改造以改变Nectin-4的表达。过表达Nectin-4的细胞以浓度和时间依赖性方式黏附于Nectin-1，并且Nectin-4和Nectin-1的抗体以及合成的Nectin肽可抑制黏附。在功能试验中，Nectin-4敲低的CAOV3细胞无法形成球体，并且比表达Nectin-4的CAOV3亲本细胞迁移得更慢。与Nectin-4敲低细胞相比，NIH:OVCAR5亲本细胞增殖更快、迁移更快并且形成更大的球体。与Nectin-4敲低细胞相比，亲本细胞系表达更高水平的上皮标志物和更低水平的间充质标志物，这表明Nectin-4在上皮-间充质转化中起作用。我们的结果表明，Nectin-4促进细胞间黏附、迁移和增殖。了解Nectin-4在卵巢癌进展中的生物学特性对于促进其作为新型治疗靶点的开发至关重要。
