Klinik für Gynäkologie, Gynäkologische Endokrinologie und Onkologie, Universitätsklinikum Giessen und Marburg GmbH, Baldingerstr. 1, 35043 Marburg, Germany.
Eur J Cancer. 2012 Jul;48(10):1558-69. doi: 10.1016/j.ejca.2011.07.004. Epub 2011 Aug 16.
The tumour-associated antigen CA125 (mucin 16, MUC16) is commonly expressed in ovarian cancer, and can also be detected in other tumour of epithelial origin, but its physiological role is largely unknown. The aim of the present study was to investigate the impact of MUC16 gene silencing on the growth properties of ovarian and breast cancer cells. We analysed cellular effects linked to oncogenesis, such as proliferation, cell cycle and apoptosis, after transient and stable transfection with MUC16 short hairpin RNA (shRNA) in diverse epithelial cancer cell lines with different MUC16 expression. Furthermore, alterations in cell adhesion, migration and invasion were evaluated in stable MUC16 knockdown clones. The growth of all tested MUC16(+) tumour cells was significantly suppressed by induction of caspase-dependent apoptosis after transient transfection with MUC16 shRNA, irrespective of the initial MUC16 expression level and cancer origin. Growth inhibition could be confirmed in stable MUC16 knockdown clones, albeit caspase-dependent death pathways seemed no longer be activated. In MUC16(low+) ovarian cancer cells, stable MUC16 gene silencing resulted in a substantial blockade of colony formation, cell adhesion, migration and invasiveness associated with reduced activation of metalloproteinases-2 (MMP-2). By contrast, the tested MUC16(high+) cell lines displayed a non-motile and non-invasive phenotype which was not affected by MUC16 knockdown, probably due to the expression of different MUC16 isoforms with divergent functions in individual cell lines. Our results provide evidence for a central role of MUC16 in cancer cell survival pathways. Additionally, MUC16 might also be involved in adhesion, migration and invasion depending on the type of cancer cell.
肿瘤相关抗原 CA125（黏蛋白 16，MUC16）通常在卵巢癌中表达，也可以在其他上皮来源的肿瘤中检测到，但它的生理作用在很大程度上是未知的。本研究旨在探讨 MUC16 基因沉默对卵巢癌和乳腺癌细胞生长特性的影响。我们分析了瞬时和稳定转染 MUC16 短发夹 RNA（shRNA）后与癌变相关的细胞效应，如增殖、细胞周期和细胞凋亡，在具有不同 MUC16 表达水平和癌症起源的多种上皮癌细胞系中进行。此外，还评估了稳定的 MUC16 敲低克隆中细胞黏附、迁移和侵袭的变化。所有测试的 MUC16(+)肿瘤细胞的生长在瞬时转染 MUC16 shRNA 后均被诱导的 caspase 依赖性凋亡显著抑制，而与初始 MUC16 表达水平和癌症起源无关。在稳定的 MUC16 敲低克隆中也可以证实生长抑制，尽管 caspase 依赖性死亡途径似乎不再被激活。在 MUC16(low+)卵巢癌细胞中，稳定的 MUC16 基因沉默导致集落形成、细胞黏附、迁移和侵袭的显著阻断，与金属蛋白酶-2（MMP-2）的激活减少有关。相比之下，测试的 MUC16(high+)细胞系表现出非运动性和非侵袭性表型，这不受 MUC16 敲低的影响，可能是由于不同的 MUC16 异构体在个别细胞系中具有不同的功能。我们的结果为 MUC16 在癌症细胞存活途径中的核心作用提供了证据。此外，MUC16 也可能参与黏附、迁移和侵袭，具体取决于癌细胞的类型。
