Department of Natural Sciences, Middlesex University London, London, UK.
Department of Histopathology, St James' Hospital and Trinity College Dublin, Dublin, Ireland.
Hum Cell. 2022 Sep;35(5):1547-1559. doi: 10.1007/s13577-022-00744-y. Epub 2022 Jul 6.
The IGROVCDDP cisplatin-resistant ovarian cancer cell line is an unusual model, as it is also cross-resistant to paclitaxel. IGROVCDDP, therefore, models the resistance phenotype of serous ovarian cancer patients who have failed frontline platinum/taxane chemotherapy. IGROVCDDP has also undergone epithelial-mesenchymal transition (EMT). We aim to determine if alterations in EMT-related genes are related to or independent from the drug-resistance phenotypes. EMT gene and protein markers, invasion, motility and morphology were investigated in IGROVCDDP and its parent drug-sensitive cell line IGROV-1. ZEB1 was investigated by qPCR, Western blotting and siRNA knockdown. ZEB1 was also investigated in publicly available ovarian cancer gene-expression datasets. IGROVCDDP cells have decreased protein levels of epithelial marker E-cadherin (6.18-fold, p = 1.58e-04) and higher levels of mesenchymal markers vimentin (2.47-fold, p = 4.43e-03), N-cadherin (4.35-fold, p = 4.76e-03) and ZEB1 (3.43-fold, p = 0.04). IGROVCDDP have a spindle-like morphology consistent with EMT. Knockdown of ZEB1 in IGROVCDDP does not lead to cisplatin sensitivity but shows a reversal of EMT-gene signalling and an increase in cell circularity. High ZEB1 gene expression (HR = 1.31, n = 2051, p = 1.31e-05) is a marker of poor overall survival in high-grade serous ovarian-cancer patients. In contrast, ZEB1 is not predictive of overall survival in high-grade serous ovarian-cancer patients known to be treated with platinum chemotherapy. The increased expression of ZEB1 in IGROVCDDP appears to be independent of the drug-resistance phenotypes. ZEB1 has the potential to be used as biomarker of overall prognosis in ovarian-cancer patients but not of platinum/taxane chemoresistance.
IGROVCDDP 顺铂耐药卵巢癌细胞系是一种不寻常的模型，因为它也对紫杉醇交叉耐药。因此，IGROVCDDP 模拟了一线铂类/紫杉醇化疗失败的浆液性卵巢癌患者的耐药表型。IGROVCDDP 还经历了上皮-间充质转化（EMT）。我们旨在确定 EMT 相关基因的改变是否与耐药表型相关或独立。在 IGROVCDDP 和其亲本药物敏感细胞系 IGROV-1 中研究了 EMT 基因和蛋白标志物、侵袭、迁移和形态。通过 qPCR、Western blot 和 siRNA 敲低研究了 ZEB1。还在公开的卵巢癌基因表达数据集中研究了 ZEB1。IGROVCDDP 细胞中上皮标志物 E-钙黏蛋白的蛋白水平降低（6.18 倍，p=1.58e-04），间充质标志物波形蛋白（2.47 倍，p=4.43e-03）、N-钙黏蛋白（4.35 倍，p=4.76e-03）和 ZEB1（3.43 倍，p=0.04）水平升高。IGROVCDDP 具有与 EMT 一致的纺锤形形态。在 IGROVCDDP 中敲低 ZEB1 不会导致顺铂敏感性，但显示 EMT 基因信号的逆转和细胞圆形度的增加。ZEB1 高表达（HR=1.31，n=2051，p=1.31e-05）是高级别浆液性卵巢癌患者总生存期不良的标志物。相比之下，在接受铂类化疗治疗的高级别浆液性卵巢癌患者中，ZEB1 不是总生存期的预测因子。IGROVCDDP 中 ZEB1 的高表达似乎独立于耐药表型。ZEB1 有可能成为卵巢癌患者总体预后的生物标志物，但不是铂类/紫杉醇化疗耐药的生物标志物。
