The EMT-activator ZEB1 is unrelated to platinum drug resistance in ovarian cancer but is predictive of survival
Article
Rae, S., Spillane, C., Blackshields, G., Madden, S., Keenan, J. and Stordal, B. 2022. The EMT-activator ZEB1 is unrelated to platinum drug resistance in ovarian cancer but is predictive of survival. Human Cell. 35 (5), pp. 1547-1559. https://doi.org/10.1007/s13577-022-00744-y
Type | Article |
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Title | The EMT-activator ZEB1 is unrelated to platinum drug resistance in ovarian cancer but is predictive of survival |
Authors | Rae, S., Spillane, C., Blackshields, G., Madden, S., Keenan, J. and Stordal, B. |
Abstract | 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. |
Keywords | EMT; ZEB1; Ovarian cancer; Cisplatin; Paclitaxel |
Sustainable Development Goals | 3 Good health and well-being |
Research Group | Biomarkers for Cancer group |
Publisher | Springer |
Journal | Human Cell |
ISSN | 0914-7470 |
Electronic | 1749-0774 |
Publication dates | |
Online | 06 Jul 2022 |
30 Sep 2022 | |
Publication process dates | |
Deposited | 07 Jul 2022 |
Submitted | 19 Apr 2022 |
Accepted | 24 Jun 2022 |
Output status | Published |
Publisher's version | License |
Accepted author manuscript | License File Access Level Restricted |
Copyright Statement | © The Author(s) 2022 |
Digital Object Identifier (DOI) | https://doi.org/10.1007/s13577-022-00744-y |
PubMed ID | 35794446 |
PubMed Central ID | 9374625 |
Web of Science identifier | WOS:000824822900002 |
Language | English |
https://repository.mdx.ac.uk/item/89x82
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