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Thymidylate synthase is functionally associated with ZEB1 and contributes to the epithelial‐to‐mesenchymal transition of cancer cells
Author(s) -
Siddiqui Aarif,
Vazakidou Maria Eleni,
Schwab Annemarie,
Napoli Francesca,
FernandezMolina Cristina,
Rapa Ida,
Stemmler Marc P,
Volante Marco,
Brabletz Thomas,
Ceppi Paolo
Publication year - 2017
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4897
Subject(s) - epithelial–mesenchymal transition , gene knockdown , cancer research , biology , cancer cell , microrna , cancer , transfection , small hairpin rna , thymidylate synthase , pancreatic cancer , metastasis , cell culture , gene , genetics , fluorouracil
Abstract Thymidylate synthase ( TS ) is a fundamental enzyme of nucleotide metabolism and one of the oldest anti‐cancer targets. Beginning from the analysis of gene array data from the NCI ‐60 panel of cancer cell lines, we identified a significant correlation at both gene and protein level between TS and the markers of epithelial‐to‐mesenchymal transition ( EMT ), a developmental process that allows cancer cells to acquire features of aggressiveness, like motility and chemoresistance. TS levels were found to be significantly augmented in mesenchymal‐like compared to epithelial‐like cancer cells, to be regulated by EMT induction, and to negatively correlate with micro‐ RNAs ( miRNAs ) usually expressed in epithelial‐like cells and known to actively suppress EMT . Transfection of EMT ‐suppressing miRNAs reduced TS levels, and a specific role for miR ‐375 in targeting the TS 3'‐untranslated region was identified. A particularly relevant association was found between TS and the powerful EMT driver ZEB1 , the shRNA ‐mediated knockdown of which up‐regulated miR ‐375 and reduced TS cellular levels. The TS–ZEB1 association was confirmed in clinical specimens from lung tumours and in a genetic mouse model of pancreatic cancer with ZEB1 deletion. Interestingly, TS itself appeared to have a regulatory role in EMT in cancer cells, as TS knockdown could directly reduce the EMT phenotype, the migratory ability of cells, the expression of stem‐like markers, and chemoresistance. Taken together, these data indicate that the TS enzyme is functionally linked with EMT and cancer differentiation, with several potential translational implications. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.