Thymidylate synthase is functionally associated with ZEB1 and contributes to the epithelial-to-mesenchymal transition of cancer cells

Siddiqui A, Vazakidou ME, Schwab A, Napoli F, Fernandez-Molina C, Rapa I, Stemmler M, Volante M, Brabletz T, Ceppi P (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Journal of Pathology Wiley-Blackwell

Book Volume: 242

Pages Range: 221-233

Journal Issue: 2

DOI: 10.1002/path.4897

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.

Authors with CRIS profile

Mohammad Siddiqui Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Maria Eleni Vazakidou Einrichtungen, die zum Universitätsklinikum Erlangen gehören Annemarie Schwab Einrichtungen, die zum Universitätsklinikum Erlangen gehören Marc Stemmler Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Thomas Brabletz Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Paolo Ceppi Einrichtungen, die zum Universitätsklinikum Erlangen gehören

Involved external institutions

University of Turin / Università degli Studi di Torino (UNITO) IT Italy (IT)

How to cite

APA:

Siddiqui, A., Vazakidou, M.E., Schwab, A., Napoli, F., Fernandez-Molina, C., Rapa, I.,... Ceppi, P. (2017). Thymidylate synthase is functionally associated with ZEB1 and contributes to the epithelial-to-mesenchymal transition of cancer cells. Journal of Pathology, 242(2), 221-233. https://dx.doi.org/10.1002/path.4897

MLA:

Siddiqui, Aarif, et al. "Thymidylate synthase is functionally associated with ZEB1 and contributes to the epithelial-to-mesenchymal transition of cancer cells." Journal of Pathology 242.2 (2017): 221-233.

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