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Dynamic Modulation of Thymidylate Synthase Gene Expression and Fluorouracil Sensitivity in Human Colorectal Cancer Cells
Biomarkers have revolutionized cancer chemotherapy. However, many biomarker candidates are still in debate. In addition to clinical studies, a priori experimental approaches are needed. Thymidylate synthase (TS) expression is a long-standing candidate as a biomarker for 5-fluorouracil (5-FU) treatme...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400010/ https://www.ncbi.nlm.nih.gov/pubmed/25881233 http://dx.doi.org/10.1371/journal.pone.0123076 |
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author | Wakasa, Kentaro Kawabata, Rumi Nakao, Seiki Hattori, Hiroyoshi Taguchi, Kenichi Uchida, Junji Yamanaka, Takeharu Maehara, Yoshihiko Fukushima, Masakazu Oda, Shinya |
author_facet | Wakasa, Kentaro Kawabata, Rumi Nakao, Seiki Hattori, Hiroyoshi Taguchi, Kenichi Uchida, Junji Yamanaka, Takeharu Maehara, Yoshihiko Fukushima, Masakazu Oda, Shinya |
author_sort | Wakasa, Kentaro |
collection | PubMed |
description | Biomarkers have revolutionized cancer chemotherapy. However, many biomarker candidates are still in debate. In addition to clinical studies, a priori experimental approaches are needed. Thymidylate synthase (TS) expression is a long-standing candidate as a biomarker for 5-fluorouracil (5-FU) treatment of cancer patients. Using the Tet-OFF system and a human colorectal cancer cell line, DLD-1, we first constructed an in vitro system in which TS expression is dynamically controllable. Quantitative assays have elucidated that TS expression in the transformant was widely modulated, and that the dynamic range covered 15-fold of the basal level. 5-FU sensitivity of the transformant cells significantly increased in response to downregulated TS expression, although being not examined in the full dynamic range because of the doxycycline toxicity. Intriguingly, our in vitro data suggest that there is a linear relationship between TS expression and the 5-FU sensitivity in cells. Data obtained in a mouse model using transformant xenografts were highly parallel to those obtained in vitro. Thus, our in vitro and in vivo observations suggest that TS expression is a determinant of 5-FU sensitivity in cells, at least in this specific genetic background, and, therefore, support the possibility of TS expression as a biomarker for 5-FU-based cancer chemotherapy. |
format | Online Article Text |
id | pubmed-4400010 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-44000102015-04-21 Dynamic Modulation of Thymidylate Synthase Gene Expression and Fluorouracil Sensitivity in Human Colorectal Cancer Cells Wakasa, Kentaro Kawabata, Rumi Nakao, Seiki Hattori, Hiroyoshi Taguchi, Kenichi Uchida, Junji Yamanaka, Takeharu Maehara, Yoshihiko Fukushima, Masakazu Oda, Shinya PLoS One Research Article Biomarkers have revolutionized cancer chemotherapy. However, many biomarker candidates are still in debate. In addition to clinical studies, a priori experimental approaches are needed. Thymidylate synthase (TS) expression is a long-standing candidate as a biomarker for 5-fluorouracil (5-FU) treatment of cancer patients. Using the Tet-OFF system and a human colorectal cancer cell line, DLD-1, we first constructed an in vitro system in which TS expression is dynamically controllable. Quantitative assays have elucidated that TS expression in the transformant was widely modulated, and that the dynamic range covered 15-fold of the basal level. 5-FU sensitivity of the transformant cells significantly increased in response to downregulated TS expression, although being not examined in the full dynamic range because of the doxycycline toxicity. Intriguingly, our in vitro data suggest that there is a linear relationship between TS expression and the 5-FU sensitivity in cells. Data obtained in a mouse model using transformant xenografts were highly parallel to those obtained in vitro. Thus, our in vitro and in vivo observations suggest that TS expression is a determinant of 5-FU sensitivity in cells, at least in this specific genetic background, and, therefore, support the possibility of TS expression as a biomarker for 5-FU-based cancer chemotherapy. Public Library of Science 2015-04-16 /pmc/articles/PMC4400010/ /pubmed/25881233 http://dx.doi.org/10.1371/journal.pone.0123076 Text en © 2015 Wakasa et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Wakasa, Kentaro Kawabata, Rumi Nakao, Seiki Hattori, Hiroyoshi Taguchi, Kenichi Uchida, Junji Yamanaka, Takeharu Maehara, Yoshihiko Fukushima, Masakazu Oda, Shinya Dynamic Modulation of Thymidylate Synthase Gene Expression and Fluorouracil Sensitivity in Human Colorectal Cancer Cells |
title | Dynamic Modulation of Thymidylate Synthase Gene Expression and Fluorouracil Sensitivity in Human Colorectal Cancer Cells |
title_full | Dynamic Modulation of Thymidylate Synthase Gene Expression and Fluorouracil Sensitivity in Human Colorectal Cancer Cells |
title_fullStr | Dynamic Modulation of Thymidylate Synthase Gene Expression and Fluorouracil Sensitivity in Human Colorectal Cancer Cells |
title_full_unstemmed | Dynamic Modulation of Thymidylate Synthase Gene Expression and Fluorouracil Sensitivity in Human Colorectal Cancer Cells |
title_short | Dynamic Modulation of Thymidylate Synthase Gene Expression and Fluorouracil Sensitivity in Human Colorectal Cancer Cells |
title_sort | dynamic modulation of thymidylate synthase gene expression and fluorouracil sensitivity in human colorectal cancer cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400010/ https://www.ncbi.nlm.nih.gov/pubmed/25881233 http://dx.doi.org/10.1371/journal.pone.0123076 |
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