Document Detail


miR-192/miR-215 influence 5-fluorouracil resistance through cell cycle-mediated mechanisms complementary to its post-transcriptional thymidilate synthase regulation.
MedLine Citation:
PMID:  20647341     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Thymidylate synthase (TYMS) is a target of the most widely used chemotherapeutic agents against gastrointestinal malignancies, the fluoropyrimidine-based therapy. TYMS expression levels have been identified as predictive biomarkers for 5-fluoruracil (FU) response in colorectal cancer, but their clinical utility remains controversial. The complexity of fluoropyrimidine response must require more mechanisms that currently have not been completely elucidated. In this context, microRNAs (miRNA) may play a role in modulating chemosensitivity. By carrying out an in silico analysis coupled to experimental validation, we detected that miR-192 and miR-215 target TYMS expression in colorectal cancer cell lines. However, downregulation of TYMS by these miRNAs does not sensitize colorectal cancer cell lines to FU treatment. The overexpression of miR-192/215 significantly reduces cell proliferation by targeting cell cycle progression. This effect was partially associated with p53 status, because reduction of cell proliferation and cell cycle arrest was associated with p21 and p27 induction. The decrease of S-phase cells by these miRNAs mitigates the effects of S phase-specific drugs and suggests that other mechanisms different from TYMS overexpression are essential to direct FU resistance. Finally, ectopic expression of miR-192/215 might have stronger impact to predict FU response than TYMS inhibition. Prospective studies to elucidate the role of these miRNAs as predictive biomarkers to FU are necessary.
Authors:
Valentina Boni; Nerea Bitarte; Ion Cristobal; Ruth Zarate; Javier Rodriguez; Evaristo Maiello; Jesus Garcia-Foncillas; Eva Bandres
Publication Detail:
Type:  Journal Article     Date:  2010-07-20
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  9     ISSN:  1538-8514     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-08-11     Completed Date:  2010-11-26     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2265-75     Citation Subset:  IM    
Copyright Information:
(c) 2010 AACR.
Affiliation:
Oncology Unit, Casa Sollievo Sofferenza, S. Giovanni Rotondo, Italy.
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MeSH Terms
Descriptor/Qualifier:
Binding Sites
Blotting, Western
Cell Cycle / drug effects*,  genetics
Cell Line, Tumor
Cell Proliferation / drug effects
Colorectal Neoplasms / enzymology,  genetics,  pathology
Computational Biology
Drug Resistance, Neoplasm / drug effects*
Fluorouracil / pharmacology*
Gene Expression Regulation, Neoplastic / drug effects*
Humans
MicroRNAs / genetics,  metabolism*
Protein Biosynthesis / genetics
Thymidylate Synthase / genetics*
Transcription, Genetic / drug effects
Transfection
Chemical
Reg. No./Substance:
0/MIRN192 microRNA, human; 0/MIRN215 microRNA, human; 0/MicroRNAs; 51-21-8/Fluorouracil; EC 2.1.1.45/Thymidylate Synthase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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