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MicroRNA-199b Downregulation Confers Resistance to 5-Fluorouracil Treatment and Predicts Poor Outcome and Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer Patients

Neoadjuvant 5-fluorouracil (5-FU)-based chemoradiotherapy followed by mesorectal excision is the current standard treatment in locally advanced rectal cancer (LARC) and the lack of complete response represents a major problem that compromises long-term patient survival. However, there is a lack of r...

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Autores principales: Cristóbal, Ion, Rubio, Jaime, Santos, Andrea, Torrejón, Blanca, Caramés, Cristina, Imedio, Laura, Mariblanca, Sofía, Luque, Melani, Sanz-Alvarez, Marta, Zazo, Sandra, Madoz-Gúrpide, Juan, Rojo, Federico, García-Foncillas, Jesús
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352382/
https://www.ncbi.nlm.nih.gov/pubmed/32580513
http://dx.doi.org/10.3390/cancers12061655
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author Cristóbal, Ion
Rubio, Jaime
Santos, Andrea
Torrejón, Blanca
Caramés, Cristina
Imedio, Laura
Mariblanca, Sofía
Luque, Melani
Sanz-Alvarez, Marta
Zazo, Sandra
Madoz-Gúrpide, Juan
Rojo, Federico
García-Foncillas, Jesús
author_facet Cristóbal, Ion
Rubio, Jaime
Santos, Andrea
Torrejón, Blanca
Caramés, Cristina
Imedio, Laura
Mariblanca, Sofía
Luque, Melani
Sanz-Alvarez, Marta
Zazo, Sandra
Madoz-Gúrpide, Juan
Rojo, Federico
García-Foncillas, Jesús
author_sort Cristóbal, Ion
collection PubMed
description Neoadjuvant 5-fluorouracil (5-FU)-based chemoradiotherapy followed by mesorectal excision is the current standard treatment in locally advanced rectal cancer (LARC) and the lack of complete response represents a major problem that compromises long-term patient survival. However, there is a lack of robust established markers predictive of response to this preoperative treatment available in the clinical routine. The tumor suppressor microRNA (miR)-199b directly targets the PP2A inhibitor SET, which has been involved in 5-FU resistance, and its downregulation has been found to correlate with poor outcome in metastatic colorectal cancer. Here, we studied the functional effects of miR-199b on 5-FU sensitivity after its ectopic modulation, and its expression was quantified by real-time-PCR in a cohort of 110 LARC patients to evaluate its potential clinical significance. Interestingly, our findings demonstrate that miR-199b enhances the sensitivity of colorectal cancer cells to 5-FU in a SET-dependent manner, and that both miR-199b overexpression and SET inhibition are able to overcome resistance to this drug using an acquired 5-FU-resistant model. MiR-199b was found downregulated in 26.4% of cases and was associated with positive lymph node levels after chemoradiotherapy (CRT, p = 0.007) and high pathological stage (p = 0.029). Moreover, miR-199b downregulation determined shorter overall (p = 0.003) and event-free survival (p = 0.005), and was an independent predictor of poor response to preoperative CRT (p = 0.004). In conclusion, our findings highlight the clinical impact of miR-199b downregulation predicting poor outcome and pathological response in LARC, and suggest the miR-199b/SET signaling axis as a novel molecular target to prevent the development of resistance to 5-FU treatment.
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spelling pubmed-73523822020-07-15 MicroRNA-199b Downregulation Confers Resistance to 5-Fluorouracil Treatment and Predicts Poor Outcome and Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer Patients Cristóbal, Ion Rubio, Jaime Santos, Andrea Torrejón, Blanca Caramés, Cristina Imedio, Laura Mariblanca, Sofía Luque, Melani Sanz-Alvarez, Marta Zazo, Sandra Madoz-Gúrpide, Juan Rojo, Federico García-Foncillas, Jesús Cancers (Basel) Article Neoadjuvant 5-fluorouracil (5-FU)-based chemoradiotherapy followed by mesorectal excision is the current standard treatment in locally advanced rectal cancer (LARC) and the lack of complete response represents a major problem that compromises long-term patient survival. However, there is a lack of robust established markers predictive of response to this preoperative treatment available in the clinical routine. The tumor suppressor microRNA (miR)-199b directly targets the PP2A inhibitor SET, which has been involved in 5-FU resistance, and its downregulation has been found to correlate with poor outcome in metastatic colorectal cancer. Here, we studied the functional effects of miR-199b on 5-FU sensitivity after its ectopic modulation, and its expression was quantified by real-time-PCR in a cohort of 110 LARC patients to evaluate its potential clinical significance. Interestingly, our findings demonstrate that miR-199b enhances the sensitivity of colorectal cancer cells to 5-FU in a SET-dependent manner, and that both miR-199b overexpression and SET inhibition are able to overcome resistance to this drug using an acquired 5-FU-resistant model. MiR-199b was found downregulated in 26.4% of cases and was associated with positive lymph node levels after chemoradiotherapy (CRT, p = 0.007) and high pathological stage (p = 0.029). Moreover, miR-199b downregulation determined shorter overall (p = 0.003) and event-free survival (p = 0.005), and was an independent predictor of poor response to preoperative CRT (p = 0.004). In conclusion, our findings highlight the clinical impact of miR-199b downregulation predicting poor outcome and pathological response in LARC, and suggest the miR-199b/SET signaling axis as a novel molecular target to prevent the development of resistance to 5-FU treatment. MDPI 2020-06-22 /pmc/articles/PMC7352382/ /pubmed/32580513 http://dx.doi.org/10.3390/cancers12061655 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Cristóbal, Ion
Rubio, Jaime
Santos, Andrea
Torrejón, Blanca
Caramés, Cristina
Imedio, Laura
Mariblanca, Sofía
Luque, Melani
Sanz-Alvarez, Marta
Zazo, Sandra
Madoz-Gúrpide, Juan
Rojo, Federico
García-Foncillas, Jesús
MicroRNA-199b Downregulation Confers Resistance to 5-Fluorouracil Treatment and Predicts Poor Outcome and Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer Patients
title MicroRNA-199b Downregulation Confers Resistance to 5-Fluorouracil Treatment and Predicts Poor Outcome and Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer Patients
title_full MicroRNA-199b Downregulation Confers Resistance to 5-Fluorouracil Treatment and Predicts Poor Outcome and Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer Patients
title_fullStr MicroRNA-199b Downregulation Confers Resistance to 5-Fluorouracil Treatment and Predicts Poor Outcome and Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer Patients
title_full_unstemmed MicroRNA-199b Downregulation Confers Resistance to 5-Fluorouracil Treatment and Predicts Poor Outcome and Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer Patients
title_short MicroRNA-199b Downregulation Confers Resistance to 5-Fluorouracil Treatment and Predicts Poor Outcome and Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer Patients
title_sort microrna-199b downregulation confers resistance to 5-fluorouracil treatment and predicts poor outcome and response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352382/
https://www.ncbi.nlm.nih.gov/pubmed/32580513
http://dx.doi.org/10.3390/cancers12061655
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