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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Published in:Cancers 2020-06, Vol.12 (6), p.1655
Main Authors: 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
Format: Article
Language:English
Subjects:
5-Fluorouracil
Cancer
Cell growth
Chemoradiotherapy
Colorectal cancer
Colorectal carcinoma
Gene expression
Lymph nodes
Medical prognosis
Metastases
Metastasis
MicroRNAs
miRNA
Patients
Rectum
Surgery
Tumor suppressor genes
Tumors
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Summary: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.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers12061655