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Open AccessArticle

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

1
Cancer Unit for Research on Novel Therapeutic Targets, Oncohealth Institute, IIS- Fundación Jiménez Díaz-UAM, E-28040 Madrid, Spain
2
Translational Oncology Division, Oncohealth Institute, IIS-Fundación Jiménez Díaz-UAM, E-28040 Madrid, Spain
3
Medical Oncology Department, University Hospital “Fundación Jiménez Díaz”, UAM, E-28040 Madrid, Spain
4
Pathology Department, IIS-Fundación Jiménez Díaz-UAM, E-28040 Madrid, Spain
*
Authors to whom correspondence should be addressed.
These authors have contributed equally to this work.
Cancers 2020, 12(6), 1655; https://doi.org/10.3390/cancers12061655
Received: 8 May 2020 / Revised: 18 June 2020 / Accepted: 18 June 2020 / Published: 22 June 2020
(This article belongs to the Special Issue Resistance to Therapy in Liver and Gastrointestinal Tumors)
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. View Full-Text
Keywords: MiR-199b; SET; locally advanced rectal cancer; prognosis; pathological response MiR-199b; SET; locally advanced rectal cancer; prognosis; pathological response
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Cristóbal, I.; Rubio, J.; Santos, A.; Torrejón, B.; Caramés, C.; Imedio, L.; Mariblanca, S.; Luque, M.; Sanz-Alvarez, M.; Zazo, S.; Madoz-Gúrpide, J.; Rojo, F.; García-Foncillas, J. MicroRNA-199b Downregulation Confers Resistance to 5-Fluorouracil Treatment and Predicts Poor Outcome and Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer Patients. Cancers 2020, 12, 1655.

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