MicroRNAs in Rectal Cancer: Functional Significance and Promising Therapeutic Value

Imedio, Laura; Cristóbal, Ion; Rubio, Jaime; Santos, Andrea; Rojo, Federico; Garcı́a-Foncillas, Jesús

doi:10.3390/cancers12082040

Cited by 12 publications

(11 citation statements)

References 73 publications

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“…However, around 30% of cases do not show any response to preoperative CRT, and surgical resection should have been done from the beginning [ 35 ]. Although some potential biomarkers have been described in this context, none of them have been established and incorporated in the clinical routine [ 11 , 36 ]. Therefore, the identification of biomarkers predictive of response to neoadjuvant treatment still remains necessary and a challenge to optimize the clinical management of LARC patients.…”

Section: Discussionmentioning

confidence: 99%

“…Then, clinicians could manage differently those subgroups of patients candidate to be resistant to chemoradiotherapy or those that likely reach a pCR before treatment in order to reduce undesirable observed morbidities and mortalities as well as delays in the resection of the primary tumor [ 9 ]. Although researchers have identified several postsurgical prognostic markers as well as few preoperative markers, none of them have been established clinically to date [ 10 , 11 , 12 ]. Thus, a major current limitation for clinical management of LARC patients is the absence of effective predictors of pathological tumor response before neoadjuvant CRT.…”

Section: Introductionmentioning

confidence: 99%

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Low MicroRNA-19b Expression Shows a Promising Clinical Impact in Locally Advanced Rectal Cancer

Rubio

Cristóbal

Santos

et al. 2021

Cancers

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The standard treatment for patients with locally advanced colorectal cancer (LARC) is neoadjuvant 5-fluorouracil (5-FU) based chemoradiotherapy (CRT) followed by surgical mesorectal excision. However, the lack of response to this preoperative treatment strongly compromises patient outcomes and leads to surgical delays and undesired toxicities in those non-responder cases. Thus, the identification of effective and robust biomarkers to predict response to preoperative CRT represents an urgent need in the current clinical management of LARC. The oncomiR microRNA-19b (miR-19b) has been reported to functionally play oncogenic roles in colorectal cancer (CRC) cells as well as regulate 5-FU sensitivity and determine outcome in CRC patients. However, its clinical impact in LARC has not been previously investigated. Here, we show that miR-19b deregulation is a common event in this disease, and its decreased expression significantly associates with lower tumor size after CRT (p = 0.003), early pathological stage (p = 0.003), and absence of recurrence (p = 0.001) in LARC patients. Interestingly, low miR-19b expression shows a predictive value of better response to neoajuvant CRT (p < 0.001), and the subgroup of LARC patients with low miR-19b levels have a markedly longer overall (p = 0.003) and event-free survival (p = 0.023). Finally, multivariate analyses determined that miR-19b independently predicts both patient outcome and response to preoperative CRT, highlighting its potential clinical usefulness in the management of LARC patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Low MicroRNA-19b Expression Shows a Promising Clinical Impact in Locally Advanced Rectal Cancer

Rubio

Cristóbal

Santos

et al. 2021

Cancers

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“…miRNAs are short noncoding RNAs, sized from 19 to 25 nucleotides, that posttranscriptionally regulate the expression of target genes and are functionally involved in many biological processes in rectal cancer. 163 Several differentially expressed miRNAs in rectal cancer were reported as biomarkers that can predict response to nCRT. 164 , 165 For instance, expression level of miR-21, a well-characterized miRNA, was found to discriminate between complete responders and noncomplete responders in rectal cancer.…”

Section: Introductionmentioning

confidence: 99%

Predicting response to neoadjuvant chemoradiotherapy in rectal cancer: from biomarkers to tumor models

Xiao

Venkatachalam

et al. 2022

Ther Adv Med Oncol

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Colorectal cancer (CRC) is a major contributor to cancer-associated morbidity worldwide and over one-third of CRC is located in the rectum. Neoadjuvant chemoradiotherapy (nCRT) followed by surgical resection is commonly applied to treat locally advanced rectal cancer (LARC). In this review, we summarize current and novel concepts of neoadjuvant therapy for LARC such as total neoadjuvant therapy and describe how these developments impact treatment response. Moreover, as response to nCRT is highly divergent in rectal cancers, we discuss the role of potential predictive biomarkers. We review recent advances in biomarker discovery, from a clinical as well as a histopathological and molecular perspective. Furthermore, the role of emerging predictive biomarkers derived from the tumor environment such as immune cell composition and gut microbiome is presented. Finally, we describe how different tumor models such as patient-derived cancer organoids are used to identify novel predictive biomarkers for chemoradiotherapy (CRT) in rectal cancer.

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“…Currently, there is a lack of well-established biomarkers that can reliably predict pathological response to preoperative CRT, which will be of crucial importance since it would improve patient outcomes as well as reduce morbidities and allow designing more effective therapeutic strategies for the subgroup of predicted non-responder LARC patients. In this context, microRNAs (miRs) have progressively emerged in the last decade as promising candidates for predicting therapy response in LARC, due to their stability, facile detection and disease-specific expression in human tissue and blood [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, growing evidence has demonstrated that deregulation of miRs contributes to tumorigenesis and tumor progression in a wide variety of tumor types, including rectal cancer, acting as oncogenic or tumor suppressor miRs, depending on the targeted mRNAs. Deregulation of miRs could be caused by multiple mechanisms, such as epigenetic alterations, chromosomal abnormalities, as well as changes in their transcriptional regulation [ 14 , 15 , 16 , 17 , 18 ]. Lately, increasing functional data of specific miRs, such as miR-199b, that play important roles in rectal cancer have been analyzed [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Validation of microRNA-199b as A Promising Predictor of Outcome and Response to Neoadjuvant Treatment in Locally Advanced Rectal Cancer Patients

Cristóbal

Santos

Rubio

et al. 2021

Cancers

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The absence of established predictive markers with value to anticipate response to neoadjuvant 5-fluorouracil (5-FU)-based chemoradiotherapy (CRT) represents a current major challenge in locally advanced rectal cancer (LARC). The tumor suppressor microRNA (miR)-199b has been reported to play a key role determining 5-FU sensitivity of colorectal cancer cells through the regulation of several signaling pathways, and has emerged as a novel molecular target to overcome the 5-FU resistant phenotype. Moreover, miR-199b downregulation was described as a common alteration that predicts lack of response to preoperative CRT in LARC but this issue needs to be confirmed in independent larger cohorts. Here, we evaluate the clinical impact of miR-199b in LARC and perform additional analyses to further clarify its potential relevance as novel marker in this disease. Thus, miR-199b expression was quantified by real-time-PCR in a cohort of 185 LARC patients, observing this miR downregulated in 22.2% of cases and significantly associated with higher tumor size (p= 0.026) and positive lymph node after CRT (p= 0.005), and higher pathological stage (p= 0.004). Notably, this alteration showed a strong independent predictive value of poor pathological response to neoadjuvant CRT (p= 0.004). Moreover, the subgroup of cases with low miR-199b levels had a markedly shorter overall (p< 001) and event-free survival (p< 0.001), and multivariate analyses showed that miR-199b deregulation represents an independent prognosticator for patient outcome in LARC. Interestingly, the prognostic impact of this miR was strongly significant in both younger and elderly patients, and was very effective determining patient recurrence (p= 0.004). Finally, we compared miR-199b expression profiles in a set of cases with pre and post-treatment samples available, observing that only a minimal response leads to miR-199b increase levels, further suggesting its potential clinical and therapeutic relevance as a promising marker and novel molecular target for the management of LARC.

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MicroRNAs in Rectal Cancer: Functional Significance and Promising Therapeutic Value

Cited by 12 publications

References 73 publications

Low MicroRNA-19b Expression Shows a Promising Clinical Impact in Locally Advanced Rectal Cancer

Low MicroRNA-19b Expression Shows a Promising Clinical Impact in Locally Advanced Rectal Cancer

Predicting response to neoadjuvant chemoradiotherapy in rectal cancer: from biomarkers to tumor models

Validation of microRNA-199b as A Promising Predictor of Outcome and Response to Neoadjuvant Treatment in Locally Advanced Rectal Cancer Patients

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