Overexpression of miR-21-5p as a predictive marker for complete tumor regression to neoadjuvant chemoradiotherapy in rectal cancer patients

Abstract

BackgroundNeoadjuvant chemoradiotherapy (nCRT) followed by radical surgery is the preferred treatment strategy for locally advanced rectal cancer. However, complete tumor regression is observed in a significant proportion of patients after nCRT, making them ideal candidates for alternative treatment strategies to this considerably morbid procedure. Identification of such patients based on clinical findings (complete clinical response - cCR) is difficult mainly because it relies on subjective clinical and imaging studies. Our goal was to identify biomarkers capable of predicting complete response to nCRT.MethodsWe analyzed miRNA expression profile using deep sequencing in rectal tumor biopsies prior to nCRT. Differential expression was investigated by EdgeR for a training (n = 27) and a validation (n = 16) set of patients to identify miRNAs associated with treatment response (complete vs. incomplete). In vitro experiments with two cancer cell lines were also performed in order to evaluate the possible role of miRNAs on response to nCRT.ResultsWe found 4 miRNAs differentially expressed between complete and incomplete responders to nCRT. In addition, validation was performed using an independent group of patients and miR-21-5p was confirmed as being overexpressed in complete responders. Overall sensitivity and specificity of miR-21-5p expression in predicting complete response to nCRT was 78% and 86% respectively. Interestingly, in a subset of patients with cCR followed by early local recurrence, the expression level of miR-21-5p was considerably low, similarly to incomplete responders. We also found SATB1, a miR-21-5p target gene and known multidrug resistance gene, whose expression was inversely correlated with miR-21-5p expression. Finally, we performed functional experiments and showed that miR-21-5p and SATB1 may be directly involved with poor response to nCRT in rectal cancer patients.ConclusionsThis study suggests miR-21-5p as a promising predictive biomarker, which should aid in the selection of patients with cCR to nCRT that potentially could be spared from radical surgery.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-014-0068-7) contains supplementary material, which is available to authorized users.

Predictive and prognostic biomarkers for neoadjuvant chemoradiotherapy in locally advanced rectal cancer

“…2 transcripts miR-519c-3p and miR-561 predicted good versus poor response with a median accuracy of 100% 20 fresh rectal biopsy samples [115] Neoadjuvant chemotherapy (capecitabine or infusional 5-FU) and radiotherapy miR-215, miR190b and miR-29b-2 were overexpressed in non-responders while let-7e, miR-196b, miR-450a, miR-450b-5-p and miR-99a were overexpressed in responders (Mandard) 85 formalin-fixed paraffin embedded post-treatment samples [116] Neoadjuvant chemotherapy (capecitabine) and radiotherapy miR-21, miR-99, miR-125b, miR-125b1, let-7c and miR-490 upregulation correlated with TRG 1-2 (Mandard). miR-21 and miR-125a-3p downregulation correlated with TRG 4 40 formalin-fixed paraffin embedded biopsy and post-treatment samples [117] Neoadjuvant chemotherapy AUC (area under curve) of 0.94 [79]. Of note, they validated their findings in an independent group of patients.miRNA has been reported to be important in determination of radiosensitivity of rectal cancers to chemoradiotherapy.…”

MicroRNA‑21‑5p induces the metastatic phenotype of human cervical carcinoma cells in vitro by targeting the von Hippel‑Lindau tumor suppressor

“…This suggests that miR-21-5p may be associated with the progression of CC malignancy. The results were corroborated by previous studies, which produced similar results (3,(9)(10)(11)(12). Notably, it was identified that miR-21-5p stimulates the proliferation and migration of CC cells through inhibition of the PTEN pathway (3).…”

“…A prior study demonstrated the association of miR-21-5p overexpression with tongue cancer cell chemo-resistance via cell adhesion molecule 1 targeting (9). miR-21-5p overexpression has also been identified as a possible predictor of tumor regression following chemoradiotherapy in patients with rectal cancer (10), and as a biomarker of recurrence in young patients with gastric cancer (11) and thymic epithelial tumors (12). It has been reported that the competing endogenous regulation of miR-21-5p by the long non-coding RNA maternally expressed 3 inhibits CC cell proliferation and apoptosis (13).…”

MicroRNA-21 predicts response to preoperative chemoradiotherapy in locally advanced rectal cancer

“…Moreover, it has been recently reported that miR-21 and SATB1 could predict complete response to preoperative CRT in rectal cancer patients. Despite that it is a wellconducted study showing very interesting findings, the relative short number of cases included in the training (n=27) and validating groups (n=16) makes necessary to further investigate the miR-21 prognostic value [33]. Finally, recent works highlight the potential clinical significance of circulating miR-21 in colorectal cancer patients [34,35].…”