Down-regulation of miRNA-148a and miRNA-625-3p in colorectal cancer is associated with tumor budding

Abstract

Background: MiRNAs are often deregulated in colorectal cancer and might function as tumor suppressors or as oncogenes. They participate in controlling key signaling pathways involved in proliferation, invasion and apoptosis and may serve as prognostic and predictive markers. In this study we aimed to evaluate the role of miRNA-148a and miRNA-625-3p in metastatic colorectal cancer.

Methods: Fifty-four patients with a first-time diagnosed CRC receiving FOLFOX ± Bevacizumab were involved in the study. Tumor samples underwent routine pathology examination including evaluation for tumor budding and KRAS. MiRNA-148a and miRNA-625-3p expression analysis was done by RT-PCR. Associations between expression of both miRNAs and clinico-pathological factors, treatment outcomes and survival were analyzed.

Results: Both miRNA-148a and miRNA-625-3p were down-regulated in the tumors compared to normal colonic mucosa. Significantly lower expression of both miRNAs was noticed in tumors with budding phenomenon compared to tumors without it (median values of miRNA-148a were 0.314 and 0.753 respectively, p = 0.011, and 0.404 and 0.620 respectively for miRNA-625-3p, p = 0.036). Significantly lower expression of miRNA-625-3p was detected in rectal tumors, compared to tumors in the colon (median 0.390 and 0.665 respectively, p = 0.037). Progression free survival was significantly lower in patients with high miRNA-148a expression (6 and 9 months respectively, p = 0.033), but there were no significant differences in PFS for miRNA-625-3p and in overall survival for both miRNAs.

Conclusions: There was a significant relationship between low miRNA-148a and miRNA-625-3p expression and tumor budding, which is thought to represent epithelial-mesenchymal transition. Both studied miRNAs may be associated with a more aggressive phenotype and could be the potential prognostic and predictive biomarkers in CRC. Further investigation is needed to confirm miRNAs involvement in EMT, and their prognostic and predictive value.

Keywords: Colorectal cancer; MiRNA-148a; Oxaliplatin; Tumor budding; miRNA-625-3p; microRNA.

Fig. 1

Differences in miRNA-148a a and miRNA-625-3p b expression in tumor tissue and normal adjacent mucosa

Fig. 2

Differences in miRNA-148a and miRNA-625-3p expression in accordance to tumor budding and tumor location. a. MiRNA-148a expression according to tumor budding; b. MiRNA-625-3p expression according to tumor budding; c. MiRNA-625-3p expression according to tumor location; d MiRNA-625-3p expression according to tumor location

Fig. 3

Influence of miRNA-148a and miRNA-625-3p expressionon OS and PFS. a Kaplan-Meier curves for PFS according to miRNA-148a expression; b Kaplan-Meier curves for PFS according to miRNA-625-3p expression; c Kaplan-Meier curves for OS according to miRNA-148a expression; d Kaplan-Meier curves for OS according to miRNA-625-3p expression

Fig. 4

miR-148a and miR-625-3p target analysis. a. Table depicting hypothetical and validated target-genes of miR-148a and miR-625-3p miRNAs; b. Venn diagram showing the overlap between miR148a and miR-625-3p target-genes; c. Venn diagram showing the overlap between miR148a/miR-625-3p target-genes and genes involved in epithelial-mesenchymal transition (EMT); d. miR-148a-gene network visualizing target-genes associated with PI3K-Akt/FoxO signaling axis (upper network) or cell adhesion (lower network)