A microRNA Signature of Metastatic Colorectal Cancer

Abstract

BackgroundAlthough microRNAs (miRNAs) are involved in all hallmarks of cancer, miRNA dysregulation in the metastatic process remains poorly understood. We investigated the role of miRNAs in metastatic evolution of colorectal cancer (CRC) by analyzing smallRNA-seq datasets from primary CRC, metastatic locations (liver, lung and peritoneum), and corresponding adjacent tissues. Addressing main challenges of miRNA analysis, a bioinformatics pipeline was developed that contains bona fide miRNA annotations from MirGeneDB, utilizes the quality control software miRTrace, applies physiologically meaningful cutoffs and accounts for contribution of cell-type specific miRNAs and host tissue effects. ResultsTwo hundred-and-seventy-five miRNA sequencing datasets were analyzed, and after adjusting for the contribution of heterogeneity in cellular composition, strong signatures for primary and metastatic CRC were identified. The signature for primary CRC contained many previously known miRNAs with known functions. Deregulation of specific miRNAs was associated with individual metastatic sites, but the metastatic signatures contained overlapping miRNAs involved in key elements of the metastatic process, such as epithelial-to-mesenchymal transition and hypoxia. Notably, four of these miRNAs (MIR-8, MIR-10, MIR-375, MIR-210) belong to deeply conserved families present in many other organisms, triggering questions about their evolutionary functions and opportunities for experimental validation. Conclusion:Applying a meticulous pipeline for the analysis of smallRNA-seq data, miRNA signatures for primary and metastatic CRC were identified, contributing novel insights into miRNA involvement in CRC metastatic evolution and site-specific metastatic adaptations. New datasets can easily be included in this publicly available pipeline to continuously improve the knowledge in the field.

miRNome Profiling and Functional Analysis Reveal Involvement of hsa-miR-1246 in Colon Adenoma-Carcinoma Transition by Targeting AXIN2 and CFTR

“…Based on the statistical estimates of differential expression analysis, numerous miRNAs were found to be deregulated along the adenoma-carcinoma sequence. Most of them, including hsa-miR-1246, hsa-miR-215-5p, hsa-miR-31, hsa-miR-135b-5p, and hsa-miR-375, have been previously shown to be deregulated in CRC [16,[24][25][26][27], underlining their possible involvement in carcinogenesis. Moreover, in our dataset, hsa-miR-1246 and hsa-miR-215-5p showed the highest correlation with the adenoma-carcinoma transition-the former displayed a gradual increase, while the latter showed a gradual decrease in expression levels along the heathy-adenoma-carcinoma groups, which is partly in line with a previous study by Nagy et al [23].…”

Human miRNome Profiling in Colon Adenoma-carcinoma Sequence Reveal Early Deregulation of miR-1246, Which Exhibits Oncogenic Properties in Vitro by Targeting AXIN2 and CFTR

“…Based on the statistical estimates of differential expression analysis, numerous miRNAs were found to be deregulated along the adenoma-carcinoma sequence. Most of them, including hsa-miR-1246, hsa-miR-215-5p, hsa-miR-31, hsa-miR-135b-5p and hsa-miR-375 have been previously shown to be deregulated in CRC [16,[35][36][37][38], underlining their possible involvement in cancerogenesis. Moreover, in our dataset hsa-miR-1246 and hsa-miR-215-5p showed the highest correlation with the adenoma-carcinoma pathway -the former displayed a gradual increase, while the latter showed a gradual decrease in expression levels along the heathy-adenoma-carcinoma sequence, which is partly in line with a previous study by Nagy et al [34].…”