Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer related deaths and the search for prognostic biomarkers that might improve treatment decisions is warranted. MicroRNAs (miRNAs) are short non-coding RNA molecules involved in regulating gene expression and have been proposed as possible biomarkers in CRC. In order to characterize the miRNA transcriptome, a large cohort including 88 CRC tumors with long-term follow-up was deep sequenced. 523 mature miRNAs were expressed in our cohort, and they exhibited largely uniform expression patterns across tumor samples. Few associations were found between clinical parameters and miRNA expression, among them, low expression of miR-592 and high expression of miR-10b-5p and miR-615-3p were associated with tumors located in the right colon relative to the left colon and rectum. High expression of miR-615-3p was also associated with poorly differentiated tumors. No prognostic biomarker candidates for overall and metastasis-free survival were identified by applying the LASSO method in a Cox proportional hazards model or univariate Cox. Examination of the five most abundantly expressed miRNAs in the cohort (miR-10a-5p, miR-21-5p, miR-22-3p, miR-143-3p and miR-192-5p) revealed that their collective expression represented 54% of the detected miRNA sequences. Pathway analysis of the target genes regulated by the five most highly expressed miRNAs uncovered a significant number of genes involved in the CRC pathway, including APC, TGFβ and PI3K, thus suggesting that these miRNAs are relevant in CRC.
Highlights
MicroRNAs are evolutionary conserved small (,20– 22 nt long), non-coding RNAs that regulate gene expression by binding to the 39UTR of mRNA, thereby inhibiting translation [1]
Deep sequencing was used to quantify miRNA expression in a large cohort of Colorectal cancer (CRC) tumor samples. This approach may contribute potential advantages in global miRNA expression analysis, and entails new challenges regarding data analysis, as the amount of data collected after deep sequencing contains millions of reads which need to be mapped to the genome and normalized [30]
The five miRNAs most abundantly expressed in the examined CRC cohort were miR-10a-5p, miR-21-5p, miR-22-3p, miR-1433p and miR-192-5p, and all of these have previously shown to be dysregulated in CRC [32,33,34,35,36,37,38]
Summary
MicroRNAs (miRNA) are evolutionary conserved small (,20– 22 nt long), non-coding RNAs that regulate gene expression by binding to the 39UTR of mRNA, thereby inhibiting translation [1] They can bind with partial complementarity to mRNA to potentially downregulate several mRNAs. They can bind with partial complementarity to mRNA to potentially downregulate several mRNAs This makes the downstream studies somewhat challenging with multiple potential targets for each miRNA. MiRNAs are essential for normal mammalian development and are involved in fine-tuning many biological processes, such as cell proliferation, differentiation, apoptosis and metabolism, and their involvement in cancer has sparked increased interest in miRNA biology [4,5,6] They have been proposed as possible biomarkers because of their regulatory functions, chemical stability and the possibility of measuring miRNA in serum, plasma, stool and tissue samples [7,8,9,10]
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