Abstract
We present the results of a global study of dysregulated miRNAs in paired samples of normal mucosa and tumor from eight patients with colorectal cancer. Although there is existing data of miRNA contribution to colorectal tumorigenesis, these studies are typically small to medium scale studies of cell lines or non-paired tumor samples. The present study is to our knowledge unique in two respects. Firstly, the normal and adjacent tumor tissue samples are paired, thus taking into account the baseline differences between individuals when testing for differential expression. Secondly, we use high-throughput sequencing, thus enabling a comprehensive survey of all miRNAs expressed in the tissues. We use Illumina sequencing technology to perform sequencing and two different tools to statistically test for differences in read counts per gene between samples: edgeR when using the pair information and DESeq when ignoring this information, i.e., treating tumor and normal samples as independent groups. We identify 37 miRNAs that are significantly dysregulated in both statistical approaches, 19 down-regulated and 18 up-regulated. Some of these miRNAs are previously published as potential regulators in colorectal adenocarcinomas such as miR-1, miR-96 and miR-145. Our comprehensive survey of differentially expressed miRNAs thus confirms some existing findings. We have also discovered 16 dysregulated miRNAs, which to our knowledge have not previously been associated with colorectal carcinogenesis: the following significantly down-regulated miR-490-3p, -628-3p/-5p, -1297, -3151, -3163, -3622a-5p, -3656 and the up-regulated miR-105, -549, -1269, -1827, -3144-3p, -3177, -3180-3p, -4326. Although the study is preliminary with only eight patients included, we believe the results add to the present knowledge on miRNA dysregulation in colorectal carcinogenesis. As such the results would serve as a robust training set for validation of potential biomarkers in a larger cohort study. Finally, we also present data supporting the hypothesis that there are differences in miRNA expression between adenocarcinomas and neuroendocrine tumors of the colon.
Highlights
Colorectal cancer (CRC) is one of the most frequently occurring cancers worldwide [1]
Histopathology was reviewed by a pathologist (Table 1), and it was evident that one patient was misclassified and harbored an atypical neuroendocrine tumor (NET) whereas the rest were adenocarcinomas
It has been indicated that global down-regulation promotes cell transformation and tumorigenesis [10,15,29], a large expression profiling study of solid tumors by Volinia et al did not observe down-regulation of miRs as previously reported [30]
Summary
Colorectal cancer (CRC) is one of the most frequently occurring cancers worldwide [1]. MicroRNAs (miRs) are small non-coding RNA molecules 18-25 nucleotides in length, first discovered in the early 1990s in C. elegans [5] They maintain homeostasis by altering gene expression in different cell processes such as differentiation, proliferation, survival and apoptosis [6]. Studies have shown that miRs may be dysregulated in different human cancers, and act as tumor suppressors or oncogenes [9,10]. These molecules are interesting since they may be potential biomarkers of diagnosis or prognosis and act as potential targets in cancer specific therapy as reviewed by Cho et al [11,12]. The ultimate goal would be personalized medicine with genotypephenotype cancer networks as the roadmap to clinical decisions [13]
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