Differential Expression of miRNAs in Colorectal Cancer: Comparison of Paired Tumor Tissue and Adjacent Normal Mucosa Using High-Throughput Sequencing

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.

Epigenetic Silencing of miR-490-3p Reactivates the Chromatin Remodeler SMARCD1 to PromoteHelicobacter pylori–Induced Gastric Carcinogenesis

“…Our findings revealed that epigenetic silencing of miR-490-3p promoted gastric tumorigenesis by upregulating SMARCD1, a member of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling family involved in cancer development (18). MiR-490-3p has been shown to exert tumor-suppressing actions in other types of cancer, such as colon and lung cancers (19,20). Here, we demonstrated that promoter DNA hypermethylation of its host gene CHRM2 might account for the downregulation of miR-490-3p in gastric cancer.…”

MicroRNAs associated with small bowel neuroendocrine tumours and their metastases

“…Accordingly, re-expression of miR-1 in bladder cancer (Yoshino et al 2011), hepatocellular carcinoma , lung cancer ) and rhabdomyosarcoma (Yan et al 2009) inhibits tumour cell growth and metastatic traits. Deep sequencing has also found miR-1 levels to be reduced in colorectal cancers (CRCs) and a case of colorectal NET (Hamfjord et al 2012). miR-1 downregulation in human CRCs has been correlated with over-expression of the MET gene, especially in advanced stages of progression (Migliore et al 2012).…”

MicroRNA-183/182/96 cooperatively regulates the proliferation of colon cancer cells

“…It has been suggested that this cluster is unregulated in colon cancer tissues. To confirm the expression levels of the members of this gene cluster in colon cancer, a total of five previous studies (Table I) (16)(17)(18)(19)(20), which investigated miRNA expression in colon cancer, were examined and the fold changes of these three miRNAs in colon cancer tissues were compared with those in normal tissue. The clinical characteristics of these studies were extracted and are listed in Table I.…”