Human tumor microRNA signatures derived from large‐scale oligonucleotide microarray datasets

Abstract

The expression profiles of microRNAs (miRNAs) are associated with the initiation and progression of human tumors. DNA microarrays are widely used to explore the expression patterns of miRNAs. Because of the limited sample size and experimental expense, the statistical power of individual research projects is not sufficient to yield a robust conclusion. However, collected microarray datasets of expression profiles provide opportunities to compile the information of individual studies. Our study carried out a comprehensive meta-analysis of miRNA expression microarray datasets from 28 published tumor studies; it comprises 33 comparisons and nearly 4,000 tumor and corresponding nontumorous samples. This work reports 52 miRNAs as common signatures that are dysregulated in tumors. In addition to the commonly altered miRNAs, five solid cancers displayed specific tissue patterns of altered miRNAs as well. The meta-analysis also revealed some novel tumorrelated miRNAs such as hsa-miR-144, hsa-miR-130b, hsa-miR-132, hsa-miR-154, hsa-miR-192 and hsa-miR-345. We further validated the expression pattern of hsa-miR-154 in human hepatocellular carcinoma by RT-PCR. Restoration of intracellular miR-154 inhibited tumor cell malignance and the G 1 /S transition in cancer cells. Both bioinformatic prediction and western blotting demonstrated that miR-154 could target CCND2. In addition, expression patterns of miR-154 were inversely correlated with those of CCND2 in hepatocellular carcinoma. Overall, this study used a large-scale data analysis to identify a qualified list of miRNAs that are consistently changed in tumors, which could lead to a better understanding of human tumor etiology.

miR-154 inhibits migration and invasion of human non-small cell lung cancer by targeting ZEB2

“…Xin et al (18) reported that miR-154 remarkably suppressed cell proliferation, colony formation, migration and invasion in colorectal cancer cells by targeting Toll-like receptor 2. Wang et al (32) reported that overexpression of miR-154 suppressed tumor cell malignance and G1/S transition in hepatocellular cancer cells by targeting CCND2. In the present study, miR-154 could significantly inhibit the migration and invasion of NSCLC cells by targeting ZEB2.…”

A new microRNA target prediction tool identifies a novel interaction of a putative miRNA with CCND2

“…Subsequent experiments confirmed that miR-154 directly targets CCND2 in hepatocellular carcinoma (HCC), reduces tumorigenicity and inhibits the G1/S transition in cancer cells. 38 In line with these findings, our luciferase reporter assay results show that CCND2 is also targeted by c-miR-Ch9 as depicted by the decreased activity of the reporter gene in wild-type binding site conditions and the increased activity in mutated binding site conditions. Moreover, addition of anti-c-miR-Ch9 LNA to pGL4-10 + wt-Triplet conditions reduced regulation as shown by the observed increase in the reporter gene activity.…”

“…This target site was further confirmed by four other tools (TargetScan, StarMir, 24 PITA, DianaMicroT) which were used to perform target prediction using our novel miRNA sequence. The gene corresponding to this 3'UTR was CCND2, a gene with documented oncogenic activity 38 that is known to play a role in the G1/S transition of the cell cycle.…”

“…Since c-miR-Ch9 was found in a genomic region that is frequently deleted in various cancer types and CCND2 has a documented oncogenic activity, 38 the predicted interaction appears, at least in principle, quite plausible. Thus, we next performed experiments using reporter constructs carrying a Firefly luciferase reporter to test whether the predicted interaction is functional.…”

“…We then test Targetprofiler's ability to identify de novo biologically significant interactions by applying it on a recently identified miRNA candidate (hereafter denoted c-mir-Ch9) 36 that is located in a cancer associated genomic region frequently deleted in bladder cancer. 37 Finally we predict cyclin D2 (CCND2), a gene with documented oncogenic activity, 38 as a key target of c-mir-Ch9 and validate this interaction using luciferase reporter assays.…”