L. GUO ET AL.
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Table 1. An example of pathway enrichment analysis of mRNA targets of deregulated miRNAs.
Pathway No. P-value Target Genes
Cell cycle 18 3.01E−30 ATM; CCNA2; CCND1; CCND2; CCNE1; CDC25A; CDK6; CDKN1A; CDKN1B;
CDKN2A; E2F1; E2F2; E2F3; EP300; RB1; RBL2; TP53; WEE1
Prostate cancer 15 3.74E−26 AKT1; BCL2; CCND1; CCNE1; CDKN1A; CDKN1B; E2F1; E2F2; E2F3; EP300;
IGF1R; NFKB1; NRAS; RB1
Pancreatic cancer
; TP53
14 3.03E−25 ACVR1C; AKT1; CCND1; CDC42; CDK6; CDKN2A; E2F1; E2 F2; E2F3; NFKB1;
RAC1; RB1
Melanoma
; TP53; VEGFA
13 3.21E−23 AKT1; CCND1; CDK6; CDKN1A; CDKN2A; E2F1; E2F2; E2 F 3; IGF1R; MET;
NRAS; RB1; TP53
These target mRNAs are regulated by at least 2 abnormal miRNAs. mRNAs in bold type indicate up-regulated speci es, underlined mRNAs indicate down-regu-
lated species, and others indicate that they are sta bly e xpre ssed or not de te c ted.
these mRNAs might be targeted by these aberrant miR-
NA/isomiRs and lead to abnormal expression levels by
miRNA-mRNA interaction. Indeed, consistent or incon-
sistent expression patterns were detected from the actu al
aberrantly expressed mRNA profiles (Table 1). Although
miRNAs were down- or up-regulated in tumor cells, their
target mRNAs might be up- or down-regulated, or stably
expressed (Table 1). The pheno menon is mainly derived
from complex and multiple regulatory patterns between
miRNAs and mRNAs. Generally, on e miRNA can target
a great amount of mRNAs, whereas one mRNA can be
targeted by a series of miRNAs by miRNA-mRNA inte-
raction. The complex feedback loops contribute to the
whole flexible regulatory network.
Compared to miRNA, another non-coding regulatory
molecule, lncRNA, still remains mysterious. Herein, we
obtained the potential relationships between lncRNA-
mRNA and lncRNA-miRNA based on sequences and
location distr ib utio ns. Some miRNA-lncRNA and mRNA-
lncRNA pairs were surveyed based on their locations on
human chromosomes. They might be located on different
strands in the same genomic region, or located on the
same strand with the completely or partly over-lapped
regions. Based on the relationships of sequences or loca-
tions, miRNA/mRNA and lncRNA could have potential
functional relationships. The expression analysis indi-
cated that these pairs showed consistent or inconsistent
expression patterns, even though they could be reverse
complementarily binding (from the sense/antisense strands).
The results were similar to miRNA-mRNA interaction.
Although different RNA molecules may have functional
relationships, they might show various expressions as
well as consistent or inconsistent deregulated expression
patterns. Among of these, consistent expression patterns
between miRNA-lncRNA and mRN A-lncRNA were more
popular.
The genome-wide analysis of ncRNA-mRNA based
on their positional and functional relationships provides a
systematical integrative method to unveil potential rela-
tionships across different RNA molecules, including
ncRNAs (as regulatory RNA molecules) and mRNAs (as
functional RNA molecules). Here, based on aberrantly
expressed miRNA, lncRNA and mRNA profiles in tumor
cells, the integrative analysis suggested a robust regula-
tory network in tumorigenesis.
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