Abstract
Micro-RNA (miRNA or miR) regulates at least 60% of the genes in the human genome through their target sites at mRNA 3’-untranslated regions (UTR), and defects in miRNA expression regulation and target sites are frequently observed in cancers. We report here a systematic analysis of the distribution of miRNA target sites. Using the evolutionarily conserved miRNA binding sites in the TargetScan database (release 7.1), we constructed a miRNA co-regulation network by connecting genes sharing common miRNA target sites. The network possesses characteristics of the ubiquitous small-world network. Non-hub genes in the network—those sharing miRNA target sites with small numbers of genes—tend to form small cliques with their neighboring genes, while hub genes exhibit high levels of promiscuousness in their neighboring genes. Additionally, miRNA target site distribution is extremely uneven. Among the miRNAs, the distribution concentrates on a small number of miRNAs, in that their target sites occur in an extraordinarily large number of genes, that is, they have large numbers of target genes. The distribution across the genes follows a similar pattern; the mRNAs of a small proportion of the genes contain extraordinarily large numbers of miRNA binding sites. Quantitatively, the patterns fit into the P(K) ∝ K−α relationship (P(K): the number of miRNAs with K target genes or genes with K miRNA sites; α: a positive constant), the mathematical description of connection distribution among the nodes and a defining characteristic of the so-called scale-free networks—a subset of small-world networks. Notably, well-known tumor-suppressive miRNAs (Let-7, miR-15/16, 26, 29, 31, 34, 145, 200, 203–205, 223, and 375) collectively have more than expected target genes, and well-known cancer genes contain more than expected miRNA binding sites. In summary, miRNA target site distribution exhibits characteristics of the small-world network. The potential to use this pattern to better understand miRNA function and their oncological roles is discussed.
Highlights
IntroductionIt is clear that microRNA (miRNA or miR) aberrancy is a critical factor in cancer
It is clear that microRNA aberrancy is a critical factor in cancer
Alterations in oncogene and tumor-suppressor gene coding regions were considered to be the only causes of tumorigenesis, as these genes are involved in cellular pathways underneath key physiological processes such as cell cycle, apoptosis and cellular homeostasis
Summary
It is clear that microRNA (miRNA or miR) aberrancy is a critical factor in cancer. Oncogenic genetic alterations are responsible for cancer initiation, gradual enlargement and disorganization of tumor tissues and, metastasis [1]. Alterations in oncogene and tumor-suppressor gene coding regions were considered to be the only causes of tumorigenesis, as these genes are involved in cellular pathways underneath key physiological processes such as cell cycle, apoptosis and cellular homeostasis. Many studies have identified a large number of non-coding RNA (ncRNA) transcripts with no significant open reading frame. These transcripts are involved in key biological processes, such as cell cycle, and exhibit aberrancy in cancers [2]. The miRNA, a family of approximately 20–22 nucleotide long RNAs, is a prominent category of ncRNA [3,4,5]
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