microRNA-1/133a and microRNA-206/133b clusters: dysregulation and functional roles in human cancers

Abstract

MicroRNAs (miRNAs) are endogenous short non-coding RNA molecules that regulate gene expression by repressing translation or cleaving RNA transcripts in a sequence-specific manner. A growing body of evidence suggests that miRNAs are aberrantly expressed in many human cancers and that they play significant roles in the initiation, development and metastasis of human cancers. Genome-wide miRNA expression signatures provide information on the aberrant expression of miRNAs in cancers rapidly and precisely. Recently, studies from our group and others revealed that microRNA-1 (miR-1), microRNA-133a (miR-133a), microRNA-133b (miR-133b) and microRNA-206 (miR-206) are frequently downregulated in various types of cancers. Interestingly, miR-1-1/miR-133a-2, miR-1-2/miR-133a-1, and miR-206/miR-133b form clusters in three different chromosomal regions of the human genome - 20q13.33, 18q11.2 and 6p12.1, respectively. Here we review highlights of recent findings on the aberrant expression and functional significance of the miR-1/miR-133a and miR-206/miR-133b clusters in human cancers.

Figure 1. The microRNA biosynthetic pathway

miRNA genes are transcribed by RNA polymerase II (Pol II). The resulting long transcript is capped with a specially-modified nucleotide at the 5' end, polyadenylated with multiple adenosines and spliced. The product is called primary miRNA (Pri-miRNA). Drosha crops Pri-miRNA into precursor-miRNA (Pre-miRNA). Pre-miRNA hairpins are exported from the nucleus to the cytoplasm by Exportin-5. In the cytoplasm, the pre-miRNA hairpin is cleaved by the RNase III enzyme Dicer. One strand is taken into the RNA-induced silencing complex (RISC), where the miRNA and its target interact. miRNAs that bind to mRNA targets with perfect matching induce mRNA cleavage, whereas translational repression is induced when matching is imperfect.

Figure 2. Gene structure of the human miR-1/133a and miR-206/133b clusters

(A) miR-1-1 and miR-133a-2 are in an intron of the C20orf166 gene on human chromosome 20q13.33, where they are separated by 10.5kb. (B) miR-1-2 and miR-133a-1 are in a complementary strand of an intron of the MIB1 gene on human chromosome 18q11.2, where they are separated by 3.2kb. (C) miR-206 and miR-133b are clustered together on human chromosome 6p12.2, where they are separated by 4.5kb.

Figure 3. Alignment of miR-1-1, miR-1-2 and miR-206

The structures of precursor miR-1-1, miR-1-2 and miR-206 as constructed by the Mfold program [92] (http://mfold.rna.albany.edu/). The respective Pre-miRNA sequences were entered into the program. Each mature miRNA sequence is shown below with red characters indicating variant nucleotides.

Figure 4. Alignment of miR-133a-1, miR-133a-2 and miR-133b

The structures of precursor miR-133a-1, miR-133a-2 and miR-133b as constructed by the Mfold program [92] (http://mfold.rna.albany.edu/). The respective Pre-miRNA sequences were entered into the program. Each mature miRNA sequence is shown below with red characters indicating variant nucleotides.

Figure 5. Workflow for the bioinformatic analysis of target genes of miR-1, miR-133a, miR-133b and miR-206

A total of 3716 genes were identified by the TargetScan program as predicted targets of miR-1, miR-133a, miR-133b and miR-206. The predicted target genes of miR-1 are the same as those of miR-206, and those of miR-133a are the same as those of miR-133b, due to the identical sequences of their seed regions. The genes were then analyzed and characterized in KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway categories [93] by the GENECODIS program (Left). Twenty significantly enriched signaling pathways are shown in descending order of the number of genes contained in each pathway (Right).