miRNAs in human cancer

Abstract

Mature microRNAs (miRNAs) are single-stranded RNA molecules of 20-23 nucleotide (nt) length that control gene expression in many cellular processes. These molecules typically reduce the stability of mRNAs, including those of genes that mediate processes in tumorigenesis, such as inflammation, cell cycle regulation, stress response, differentiation, apoptosis and invasion. miRNA targeting is mostly achieved through specific base-pairing interactions between the 5' end ('seed' region) of the miRNA and sites within coding and untranslated regions (UTRs) of mRNAs; target sites in the 3' UTR lead to more effective mRNA destabilization. Since miRNAs frequently target hundreds of mRNAs, miRNA regulatory pathways are complex. To provide a critical overview of miRNA dysregulation in cancer, we first discuss the methods currently available for studying the role of miRNAs in cancer and then review miRNA genomic organization, biogenesis and mechanism of target recognition, examining how these processes are altered in tumorigenesis. Given the critical role miRNAs play in tumorigenesis processes and their disease-specific expression, they hold potential as therapeutic targets and novel biomarkers.

Figure 1

miRNA biogenesis pathway. miRNAs are transcribed by RNAPII to produce pri-miRNAs. Canonical miRNAs are processed by the endoribonuclease Drosha in partnership with its RBP partner DGCR8; mirtrons are instead processed by the spliceosome. The processed pre-miRNA is transported to the cytoplasm through an export complex consisting of Exportin 5. The pre-miRNA is subsequently processed in the cytoplasm by another endoribonuclease Dicer in partnership with its RBP partner TRBP to form the final 21–23 nucleotide miRNA product. miR-451 is not processed by Dicer but is rather cleaved by Ago2. Mature miRNAs (indicated in red) are then incorporated into Ago 1 through 4 forming miRNPs, also known as miRISC. miRNPs also incorporate other proteins, such as GW182. miRNPs are thought to direct miRNA mediated destabilization (i.e. through interaction with CCR4) or miRNA mediated translational repression (i.e. through interaction with ribosomes) of miRNAs without perfectly complementary mRNA targets. miRISC is thought to direct Ago2 catalyzed target mRNA cleavage of miRNA fully or nearly fully complementary mRNA targets.

Figure 2

miRNA genomic and functional organization. The genomic and functional organization of 4 miRNA clusters/families is clarified: (A) let-7/98, (B) mir-141/200a, (C) mir-21 and (D) mir-17-92. The genomic locations for each of the miRNA members are defined. Grey lines denote intronic regions. miRNA mature sequences are color coded according to the sequence family they belong to (i.e. in the let-7 cluster red signifies the let-7/miR-98 sequence family. The star sequence is defined with a grey bar. The sequence families are depicted as sequence alignments compared to the most highly expressed miRNA family member shown on top, based on profiles of over 1,000 human specimens (Tuschl unpublished data). Shaded residues denote differences from the most highly expressed miRNA family member.

Figure 3

miRNA breast tumor and cell line profiles. Comparison of abundance profiles of the top expressed miRNA sequence families of normal breast, an estrogen receptor positive invasive ductal carcinoma breast tumor (ER+), the MCF7 ductal derived cell line, human subcutaneous adipose tissue and red blood cells.