MicroRNA biogenesis pathways in cancer

Abstract

MicroRNAs (miRNAs) are critical regulators of gene expression. Amplification and overexpression of individual 'oncomiRs' or genetic loss of tumour suppressor miRNAs are associated with human cancer and are sufficient to drive tumorigenesis in mouse models. Furthermore, global miRNA depletion caused by genetic and epigenetic alterations in components of the miRNA biogenesis machinery is oncogenic. This, together with the recent identification of novel miRNA regulatory factors and pathways, highlights the importance of miRNA dysregulation in cancer.

Figure 1. Overview of miRNA biogenesis pathway

MicroRNA (miRNA) genes are transcribed as primary miRNAs (pri-miRNAs) by RNA polymerase II (Pol II) in the nucleus. The long pri-miRNAs are cleaved by Microprocessor, which includes DROSHA and DiGeorge syndrome critical region 8 (DGCR8), to produce the 60–70-nucleotide precursor miRNAs (pre-miRNAs). The pre-miRNAs are then exported from the nucleus to the cytoplasm by exportin 5 (XPO5) and further processed by DICER1, a ribonuclease III (RIII) enzyme that produces the mature miRNAs. One strand of the mature miRNA (the guide strand) is loaded into the miRNA-induced silencing complex (miRISC), which contains DICER1 and Argonaute (AGO) proteins, directs the miRISC to target mRNAs by sequence complementary binding and mediates gene suppression by targeted mRNA degradation and translational repression in processing bodies (P-bodies). TRBP, transactivation-responsive RNA-binding protein.

Figure 2. Mutation of the miRNA biogenesis pathway in cancer

Mutations of the microRNA (miRNA) biogenesis pathway genes identified in cancer are summarized and represented by their relative locations in the protein and the type of mutation. The detailed mutational information (mutation locations, mutation types and tumour types) is provided in Supplementary information S1 (table). ATF, armadillo-type fold; DGCR8, DiGeorge syndrome critical region 8; Dimer, dimerization domain; dsRBD, double-stranded RNA-binding domain; IBN_N, importin-β amino-terminal domain; NLS, nuclear localization signal; PAZ, Piwi–Argonaute–Zwille domain; RNase, ribonuclease; pre-miRNA, precursor miRNA; TRBP, transactivation-responsive RNA-binding protein; WW, WW domain (also known as WWP-repeating motif); XPO1, exportin 1/importin β-like domain; XPO5, exportin 5.

Figure 3. Dysregulated miRNA biogenesis in cancer

Aberrant microRNA (miRNA) biogenesis in cancer occurs at different steps during miRNA maturation. a | Genetic alterations, epigenetic modifications, oncogenes and tumour suppressors negatively or positively regulate primary miRNA (pri-miRNA) transcription in cancer. b | Pri-miRNA processing is regulated in the following ways: hypoxia, genetic mutations and transcriptional regulation control DROSHA and DiGeorge syndrome critical region 8 (DGCR8) expression in cancer; RNA-binding proteins such as DEAD box protein 5 (DDX5), DDX17 and BRCA1 modulate Microprocessor activity in cancer; cell signalling pathways such as Hippo and bone morphogenetic protein (BMP) regulate pri-miRNA processing; and LIN28 proteins selectively block the processing of pri-let-7. c | Genetic mutations in and transcriptional regulation of exportin 5 (XPO5) affect XPO5-mediated precursor miRNA (pre-miRNA) export in cancer. d | Pre-miRNA processing in cancer is regulated in the following ways: hypoxia, genetic mutations and transcriptional regulation modulate DICER1 expression and function to control pre-miRNA cleavage in cancer; LIN28 proteins selectively bind to pre-let-7 and recruit terminal uridylyltransferase 4 (TUT4), TUT7 and DIS3-like exonuclease 2 (DIS3L2) to degrade pre-let-7; and hypoxia-induced and epidermal growth factor receptor (EGFR)-induced phosphorylation of Y393 of Argonaute 2 (AGO2) inhibits pre-miRNA processing. e | miRNA function is regulated in the following ways: competing endogenous RNA (ceRNA) inhibits miRNA function in cancer (high-mobility group AT-hook 2 (HMGA2) blocks let-7 function), as do mutations of miRNA-binding sites in non-small cell lung cancer (mutation of let-7-binding site in the 3′ untranslated region (UTR) of KRAS mRNA). hnRNP, heterogeneous nuclear ribonucleoprotein; KDM6, lysine-specific demethylase 6; KSRP, KH-type splicing regulatory protein; Pol II, RNA polymerase II; RIII, ribonuclease III; SRSF1, serine/arginine-rich splicing factor 1; TGFβ, transforming growth factor-β; TRBP, transactivation-responsive RNA-binding protein; YAP, Yes-associated protein; ZEB, zinc-finger E-box-binding homeobox.