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MicroRNA Processing and Human Cancer.

Ohtsuka M, Ling H, Doki Y, Mori M, Calin GA - J Clin Med (2015)

Bottom Line: Since the first report on the clinical relevance of miRNAs in cancer, many miRNAs have been demonstrated to act as oncogenes, whereas others function as tumor suppressors.As previous studies have shown, the sequential miRNA processing can be divided into three steps: processing by RNAse in the nucleus; transportation by Exportin-5 (XPO5) from the nucleus; and processing by the RNA-induced silencing complex (RISC) in the cytoplasm.Alteration in miRNA processing genes, by genomic mutations, aberrant expression or other means, could significantly affect cancer initiation, progression and metastasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, 1881 East Road, Unit 1950, APT 1125, Houston, TX 77030, USA. MOhtsuka@mdanderson.org.

ABSTRACT
MicroRNAs (miRNAs) are short non-coding RNAs of 20 to 25 nucleotides that regulate gene expression post-transcriptionally mainly by binding to a specific sequence of the 3' end of the untranslated region (3'UTR) of target genes. Since the first report on the clinical relevance of miRNAs in cancer, many miRNAs have been demonstrated to act as oncogenes, whereas others function as tumor suppressors. Furthermore, global miRNA dysregulation, due to alterations in miRNA processing factors, has been observed in a large variety of human cancer types. As previous studies have shown, the sequential miRNA processing can be divided into three steps: processing by RNAse in the nucleus; transportation by Exportin-5 (XPO5) from the nucleus; and processing by the RNA-induced silencing complex (RISC) in the cytoplasm. Alteration in miRNA processing genes, by genomic mutations, aberrant expression or other means, could significantly affect cancer initiation, progression and metastasis. In this review, we focus on the biogenesis of miRNAs with emphasis on the potential of miRNA processing factors in human cancers.

No MeSH data available.


Related in: MedlinePlus

MiRNAs Biogenesis Pathway; Canonical Pathway; First, miRNAs are transcribed from the genome by RNA polymerase II (RNAP II) into primary transcripts (pri-miRNA) in the nucleus. Second, pri-miRNAs are cleaved into precursor miRNAs (pre-miRNAs) by the ribonuclease (RNAase) III family enzyme Drosha, which forms a micro-processor complex with the DNA-binding protein DGCR8. Third, miRNA precursors (pre-miRNAs) are exported to the cytoplasm by a Ran-GTP-dependent dsRNA-binding protein, Exportin-5 (XPO5). Fourth, Dicer, an RNAase III-type endonuclease, together with transactivating response RNA-binding protein (TRBP) and Kinase R-activating protein (PACT), cleaves pre-miRNAs in the cytoplasm. Finally, the guide miRNA generated by Dicer is loaded onto the RNA-induced silencing complex (RISC) consisting of Dicer, TRBP and PACT and Argonaute 2 (AGO2) and consequently binds to the 3′UTR of target genes, inducing degradation or translational inhibition of the target mRNA. Non-canonical Pathway (Dicer independent); Following transportation from nucleus to cytoplasm, pre-miR-451 is directly assembled onto AGO2-eIF1A complex. Consequently, the pre-miR-451 hairpin structure is cleaved by the Argonaute RNAase H-like motif to form the single strand mature miR-451. The generated mature miR-451 binds to the 3′UTR, and regulate expression of target genes.
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jcm-04-01651-f001: MiRNAs Biogenesis Pathway; Canonical Pathway; First, miRNAs are transcribed from the genome by RNA polymerase II (RNAP II) into primary transcripts (pri-miRNA) in the nucleus. Second, pri-miRNAs are cleaved into precursor miRNAs (pre-miRNAs) by the ribonuclease (RNAase) III family enzyme Drosha, which forms a micro-processor complex with the DNA-binding protein DGCR8. Third, miRNA precursors (pre-miRNAs) are exported to the cytoplasm by a Ran-GTP-dependent dsRNA-binding protein, Exportin-5 (XPO5). Fourth, Dicer, an RNAase III-type endonuclease, together with transactivating response RNA-binding protein (TRBP) and Kinase R-activating protein (PACT), cleaves pre-miRNAs in the cytoplasm. Finally, the guide miRNA generated by Dicer is loaded onto the RNA-induced silencing complex (RISC) consisting of Dicer, TRBP and PACT and Argonaute 2 (AGO2) and consequently binds to the 3′UTR of target genes, inducing degradation or translational inhibition of the target mRNA. Non-canonical Pathway (Dicer independent); Following transportation from nucleus to cytoplasm, pre-miR-451 is directly assembled onto AGO2-eIF1A complex. Consequently, the pre-miR-451 hairpin structure is cleaved by the Argonaute RNAase H-like motif to form the single strand mature miR-451. The generated mature miR-451 binds to the 3′UTR, and regulate expression of target genes.

Mentions: The processing of miRNAs includes multiple steps that initiate in the nucleus and complete in the cytoplasm. First, miRNAs are transcribed from the genome by RNA polymerase II (RNAP II) into primary transcripts (pri-miRNA) that contain a stem-loop structure [22]. Second, pri-miRNAs are cleaved into precursor miRNAs (pre-miRNAs) with hairpin structures by the ribonuclease (RNAase) III family enzyme Drosha, which forms a micro-processor complex with the DNA-binding protein DGCR8 [23]. Previous research showed that the double-stranded stem structure and the unpaired flanking regions of pri-miRNAs are essential for binding and cleavage by DGCR8 and Drosha. DGCR8 binds to pri-miRNAs and the central part of the Drosha protein, ensuring a correct assembling. Drosha has two RNAase III domains (RIIIDs), which cleave the 3′- and 5′-strand of the stem-loop structure of miRNAs, respectively to create pre-miRNAs [24,25]. Third, pre-miRNAs are exported to the cytoplasm by a Ran-GTP-dependent dsRNA-binding protein, XPO5 [26,27]. Fourth, Dicer, an RNAase III-type endonuclease, together with transactivating response RNA-binding protein (TRBP) and Kinase R-activating protein (PACT), cleaves pre-miRNAs in the cytoplasm. The cleavage by Dicer generates a 20–25 nucleotide miRNA duplex consisting of a guide (referred to as miRNA) and passenger (referred to as miRNA*) strand [28,29]. The guide miRNA generated by Dicer is loaded onto RISC, consisting of Dicer, TRBP and PACT, Argonaute 2 (AGO2) and GW182/TNRC6 [28,30]. The RISC-miRNA complex (named miRISC) functions as a guide to detect the 3′UTR of target genes [31]. This process induces degradation or translational inhibition of the target mRNA, depending on the degree of complementarity between miRNA and its mRNA targets [32]. Generally, miRNA from the passive strand (miRNA*) is degraded and exhibits no effect on gene regulation. However, recent studies have shown that miRNA*s can also associate with the RISC complex and subsequently repress target mRNAs with biological effects similar to that of mature miRNAs [33]. Therefore, biogenesis of miRNAs is tightly controlled at multiple levels, and any defects in such processes could have important biological effects in cancer (Figure 1).


MicroRNA Processing and Human Cancer.

Ohtsuka M, Ling H, Doki Y, Mori M, Calin GA - J Clin Med (2015)

MiRNAs Biogenesis Pathway; Canonical Pathway; First, miRNAs are transcribed from the genome by RNA polymerase II (RNAP II) into primary transcripts (pri-miRNA) in the nucleus. Second, pri-miRNAs are cleaved into precursor miRNAs (pre-miRNAs) by the ribonuclease (RNAase) III family enzyme Drosha, which forms a micro-processor complex with the DNA-binding protein DGCR8. Third, miRNA precursors (pre-miRNAs) are exported to the cytoplasm by a Ran-GTP-dependent dsRNA-binding protein, Exportin-5 (XPO5). Fourth, Dicer, an RNAase III-type endonuclease, together with transactivating response RNA-binding protein (TRBP) and Kinase R-activating protein (PACT), cleaves pre-miRNAs in the cytoplasm. Finally, the guide miRNA generated by Dicer is loaded onto the RNA-induced silencing complex (RISC) consisting of Dicer, TRBP and PACT and Argonaute 2 (AGO2) and consequently binds to the 3′UTR of target genes, inducing degradation or translational inhibition of the target mRNA. Non-canonical Pathway (Dicer independent); Following transportation from nucleus to cytoplasm, pre-miR-451 is directly assembled onto AGO2-eIF1A complex. Consequently, the pre-miR-451 hairpin structure is cleaved by the Argonaute RNAase H-like motif to form the single strand mature miR-451. The generated mature miR-451 binds to the 3′UTR, and regulate expression of target genes.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4555082&req=5

jcm-04-01651-f001: MiRNAs Biogenesis Pathway; Canonical Pathway; First, miRNAs are transcribed from the genome by RNA polymerase II (RNAP II) into primary transcripts (pri-miRNA) in the nucleus. Second, pri-miRNAs are cleaved into precursor miRNAs (pre-miRNAs) by the ribonuclease (RNAase) III family enzyme Drosha, which forms a micro-processor complex with the DNA-binding protein DGCR8. Third, miRNA precursors (pre-miRNAs) are exported to the cytoplasm by a Ran-GTP-dependent dsRNA-binding protein, Exportin-5 (XPO5). Fourth, Dicer, an RNAase III-type endonuclease, together with transactivating response RNA-binding protein (TRBP) and Kinase R-activating protein (PACT), cleaves pre-miRNAs in the cytoplasm. Finally, the guide miRNA generated by Dicer is loaded onto the RNA-induced silencing complex (RISC) consisting of Dicer, TRBP and PACT and Argonaute 2 (AGO2) and consequently binds to the 3′UTR of target genes, inducing degradation or translational inhibition of the target mRNA. Non-canonical Pathway (Dicer independent); Following transportation from nucleus to cytoplasm, pre-miR-451 is directly assembled onto AGO2-eIF1A complex. Consequently, the pre-miR-451 hairpin structure is cleaved by the Argonaute RNAase H-like motif to form the single strand mature miR-451. The generated mature miR-451 binds to the 3′UTR, and regulate expression of target genes.
Mentions: The processing of miRNAs includes multiple steps that initiate in the nucleus and complete in the cytoplasm. First, miRNAs are transcribed from the genome by RNA polymerase II (RNAP II) into primary transcripts (pri-miRNA) that contain a stem-loop structure [22]. Second, pri-miRNAs are cleaved into precursor miRNAs (pre-miRNAs) with hairpin structures by the ribonuclease (RNAase) III family enzyme Drosha, which forms a micro-processor complex with the DNA-binding protein DGCR8 [23]. Previous research showed that the double-stranded stem structure and the unpaired flanking regions of pri-miRNAs are essential for binding and cleavage by DGCR8 and Drosha. DGCR8 binds to pri-miRNAs and the central part of the Drosha protein, ensuring a correct assembling. Drosha has two RNAase III domains (RIIIDs), which cleave the 3′- and 5′-strand of the stem-loop structure of miRNAs, respectively to create pre-miRNAs [24,25]. Third, pre-miRNAs are exported to the cytoplasm by a Ran-GTP-dependent dsRNA-binding protein, XPO5 [26,27]. Fourth, Dicer, an RNAase III-type endonuclease, together with transactivating response RNA-binding protein (TRBP) and Kinase R-activating protein (PACT), cleaves pre-miRNAs in the cytoplasm. The cleavage by Dicer generates a 20–25 nucleotide miRNA duplex consisting of a guide (referred to as miRNA) and passenger (referred to as miRNA*) strand [28,29]. The guide miRNA generated by Dicer is loaded onto RISC, consisting of Dicer, TRBP and PACT, Argonaute 2 (AGO2) and GW182/TNRC6 [28,30]. The RISC-miRNA complex (named miRISC) functions as a guide to detect the 3′UTR of target genes [31]. This process induces degradation or translational inhibition of the target mRNA, depending on the degree of complementarity between miRNA and its mRNA targets [32]. Generally, miRNA from the passive strand (miRNA*) is degraded and exhibits no effect on gene regulation. However, recent studies have shown that miRNA*s can also associate with the RISC complex and subsequently repress target mRNAs with biological effects similar to that of mature miRNAs [33]. Therefore, biogenesis of miRNAs is tightly controlled at multiple levels, and any defects in such processes could have important biological effects in cancer (Figure 1).

Bottom Line: Since the first report on the clinical relevance of miRNAs in cancer, many miRNAs have been demonstrated to act as oncogenes, whereas others function as tumor suppressors.As previous studies have shown, the sequential miRNA processing can be divided into three steps: processing by RNAse in the nucleus; transportation by Exportin-5 (XPO5) from the nucleus; and processing by the RNA-induced silencing complex (RISC) in the cytoplasm.Alteration in miRNA processing genes, by genomic mutations, aberrant expression or other means, could significantly affect cancer initiation, progression and metastasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, 1881 East Road, Unit 1950, APT 1125, Houston, TX 77030, USA. MOhtsuka@mdanderson.org.

ABSTRACT
MicroRNAs (miRNAs) are short non-coding RNAs of 20 to 25 nucleotides that regulate gene expression post-transcriptionally mainly by binding to a specific sequence of the 3' end of the untranslated region (3'UTR) of target genes. Since the first report on the clinical relevance of miRNAs in cancer, many miRNAs have been demonstrated to act as oncogenes, whereas others function as tumor suppressors. Furthermore, global miRNA dysregulation, due to alterations in miRNA processing factors, has been observed in a large variety of human cancer types. As previous studies have shown, the sequential miRNA processing can be divided into three steps: processing by RNAse in the nucleus; transportation by Exportin-5 (XPO5) from the nucleus; and processing by the RNA-induced silencing complex (RISC) in the cytoplasm. Alteration in miRNA processing genes, by genomic mutations, aberrant expression or other means, could significantly affect cancer initiation, progression and metastasis. In this review, we focus on the biogenesis of miRNAs with emphasis on the potential of miRNA processing factors in human cancers.

No MeSH data available.


Related in: MedlinePlus