Key Points
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MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate target gene expression through mRNA degradation or translational inhibition.
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The miRNA biogenesis pathway is a multi-step process that has a crucial role in regulating miRNA maturation.
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miRNAs can be oncogenes or tumour suppressors and are globally repressed in cancers.
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Mutations in or dysregulation of components of the miRNA biogenesis pathway are frequently found in cancers and have important functions in oncogenesis.
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Important oncogenic signalling proteins — such as LIN28A, LIN28B, epidermal growth factor receptor (EGFR) and Hippo — target miRNA biogenesis in cancers.
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The targeting of abnormal miRNA biogenesis pathways is a novel, promising therapeutic strategy for cancers.
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.
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References
Bartel, D. P. MicroRNAs: target recognition and regulatory functions. Cell 136, 215–233 (2009).
Calin, G. A. & Croce, C. M. MicroRNA signatures in human cancers. Nature Rev. Cancer 6, 857–866 (2006).
Calin, G. A. et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc. Natl Acad. Sci. USA 99, 15524–15529 (2002).
Di Leva, G. & Croce, C. M. Roles of small RNAs in tumor formation. Trends Mol. Med. 16, 257–267 (2010).
Mendell, J. T. & Olson, E. N. MicroRNAs in stress signaling and human disease. Cell 148, 1172–1187 (2012).
He, L. et al. A microRNA polycistron as a potential human oncogene. Nature 435, 828–833 (2005). This paper was the first to revealthat genes in the miR-17∼92 cluster function as potential human oncogenes.
Kim, H. H. et al. HuR recruits let-7/RISC to repress c-Myc expression. Genes Dev. 23, 1743–1748 (2009).
Johnson, S. M. et al. RAS is regulated by the let-7 microRNA family. Cell 120, 635–647 (2005). This paper was the first to show that members of the let-7 family of miRNAs function as tumour suppressors by targeting RAS.
Kumar, M. S. et al. Suppression of non-small cell lung tumor development by the let-7 microRNA family. Proc. Natl Acad. Sci. USA 105, 3903–3908 (2008).
Lu, J. et al. MicroRNA expression profiles classify human cancers. Nature 435, 834–838 (2005). This paper was the first to report that miRNAs are globally downregulated in cancers.
Thomson, J. M. et al. Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes Dev. 20, 2202–2207 (2006).
Karube, Y. et al. Reduced expression of Dicer associated with poor prognosis in lung cancer patients. Cancer Sci. 96, 111–115 (2005).
Lin, R. J. et al. microRNA signature and expression of Dicer and Drosha can predict prognosis and delineate risk groups in neuroblastoma. Cancer Res. 70, 7841–7850 (2010).
Merritt, W. M. et al. Dicer, Drosha, and outcomes in patients with ovarian cancer. N. Engl. J. Med. 359, 2641–2650 (2008). This paper reveals that the expression levels of DICER1 and DROSHA are associated with clinical outcomes in patients with ovarian cancer.
Kumar, M. S., Lu, J., Mercer, K. L., Golub, T. R. & Jacks, T. Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nature Genet. 39, 673–677 (2007). This paper shows that impaired miRNA biogenesis promotes oncogenesis.
Hill, D. A. et al. DICER1 mutations in familial pleuropulmonary blastoma. Science 325, 965 (2009). This study was the first to identify the germline mutations of DICER1 in patients with familial PPB.
Anglesio, M. S. et al. Cancer-associated somatic DICER1 hotspot mutations cause defective miRNA processing and reverse-strand expression bias to predominantly mature 3p strands through loss of 5p strand cleavage. J. Pathol. 229, 400–409 (2013).
Heravi-Moussavi, A. et al. Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers. N. Engl. J. Med. 366, 234–242 (2012). This study identified the recurrent somatic mutations encoding the RNase IIIb catalytic domain of DICER1 that affect the processing of 5′ derived miRNAs.
Foulkes, W. D., Priest, J. R. & Duchaine, T. F. DICER1: mutations, microRNAs and mechanisms. Nature Rev. Cancer 14, 662–672 (2014).
Slade, I. et al. DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome. J. Med. Genet. 48, 273–278 (2011).
Rakheja, D. et al. Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis through distinct mechanisms in Wilms tumours. Nature Commun. 2, 4802 (2014).
Torrezan, G. T. et al. Recurrent somatic mutation in DROSHA induces microRNA profile changes in Wilms tumour. Nature Commun. 5, 4039 (2014).
Wegert, J. et al. Mutations in the SIX1/2 pathway and the DROSHA/DGCR8 miRNA microprocessor complex underlie high-risk blastemal type Wilms tumors. Cancer Cell 27, 298–311 (2015).
Walz, A. L. et al. Recurrent DGCR8, DROSHA, and SIX homeodomain mutations in favorable histology Wilms tumors. Cancer Cell 27, 286–297 (2015). References 21–24 identified the recurrent somatic mutation of DROSHA and DGCR8 in Wilms tumours.
Lee, R. C., Feinbaum, R. L. & Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843–854 (1993). This study was the first to identify miRNA.
Lagos-Quintana, M., Rauhut, R., Lendeckel, W. & Tuschl, T. Identification of novel genes coding for small expressed RNAs. Science 294, 853–858 (2001).
Lau, N. C., Lim, L. P., Weinstein, E. G. & Bartel, D. P. An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science 294, 858–862 (2001).
Lee, R. C. & Ambros, V. An extensive class of small RNAs in Caenorhabditis elegans. Science 294, 862–864 (2001).
Kozomara, A. & Griffiths-Jones, S. miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res. 39, D152–D157 (2011).
Filipowicz, W., Bhattacharyya, S. N. & Sonenberg, N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nature Rev. Genet. 9, 102–114 (2008).
Lee, Y. et al. MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 23, 4051–4060 (2004).
Gregory, R. I. et al. The Microprocessor complex mediates the genesis of microRNAs. Nature 432, 235–240 (2004).
Denli, A. M., Tops, B. B., Plasterk, R. H., Ketting, R. F. & Hannon, G. J. Processing of primary microRNAs by the Microprocessor complex. Nature 432, 231–235 (2004).
Lee, Y. et al. The nuclear RNase III Drosha initiates microRNA processing. Nature 425, 415–419 (2003).
Han, J. et al. The Drosha–DGCR8 complex in primary microRNA processing. Genes Dev. 18, 3016–3027 (2004).
Han, J. et al. Molecular basis for the recognition of primary microRNAs by the Drosha–DGCR8 complex. Cell 125, 887–901 (2006).
Zeng, Y., Yi, R. & Cullen, B. R. Recognition and cleavage of primary microRNA precursors by the nuclear processing enzyme Drosha. EMBO J. 24, 138–148 (2005).
Burke, J. M., Kelenis, D. P., Kincaid, R. P. & Sullivan, C. S. A central role for the primary microRNA stem in guiding the position and efficiency of Drosha processing of a viral pri-miRNA. RNA 20, 1068–1077 (2014).
Heo, I. et al. Mono-uridylation of pre-microRNA as a key step in the biogenesis of group II let-7 microRNAs. Cell 151, 521–532 (2012).
Yi, R., Qin, Y., Macara, I. G. & Cullen, B. R. Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev. 17, 3011–3016 (2003).
Lund, E., Guttinger, S., Calado, A., Dahlberg, J. E. & Kutay, U. Nuclear export of microRNA precursors. Science 303, 95–98 (2004).
Bohnsack, M. T., Czaplinski, K. & Gorlich, D. Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs. RNA 10, 185–191 (2004).
Park, J. E. et al. Dicer recognizes the 5′ end of RNA for efficient and accurate processing. Nature 475, 201–205 (2011).
Bernstein, E., Caudy, A. A., Hammond, S. M. & Hannon, G. J. Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409, 363–366 (2001).
Chendrimada, T. P. et al. TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature 436, 740–744 (2005).
Lee, H. Y. & Doudna, J. A. TRBP alters human precursor microRNA processing in vitro. RNA 18, 2012–2019 (2012).
Kim, Y. et al. Deletion of human tarbp2 reveals cellular microRNA targets and cell-cycle function of TRBP. Cell Rep. 9, 1061–1074 (2014).
Gregory, R. I., Chendrimada, T. P., Cooch, N. & Shiekhattar, R. Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell 123, 631–640 (2005).
Liu, J., Valencia-Sanchez, M. A., Hannon, G. J. & Parker, R. MicroRNA-dependent localization of targeted mRNAs to mammalian P-bodies. Nature Cell Biol. 7, 719–723 (2005).
Eulalio, A., Behm-Ansmant, I., Schweizer, D. & Izaurralde, E. P-body formation is a consequence, not the cause, of RNA-mediated gene silencing. Mol. Cell. Biol. 27, 3970–3981 (2007).
Calin, G. A. et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc. Natl Acad. Sci. USA 101, 2999–3004 (2004).
Zhang, L. et al. microRNAs exhibit high frequency genomic alterations in human cancer. Proc. Natl Acad. Sci. USA 103, 9136–9141 (2006).
Cimmino, A. et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc. Natl Acad. Sci. USA 102, 13944–13949 (2005).
Kotani, A. et al. A novel mutation in the miR-128b gene reduces miRNA processing and leads to glucocorticoid resistance of MLL–AF4 acute lymphocytic leukemia cells. Cell Cycle 9, 1037–1042 (2010).
He, L. et al. A microRNA component of the p53 tumour suppressor network. Nature 447, 1130–1134 (2007).
Raver-Shapira, N. et al. Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol. Cell 26, 731–743 (2007).
Chang, T. C. et al. Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol. Cell 26, 745–752 (2007).
Bommer, G. T. et al. p53-mediated activation of miRNA34 candidate tumor-suppressor genes. Curr. Biol. 17, 1298–1307 (2007).
Tarasov, V. et al. Differential regulation of microRNAs by p53 revealed by massively parallel sequencing: miR-34a is a p53 target that induces apoptosis and G1-arrest. Cell Cycle 6, 1586–1593 (2007).
O'Donnell, K. A., Wentzel, E. A., Zeller, K. I., Dang, C. V. & Mendell, J. T. c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435, 839–843 (2005).
Dews, M. et al. Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster. Nature Genet. 38, 1060–1065 (2006).
Chang, T. C. et al. Widespread microRNA repression by Myc contributes to tumorigenesis. Nature Genet. 40, 43–50 (2008).
Gregory, P. A. et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nature Cell Biol. 10, 593–601 (2008).
Bracken, C. P. et al. A double-negative feedback loop between ZEB1–SIP1 and the microRNA-200 family regulates epithelial–mesenchymal transition. Cancer Res. 68, 7846–7854 (2008).
Lujambio, A. et al. A microRNA DNA methylation signature for human cancer metastasis. Proc. Natl Acad. Sci. USA 105, 13556–13561 (2008).
Guil, S. & Esteller, M. DNA methylomes, histone codes and miRNAs: tying it all together. Int. J. Biochem. Cell Biol. 41, 87–95 (2009).
Han, J. et al. Posttranscriptional crossregulation between Drosha and DGCR8. Cell 136, 75–84 (2009).
Triboulet, R., Chang, H. M., Lapierre, R. J. & Gregory, R. I. Post-transcriptional control of DGCR8 expression by the Microprocessor. RNA 15, 1005–1011 (2009).
Kadener, S. et al. Genome-wide identification of targets of the Drosha–Pasha/DGCR8 complex. RNA 15, 537–545 (2009).
Muralidhar, B. et al. Functional evidence that Drosha overexpression in cervical squamous cell carcinoma affects cell phenotype and microRNA profiles. J. Pathol. 224, 496–507 (2011).
Sugito, N. et al. RNASEN regulates cell proliferation and affects survival in esophageal cancer patients. Clin. Cancer Res. 12, 7322–7328 (2006).
Shu, G. S., Yang, Z. L. & Liu, D. C. Immunohistochemical study of Dicer and Drosha expression in the benign and malignant lesions of gallbladder and their clinicopathological significances. Pathol. Res. Pract. 208, 392–397 (2012).
Guo, X. et al. The microRNA-processing enzymes: Drosha and Dicer can predict prognosis of nasopharyngeal carcinoma. J. Cancer Res. Clin. Oncol. 138, 49–56 (2012).
Jafarnejad, S. M., Sjoestroem, C., Martinka, M. & Li, G. Expression of the RNase III enzyme DROSHA is reduced during progression of human cutaneous melanoma. Mod. Pathol. 26, 902–910 (2013).
Grund, S. E., Polycarpou-Schwarz, M., Luo, C., Eichmuller, S. B. & Diederichs, S. Rare Drosha splice variants are deficient in microRNA processing but do not affect general microRNA expression in cancer cells. Neoplasia 14, 238–248 (2012).
Melo, S. A. et al. A genetic defect in exportin-5 traps precursor microRNAs in the nucleus of cancer cells. Cancer Cell 18, 303–315 (2010).
Leaderer, D. et al. Genetic and epigenetic association studies suggest a role of microRNA biogenesis gene exportin-5 (XPO5) in breast tumorigenesis. Int. J. Mol. Epidemiol. Genet. 2, 9–18 (2011).
Hutvagner, G. et al. A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science 293, 834–838 (2001).
Kumar, M. S. et al. Dicer1 functions as a haploinsufficient tumor suppressor. Genes Dev. 23, 2700–2704 (2009).
Pugh, T. J. et al. Exome sequencing of pleuropulmonary blastoma reveals frequent biallelic loss of TP53 and two hits in DICER1 resulting in retention of 5p-derived miRNA hairpin loop sequences. Oncogene 33, 5295–5302 (2014).
Wagh, P. K. et al. Cell- and developmental stage-specific Dicer1 ablation in the lung epithelium models cystic pleuropulmonary blastoma. J. Pathol. 236, 41–52 (2014).
de Kock, L. et al. Germ-line and somatic DICER1 mutations in a pleuropulmonary blastoma. Pediatr. Blood Cancer 60, 2091–2092 (2013).
Seki, M. et al. Biallelic DICER1 mutations in sporadic pleuropulmonary blastoma. Cancer Res. 74, 2742–2749 (2014).
Schultz, K. A. et al. Ovarian sex cord-stromal tumors, pleuropulmonary blastoma and DICER1 mutations: a report from the International Pleuropulmonary Blastoma Registry. Gynecol. Oncol. 122, 246–250 (2011).
Witkowski, L. et al. DICER1 hotspot mutations in non-epithelial gonadal tumours. Br. J. Cancer 109, 2744–2750 (2013).
Foulkes, W. D. et al. Extending the phenotypes associated with DICER1 mutations. Hum. Mutat. 32, 1381–1384 (2011).
Wu, M. K. et al. Biallelic DICER1 mutations occur in Wilms tumours. J. Pathol. 230, 154–164 (2013).
de Kock, L. et al. Pituitary blastoma: a pathognomonic feature of germ-line DICER1 mutations. Acta Neuropathol. 128, 111–122 (2014).
Doros, L. A. et al. DICER1 mutations in childhood cystic nephroma and its relationship to DICER1-renal sarcoma. Mod. Pathol. 27, 1267–1280 (2014).
Doros, L. et al. DICER1 mutations in embryonal rhabdomyosarcomas from children with and without familial PPB-tumor predisposition syndrome. Pediatr. Blood Cancer 59, 558–560 (2012).
Schultze-Florey, R. E. et al. DICER1 syndrome: a new cancer syndrome. Klin. Padiatr. 225, 177–178 (2013).
Su, X. et al. TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature 467, 986–990 (2010).
Melo, S. A. et al. A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 function. Nature Genet. 41, 365–370 (2009).
Garre, P., Perez-Segura, P., Diaz-Rubio, E., Caldes, T. & de la Hoya, M. Reassessing the TARBP2 mutation rate in hereditary nonpolyposis colorectal cancer. Nature Genet. 42, 817–818 (2010).
De Vito, C. et al. A TARBP2-dependent miRNA expression profile underlies cancer stem cell properties and provides candidate therapeutic reagents in Ewing sarcoma. Cancer Cell 21, 807–821 (2012).
van Kouwenhove, M., Kedde, M. & Agami, R. MicroRNA regulation by RNA-binding proteins and its implications for cancer. Nature Rev. Cancer 11, 644–656 (2011).
Kawai, S. & Amano, A. BRCA1 regulates microRNA biogenesis via the DROSHA microprocessor complex. J. Cell Biol. 197, 201–208 (2012).
Trabucchi, M. et al. The RNA-binding protein KSRP promotes the biogenesis of a subset of microRNAs. Nature 459, 1010–1014 (2009).
Wu, H. et al. A splicing-independent function of SF2/ASF in microRNA processing. Mol. Cell 38, 67–77 (2010).
Guil, S. & Caceres, J. F. The multifunctional RNA-binding protein hnRNP A1 is required for processing of miR-18a. Nature Struct. Mol. Biol. 14, 591–596 (2007).
Michlewski, G., Guil, S., Semple, C. A. & Caceres, J. F. Posttranscriptional regulation of miRNAs harboring conserved terminal loops. Mol. Cell 32, 383–393 (2008).
Morlando, M. et al. FUS stimulates microRNA biogenesis by facilitating co-transcriptional Drosha recruitment. EMBO J. 31, 4502–4510 (2012).
Suzuki, H. I. et al. Modulation of microRNA processing by p53. Nature 460, 529–533 (2009).
Davis, B. N., Hilyard, A. C., Lagna, G. & Hata, A. SMAD proteins control DROSHA-mediated microRNA maturation. Nature 454, 56–61 (2008).
Davis, B. N., Hilyard, A. C., Nguyen, P. H., Lagna, G. & Hata, A. Smad proteins bind a conserved RNA sequence to promote microRNA maturation by Drosha. Mol. Cell 39, 373–384 (2010).
Ha, M. & Kim, V. N. Regulation of microRNA biogenesis. Nature Rev. Mol. Cell Biol. 15, 509–524 (2014).
Drake, M. et al. A requirement for ERK-dependent dicer phosphorylation in coordinating oocyte-to-embryo transition in C. elegans. Dev. Cell 31, 614–628 (2014).
Mori, M. et al. Hippo signaling regulates Microprocessor and links cell-density-dependent miRNA biogenesis to cancer. Cell 156, 893–906 (2014).
Harvey, K. F., Zhang, X. & Thomas, D. M. The Hippo pathway and human cancer. Nature Rev. Cancer 13, 246–257 (2013).
Hwang, H. W., Wentzel, E. A. & Mendell, J. T. Cell–cell contact globally activates microRNA biogenesis. Proc. Natl Acad. Sci. USA 106, 7016–7021 (2009).
Leung, A. K. & Sharp, P. A. MicroRNA functions in stress responses. Mol. Cell 40, 205–215 (2010).
Franovic, A. et al. Translational up-regulation of the EGFR by tumor hypoxia provides a nonmutational explanation for its overexpression in human cancer. Proc. Natl Acad. Sci. USA 104, 13092–13097 (2007).
Shen, J. et al. EGFR modulates microRNA maturation in response to hypoxia through phosphorylation of AGO2. Nature 497, 383–387 (2013).
Rupaimoole, R. et al. Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression. Nature Commun. 5, 5202 (2014).
van den Beucken, T. et al. Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER. Nature Commun. 5, 5203 (2014).
Peter, M. E. Let-7 and miR-200 microRNAs: guardians against pluripotency and cancer progression. Cell Cycle 8, 843–852 (2009).
Barh, D., Malhotra, R., Ravi, B. & Sindhurani, P. MicroRNA let-7: an emerging next-generation cancer therapeutic. Curr. Oncol. 17, 70–80 (2010).
Mayr, C., Hemann, M. T. & Bartel, D. P. Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science 315, 1576–1579 (2007).
Akao, Y. Nakagawa, Y. & Naoe, T. let-7 microRNA functions as a potential growth suppressor in human colon cancer cells. Biol. Pharm. Bull. 29, 903–906 (2006).
Boyerinas, B., Park, S. M., Hau, A., Murmann, A. E. & Peter, M. E. The role of let-7 in cell differentiation and cancer. Endocr. Relat. Cancer 17, F19–F36 (2010).
Bussing, I., Slack, F. J. & Grosshans, H. let-7 microRNAs in development, stem cells and cancer. Trends Mol. Med. 14, 400–409 (2008).
Droge, P. & Davey, C. A. Do cells let-7 determine stemness? Cell Stem Cell 2, 8–9 (2008).
Rybak, A. et al. A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment. Nature Cell Biol. 10, 987–993 (2008).
Viswanathan, S. R., Daley, G. Q. & Gregory, R. I. Selective blockade of microRNA processing by Lin28. Science 320, 97–100 (2008).
Heo, I. et al. Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA. Mol. Cell 32, 276–284 (2008). References 124–126 reveal that LIN28A and LIN28B selectively inhibit let-7 miRNA biogenesis.
Newman, M. A., Thomson, J. M. & Hammond, S. M. Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing. RNA 14, 1539–1549 (2008).
Madison, B. B. et al. LIN28B promotes growth and tumorigenesis of the intestinal epithelium via Let-7. Genes Dev. 27, 2233–2245 (2013).
Urbach, A. et al. Lin28 sustains early renal progenitors and induces Wilms tumor. Genes Dev. 28, 971–982 (2014).
Viswanathan, S. R. et al. Lin28 promotes transformation and is associated with advanced human malignancies. Nature Genet. 41, 843–848 (2009). This paper reveals the roles of the LIN28–let-7 pathway in the regulation of oncogenesis.
Nguyen, L. H. et al. Lin28b is sufficient to drive liver cancer and necessary for its maintenance in murine models. Cancer Cell 26, 248–261 (2014).
Molenaar, J. J. et al. LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression. Nature Genet. 44, 1199–1206 (2012).
Beachy, S. H. et al. Enforced expression of Lin28b leads to impaired T-cell development, release of inflammatory cytokines, and peripheral T-cell lymphoma. Blood 120, 1048–1059 (2012).
King, C. E. et al. LIN28B fosters colon cancer migration, invasion and transformation through let-7-dependent and -independent mechanisms. Oncogene 30, 4185–4193 (2011).
Thornton, J. E. & Gregory, R. I. How does Lin28 let-7 control development and disease? Trends Cell Biol. 22, 474–482 (2012).
Zhu, H. et al. The Lin28/let-7 axis regulates glucose metabolism. Cell 147, 81–94 (2011).
Iliopoulos, D., Hirsch, H. A. & Struhl, K. An epigenetic switch involving NF-κB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell 139, 693–706 (2009).
Hamano, R. et al. High expression of Lin28 is associated with tumour aggressiveness and poor prognosis of patients in oesophagus cancer. Br. J. Cancer 106, 1415–1423 (2012).
Picard, D. et al. Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumours: an integrative genomic analysis. Lancet Oncol. 13, 838–848 (2012).
Diskin, S. J. et al. Common variation at 6q16 within HACE1 and LIN28B influences susceptibility to neuroblastoma. Nature Genet. 44, 1126–1130 (2012).
Hovestadt, V. et al. Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature 510, 537–541 (2014).
Zhang, W. C. et al. Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. Cell 148, 259–272 (2012).
Piskounova, E. et al. Determinants of microRNA processing inhibition by the developmentally regulated RNA-binding protein Lin28. J. Biol. Chem. 283, 21310–21314 (2008).
Nam, Y., Chen, C., Gregory, R. I., Chou, J. J. & Sliz, P. Molecular basis for interaction of let-7 microRNAs with Lin28. Cell 147, 1080–1091 (2011).
Hagan, J. P., Piskounova, E. & Gregory, R. I. Lin28 recruits the TUTase Zcchc11 to inhibit let-7 maturation in mouse embryonic stem cells. Nature Struct. Mol. Biol. 16, 1021–1025 (2009).
Heo, I. et al. TUT4 in concert with Lin28 suppresses microRNA biogenesis through pre-microRNA uridylation. Cell 138, 696–708 (2009).
Thornton, J. E., Chang, H. M., Piskounova, E. & Gregory, R. I. Lin28-mediated control of let-7 microRNA expression by alternative TUTases Zcchc11 (TUT4) and Zcchc6 (TUT7). RNA 18, 1875–1885 (2012).
Chang, H. M., Triboulet, R., Thornton, J. E. & Gregory, R. I. A role for the Perlman syndrome exonuclease Dis3l2 in the Lin28–let-7 pathway. Nature 497, 244–248 (2013).
Faehnle, C. R., Walleshauser, J. & Joshua-Tor, L. Mechanism of Dis3l2 substrate recognition in the Lin28–let-7 pathway. Nature 514, 252–256 (2014).
Ustianenko, D. et al. Mammalian DIS3L2 exoribonuclease targets the uridylated precursors of let-7 miRNAs. RNA 19, 1632–1638 (2013).
Astuti, D. et al. Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility. Nature Genet. 44, 277–284 (2012).
Kumar, M. S. et al. HMGA2 functions as a competing endogenous RNA to promote lung cancer progression. Nature 505, 212–217 (2014).
Chin, L. J. et al. A SNP in a let-7 microRNA complementary site in the KRAS 3′ untranslated region increases non-small cell lung cancer risk. Cancer Res. 68, 8535–8540 (2008).
Kanellopoulou, C. et al. Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing. Genes Dev. 19, 489–501 (2005).
Wang, Y., Medvid, R., Melton, C., Jaenisch, R. & Blelloch, R. DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal. Nature Genet. 39, 380–385 (2007).
Chakravarti, D. et al. Induced multipotency in adult keratinocytes through down-regulation of ΔNp63 or DGCR8. Proc. Natl Acad. Sci. USA 111, E572–E581 (2014).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Gurtan, A. M. et al. Let-7 represses Nr6a1 and a mid-gestation developmental program in adult fibroblasts. Genes Dev. 27, 941–954 (2013).
Melton, C., Judson, R. L. & Blelloch, R. Opposing microRNA families regulate self-renewal in mouse embryonic stem cells. Nature 463, 621–626 (2010).
Trang, P. et al. Regression of murine lung tumors by the let-7 microRNA. Oncogene 29, 1580–1587 (2009).
Yu, F. et al. let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 131, 1109–1123 (2007).
Li, X. et al. Oncogenic transformation of diverse gastrointestinal tissues in primary organoid culture. Nature Med. 20, 769–777 (2014).
Muralidhar, B. et al. Global microRNA profiles in cervical squamous cell carcinoma depend on Drosha expression levels. J. Pathol. 212, 368–377 (2007).
Sand, M. et al. Expression levels of the microRNA processing enzymes Drosha and dicer in epithelial skin cancer. Cancer Invest. 28, 649–653 (2010).
Passon, N. et al. Expression of Dicer and Drosha in triple-negative breast cancer. J. Clin. Pathol. 65, 320–326 (2012).
Avery-Kiejda, K. A., Braye, S. G., Forbes, J. F. & Scott, R. J. The expression of Dicer and Drosha in matched normal tissues, tumours and lymph node metastases in triple negative breast cancer. BMC Cancer 14, 253 (2014).
Papachristou, D. J. et al. Immunohistochemical analysis of the endoribonucleases Drosha, Dicer and Ago2 in smooth muscle tumours of soft tissues. Histopathology 60, E28–E36 (2012).
Tchernitsa, O. et al. Systematic evaluation of the miRNA-ome and its downstream effects on mRNA expression identifies gastric cancer progression. J. Pathol. 222, 310–319 (2010).
Vaksman, O., Hetland, T. E., Trope, C. G., Reich, R. & Davidson, B. Argonaute, Dicer, and Drosha are up-regulated along tumor progression in serous ovarian carcinoma. Hum. Pathol. 43, 2062–2069 (2012).
Diaz-Garcia, C. V. et al. DICER1, DROSHA and miRNAs in patients with non-small cell lung cancer: implications for outcomes and histologic classification. Carcinogenesis 34, 1031–1038 (2013).
Catto, J. W. et al. Distinct microRNA alterations characterize high- and low-grade bladder cancer. Cancer Res. 69, 8472–8481 (2009).
Torres, A. et al. Major regulators of microRNAs biogenesis Dicer and Drosha are down-regulated in endometrial cancer. Tumour Biol. 32, 769–776 (2011).
Yan, M. et al. Dysregulated expression of dicer and drosha in breast cancer. Pathol. Oncol. Res. 18, 343–348 (2012).
Sand, M. et al. Expression levels of the microRNA maturing microprocessor complex component DGCR8 and the RNA-induced silencing complex (RISC) components argonaute-1, argonaute-2, PACT, TARBP1, and TARBP2 in epithelial skin cancer. Mol. Carcinog. 51, 916–922 (2011).
Ambs, S. et al. Genomic profiling of microRNA and messenger RNA reveals deregulated microRNA expression in prostate cancer. Cancer Res. 68, 6162–6170 (2008).
Kim, B. et al. An essential microRNA maturing microprocessor complex component DGCR8 is up-regulated in colorectal carcinomas. Clin. Exp. Med. 14, 331–336 (2013).
Guo, Y. et al. Silencing the double-stranded RNA binding protein DGCR8 inhibits ovarian cancer cell proliferation, migration, and invasion. Pharm. Res. 32, 769–778 (2013).
Chiosea, S. et al. Up-regulation of dicer, a component of the microRNA machinery, in prostate adenocarcinoma. Am. J. Pathol. 169, 1812–1820 (2006).
Jakymiw, A. et al. Overexpression of dicer as a result of reduced let-7 microRNA levels contributes to increased cell proliferation of oral cancer cells. Genes Chromosomes Cancer 49, 549–559 (2010).
Faber, C., Horst, D., Hlubek, F. & Kirchner, T. Overexpression of Dicer predicts poor survival in colorectal cancer. Eur. J. Cancer 47, 1414–1419 (2011).
Stratmann, J. et al. Dicer and miRNA in relation to clinicopathological variables in colorectal cancer patients. BMC Cancer 11, 345 (2011).
Papachristou, D. J. et al. Expression of the ribonucleases Drosha, Dicer, and Ago2 in colorectal carcinomas. Virchows Arch. 459, 431–440 (2011).
Chiosea, S. et al. Overexpression of Dicer in precursor lesions of lung adenocarcinoma. Cancer Res. 67, 2345–2350 (2007).
Ma, Z. et al. Up-regulated Dicer expression in patients with cutaneous melanoma. PLoS ONE 6, e20494 (2011).
Dedes, K. J. et al. Down-regulation of the miRNA master regulators Drosha and Dicer is associated with specific subgroups of breast cancer. Eur. J. Cancer 47, 138–150 (2011).
Wu, D. et al. Downregulation of Dicer, a component of the microRNA machinery, in bladder cancer. Mol. Med. Rep. 5, 695–699 (2012).
Pampalakis, G., Diamandis, E. P., Katsaros, D. & Sotiropoulou, G. Down-regulation of dicer expression in ovarian cancer tissues. Clin. Biochem. 43, 324–327 (2010).
Faggad, A. et al. Prognostic significance of Dicer expression in ovarian cancer — link to global microRNA changes and oestrogen receptor expression. J. Pathol. 220, 382–391 (2010).
Khoshnaw, S. M. et al. Loss of Dicer expression is associated with breast cancer progression and recurrence. Breast Cancer Res. Treat. 135, 403–413 (2012).
Wu, J. F. et al. Down-regulation of Dicer in hepatocellular carcinoma. Med. Oncol. 28, 804–809 (2011).
Zhu, D. X. et al. Downregulated Dicer expression predicts poor prognosis in chronic lymphocytic leukemia. Cancer Sci. 103, 875–881 (2012).
Faggad, A. et al. Down-regulation of the microRNA processing enzyme Dicer is a prognostic factor in human colorectal cancer. Histopathology 61, 552–561 (2012).
Acknowledgements
S.L. is a Damon Runyon-Sohn Pediatric Cancer Research Fellow supported by the Damon Runyon Cancer Research Foundation (DRSG-7-13). R.I.G. is supported by grants from the US National Cancer Institute (NCI) (R01CA163467) and the American Cancer Society (121635-RSG-11-175-01-RMC).
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Glossary
- 3′ untranslated region
-
(3′ UTR). The non-coding region of mRNA between the translation termination codon and the poly(A) tail. The 3′ UTR often contains regulatory elements, such as miRNA binding sites, for post-transcriptional regulation of gene expression.
- Ribonuclease III
-
(RNase III). Enzymes that can specifically recognize and cleave double-stranded RNA with their ribonuclease III domains.
- Germline mutations
-
Heritable gene mutations that occur in germline tissues.
- Somatic mutations
-
Gene mutations that occur in non-germline tissues that are not inherited.
- Post-transcriptional gene silencing
-
A gene-silencing effect that controls gene expression after transcription, often mediated by small non-coding RNAs such as small interfering RNAs (siRNAs) and microRNAs (miRNAs).
- Epithelial–mesenchymal transition
-
(EMT). A process that occurs during development or cancer progression in which the epithelial cells lose their cell polarity and cell–cell adhesion to become mesenchymal cells with migratory and invasive characteristics.
- CpG islands
-
Genetic regions with high CpG content, often located at the gene promoter, that have important functions in regulating gene expression.
- Microsatellite
-
Short (2–5 bp) tandem repeat of DNA that can be used as a genetic marker.
- Loss of heterozygosity
-
(LOH). Deletion or mutation of the normal allele of a gene, of which the other allele is already deleted or inactivated, resulting in loss of both alleles of the gene.
- Cold-shock domain
-
A protein domain of ∼70 amino acids that is often found in DNA- or RNA-binding proteins and that functions to protect cells during cold temperatures.
- Cys-Cys-His-Cys (CCHC)-type zinc-fingers
-
Protein domains that are found in RNA-binding proteins or single-stranded DNA-binding proteins.
- Terminal uridylyltransferases
-
(TUTases). Enzymes that catalyse the addition of one or more uridine monophosphate (UMP) molecules to the 3′ end of RNA.
- Oncofetal genes
-
Genes that are typically highly expressed during fetal development and repressed in adult life, and reactivated in cancers.
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Lin, S., Gregory, R. MicroRNA biogenesis pathways in cancer. Nat Rev Cancer 15, 321–333 (2015). https://doi.org/10.1038/nrc3932
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DOI: https://doi.org/10.1038/nrc3932