Review

Non-coding RNA networks in cancer

Published online:

Abstract

Thousands of unique non-coding RNA (ncRNA) sequences exist within cells. Work from the past decade has altered our perception of ncRNAs from 'junk' transcriptional products to functional regulatory molecules that mediate cellular processes including chromatin remodelling, transcription, post-transcriptional modifications and signal transduction. The networks in which ncRNAs engage can influence numerous molecular targets to drive specific cell biological responses and fates. Consequently, ncRNAs act as key regulators of physiological programmes in developmental and disease contexts. Particularly relevant in cancer, ncRNAs have been identified as oncogenic drivers and tumour suppressors in every major cancer type. Thus, a deeper understanding of the complex networks of interactions that ncRNAs coordinate would provide a unique opportunity to design better therapeutic interventions.

  • Subscribe to Nature Reviews Cancer for full access:

    $59

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

References

  1. 1.

    Central dogma of molecular biology. Nature 227, 561–563 (1970).

  2. 2.

    On protein synthesis. Symp. Soc. Exp. Biol. 12, 138–163 (1958).

  3. 3.

    Non-coding RNA genes and the modern RNA world. Nat. Rev. Genet. 2, 919–929 (2001).

  4. 4.

    , & The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843–854 (1993).

  5. 5.

    et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403, 901–906 (2000).

  6. 6.

    et al. Ultraconserved elements in the human genome. Science 304, 1321–1325 (2004).

  7. 7.

    , , & Evolutionary conservation of long noncoding RNAs; sequence, structure, function. Biochim. Biophys. Acta 1840, 1063–1071 (2014).

  8. 8.

    et al. Landscape of transcription in human cells. Nature 489, 101–108 (2012).

  9. 9.

    ENCODE Project Consortium. The ENCODE (ENCyclopedia Of DNA Elements) project. Science 306, 636 (2004).

  10. 10.

    & Roles for microRNAs in conferring robustness to biological processes. Cell 149, 515–524 (2012).

  11. 11.

    , , & Interaction and cross-talk between non-coding RNAs. Cell. Mol. Life Sci. (2017).

  12. 12.

    & Network biology: understanding the cell's functional organization. Nat. Rev. Genet. 5, 101–113 (2004).

  13. 13.

    Network motifs: theory and experimental approaches. Nat. Rev. Genet. 8, 450–461 (2007).

  14. 14.

    & MicroRNAs en route to the clinic: progress in validating and targeting microRNAs for cancer therapy. Nat. Rev. Cancer 11, 849–864 (2011).

  15. 15.

    & MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat. Rev. Drug Discov. 16, 203–222 (2017).

  16. 16.

    et al. A feed-forward loop between lncARSR and YAP activity promotes expansion of renal tumour-initiating cells. Nature Commun. 7, 12692 (2016).

  17. 17.

    et al. miR-17-92 fine-tunes MYC expression and function to ensure optimal B cell lymphoma growth. Nature Commun. 6, 8725 (2015).

  18. 18.

    , & OncomiR or tumor suppressor? The duplicity of MicroRNAs in cancer. Cancer Res. 76, 3666–3670 (2016). This is an excellent review of the dual role of miRNAs in cancer.

  19. 19.

    & Is miR-29 an oncogene or tumor suppressor in CLL? Oncotarget 1, 224–227 (2010). This article represents one of the first examples of the dualistic function of a miRNA in the same or in different types of cancer.

  20. 20.

    et al. Epstein-Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b. Oncogene 29, 1316–1328 (2010).

  21. 21.

    et al. MicroRNA-375 plays a dual role in prostate carcinogenesis. Clin. Epigenet. 7, 42 (2015).

  22. 22.

    et al. Estrogen mediated-activation of miR-191/425 cluster modulates tumorigenicity of breast cancer cells depending on estrogen receptor status. PLoS Genet. 9, e1003311 (2013).

  23. 23.

    et al. Regulated post-transcriptional RNA cleavage diversifies the eukaryotic transcriptome. Genome Res. 20, 1639–1650 (2010).

  24. 24.

    , , & Non-coding RNAs in development and disease: background, mechanisms, and therapeutic approaches. Physiol. Rev. 96, 1297–1325 (2016).

  25. 25.

    et al. UV irradiation induces a non-coding RNA that functionally opposes the protein encoded by the same gene. Cell 168, 843–855.e13 (2017).

  26. 26.

    & Failure of RNA synthesis to recover after UV irradiation: an early defect in cells from individuals with Cockayne's syndrome and xeroderma pigmentosum. Cancer Res. 42, 1473–1478 (1982).

  27. 27.

    et al. Control of stress-dependent cardiac growth and gene expression by a microRNA. Science 316, 575–579 (2007).

  28. 28.

    et al. Oncogenic role of miR-483-3p at the IGF2/483 locus. Cancer Res. 70, 3140–3149 (2010).

  29. 29.

    , , , & Discovery of hundreds of mirtrons in mouse and human small RNA data. Genome Res. 22, 1634–1645 (2012).

  30. 30.

    et al. Exon-intron circular RNAs regulate transcription in the nucleus. Nat. Struct. Mol. Biol. 22, 256–264 (2015).

  31. 31.

    et al. Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes. Nature 453, 539–543 (2008).

  32. 32.

    et al. Transcribed pseudogene psiPPM1K generates endogenous siRNA to suppress oncogenic cell growth in hepatocellular carcinoma. Nucleic Acids Res. 41, 3734–3747 (2013).

  33. 33.

    , & 3′ end processing of a long nuclear-retained noncoding RNA yields a tRNA-like cytoplasmic RNA. Cell 135, 919–932 (2008).

  34. 34.

    et al. A triple helix stabilizes the 3′ ends of long noncoding RNAs that lack poly(A) tails. Genes Dev. 26, 2392–2407 (2012).

  35. 35.

    , , , & Formation of triple-helical structures by the 3′-end sequences of MALAT1 and MENbeta noncoding RNAs. Proc. Natl Acad. Sci. USA 109, 19202–19207 (2012).

  36. 36.

    et al. The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol. Cell 39, 925–938 (2010).

  37. 37.

    et al. Long noncoding RNA MALAT1-derived mascRNA is involved in cardiovascular innate immunity. J. Mol. Cell Biol. 8, 178–181 (2016).

  38. 38.

    , , & A novel class of small RNAs: tRNA-derived RNA fragments (tRFs). Genes Dev. 23, 2639–2649 (2009).

  39. 39.

    , & Biogenesis and function of transfer RNA-related fragments (tRFs). Trends Biochem. Sci. 41, 679–689 (2016).

  40. 40.

    et al. Filtering of deep sequencing data reveals the existence of abundant Dicer-dependent small RNAs derived from tRNAs. RNA 15, 2147–2160 (2009).

  41. 41.

    et al. tRNA-derived microRNA modulates proliferation and the DNA damage response and is down-regulated in B cell lymphoma. Proc. Natl Acad. Sci. USA 110, 1404–1409 (2013).

  42. 42.

    , , , & Angiogenin-induced tRNA fragments inhibit translation initiation. Mol. Cell 43, 613–623 (2011).

  43. 43.

    et al. Identification and functional characterization of tRNA-derived RNA fragments (tRFs) in respiratory syncytial virus infection. Mol. Ther. 21, 368–379 (2013).

  44. 44.

    et al. Human tRNA-derived small RNAs in the global regulation of RNA silencing. RNA 16, 673–695 (2010).

  45. 45.

    et al. Dysregulation of a family of short noncoding RNAs, tsRNAs, in human cancer. Proc. Natl Acad. Sci. USA 113, 5071–5076 (2016).

  46. 46.

    et al. A comprehensive repertoire of tRNA-derived fragments in prostate cancer. Oncotarget 7, 24766–24777 (2016).

  47. 47.

    et al. Endogenous tRNA-derived fragments suppress breast cancer progression via YBX1 displacement. Cell 161, 790–802 (2016).

  48. 48.

    & The imprinted H19 noncoding RNA is a primary microRNA precursor. RNA 13, 313–316 (2007). This is one of three articles that demonstrate the various gene products made from the single H19 locus.

  49. 49.

    et al. The H19 locus acts in vivo as a tumor suppressor. Proc. Natl Acad. Sci. USA 105, 12417–12422 (2008).

  50. 50.

    et al. H19 lncRNA alters DNA methylation genome wide by regulating S-adenosylhomocysteine hydrolase. Nat. Commun. 6, 10221 (2015).

  51. 51.

    et al. Integrative genomic analyses reveal clinically relevant long noncoding RNAs in human cancer. Nat. Struct. Mol. Biol. 20, 908–913 (2013).

  52. 52.

    et al. The lncRNA H19 mediates breast cancer cell plasticity during EMT and MET plasticity by differentially sponging miR-200b/c and let-7b. Sci. Signal. 10, eaak9557 (2017).

  53. 53.

    et al. The imprinted H19 lncRNA antagonizes let-7 microRNAs. Mol. Cell 52, 101–112 (2013).

  54. 54.

    et al. Up-regulation of 91H promotes tumor metastasis and predicts poor prognosis for patients with colorectal cancer. PLoS ONE 9, e103022 (2014). This is one of three articles that demonstrate the various gene products made from the single H19 locus.

  55. 55.

    & A nucleolar protein, H19 opposite tumor suppressor (HOTS), is a tumor growth inhibitor encoded by a human imprinted H19 antisense transcript. Proc. Natl Acad. Sci. USA 108, 16759–16764 (2011). This is one of three articles that demonstrate the various gene products made from the single H19 locus.

  56. 56.

    et al. lncRNA H19/miR-675 axis represses prostate cancer metastasis by targeting TGFBI. FEBS J. 281, 3766–3775 (2014).

  57. 57.

    et al. Down-regulation of miR-675-5p contributes to tumor progression and development by targeting pro-tumorigenic GPR55 in non-small cell lung cancer. Mol. Cancer 14, 73 (2015).

  58. 58.

    et al. H19 non coding RNA-derived miR-675 enhances tumorigenesis and metastasis of breast cancer cells by downregulating c-Cbl and Cbl-b. Oncotarget 6, 29209–29223 (2015).

  59. 59.

    et al. miR675 upregulates long noncoding RNA H19 through activating EGR1 in human liver cancer. Oncotarget 6, 31958–31984 (2015).

  60. 60.

    et al. The H19 lincRNA is a developmental reservoir of miR-675 that suppresses growth and Igf1r. Nat. Cell Biol. 14, 659–665 (2012).

  61. 61.

    , & Revealing protein-lncRNA interaction. Brief. Bioinform. 17, 106–116 (2016).

  62. 62.

    et al. The RNA component of human telomerase. Science 269, 1236–1241 (1995).

  63. 63.

    et al. Molecular Biology of the Cell 4 edn (Garland Science, 2002).

  64. 64.

    & Applications of the CRISPR-Cas9 system in cancer biology. Nat. Rev. Cancer 15, 387–395 (2015).

  65. 65.

    & Towards a molecular understanding of microRNA-mediated gene silencing. Nat. Rev. Genet. 16, 421–433 (2015).

  66. 66.

    et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464, 1071–1076 (2010). This study provides an example of a lncRNA that alters the occupancy of a protein complex on chromatin.

  67. 67.

    et al. NBAT1 suppresses breast cancer metastasis by regulating DKK1 via PRC2. Oncotarget 6, 32410–32425 (2015).

  68. 68.

    et al. The lncRNA MIR31HG regulates p16(INK4A) expression to modulate senescence. Nat. Commun. 6, 6967 (2015).

  69. 69.

    et al. Toward a consensus on the binding specificity and promiscuity of PRC2 for RNA. Mol. Cell 57, 552–558 (2015).

  70. 70.

    et al. The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex. Nat. Genet. 45, 1392–1398 (2013).

  71. 71.

    et al. The long noncoding RNA lncTCF7 promotes self-renewal of human liver cancer stem cells through activation of Wnt signaling. Stem Cell 16, 413–425 (2015).

  72. 72.

    et al. Long noncoding RNA TARID directs demethylation and activation of the tumor suppressor TCF21 via GADD45A Mol. Cell 55, 604–614 (2014).

  73. 73.

    et al. Target mimicry provides a new mechanism for regulation of microRNA activity. Nat. Genet. 39, 1033–1037 (2007).

  74. 74.

    , , , & ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell 146, 353–358 (2011).

  75. 75.

    , & The multilayered complexity of ceRNA crosstalk and competition. Nature 505, 344–352 (2014).

  76. 76.

    et al. Endogenous microRNA can be broadly exploited to regulate transgene expression according to tissue, lineage and differentiation state. Nat. Biotechnol. 25, 1457–1467 (2007).

  77. 77.

    , & MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat. Methods 4, 721–726 (2007).

  78. 78.

    et al. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell 147, 358–369 (2011).

  79. 79.

    et al. Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs. Cell 147, 344–357 (2011).

  80. 80.

    et al. An extensive microRNA-mediated network of RNA-RNA interactions regulates established oncogenic pathways in glioblastoma. Cell 147, 370–381 (2011).

  81. 81.

    et al. In vivo identification of tumor- suppressive PTEN ceRNAs in an oncogenic BRAF-induced mouse model of melanoma. Cell 147, 382–395 (2011).

  82. 82.

    , , , & Assessing the ceRNA hypothesis with quantitative measurements of miRNA and target abundance. Mol. Cell 54, 766–776 (2014).

  83. 83.

    , & Endogenous miRNA and target concentrations determine susceptibility to potential ceRNA competition. Mol. Cell 56, 347–359 (2014).

  84. 84.

    et al. Computational prediction of microRNA networks incorporating environmental toxicity and disease etiology. Sci. Rep. 4, 5576 (2014).

  85. 85.

    & Competing endogenous RNA database. Bioinformation 8, 731–733 (2012).

  86. 86.

    et al. dbDEMC: a database of differentially expressed miRNAs in human cancers. BMC Genomics 11 (Suppl. 4), S5 (2010).

  87. 87.

    et al. Cupid: simultaneous reconstruction of microRNA-target and ceRNA networks. Genome Res. 25, 257–267 (2015).

  88. 88.

    , , & lnCeDB: database of human long noncoding RNA acting as competing endogenous RNA. PLoS ONE 9, e98965 (2014).

  89. 89.

    , , , & MicroRNA processing and human cancer. J. Clin. Med. 4, 1651–1667 (2015).

  90. 90.

    & Endogenous microRNA sponges: evidence and controversy. Nat. Rev. Genet. 17, 272–283 (2016).

  91. 91.

    et al. The BRAF pseudogene functions as a competitive endogenous RNA and induces lymphoma in vivo. Cell 161, 319–332 (2015). This study provides an example of a lncRNA that acts as sponge to sequester miRNAs.

  92. 92.

    et al. Circular transcripts of the testis-determining gene Sry in adult mouse testis. Cell 73, 1019–1030 (1993).

  93. 93.

    et al. Natural RNA circles function as efficient microRNA sponges. Nature 495, 384–388 (2013).

  94. 94.

    et al. Circular RNA ITCH has inhibitory effect on ESCC by suppressing the Wnt/beta-catenin pathway. Oncotarget 6, 6001–6013 (2015).

  95. 95.

    et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495, 333–338 (2013).

  96. 96.

    et al. miR-7 suppresses brain metastasis of breast cancer stem-like cells by modulating KLF4. Cancer Res. 73, 1434–1444 (2013).

  97. 97.

    , & Circular RNA and miR-7 in cancer. Cancer Res. 73, 5609–5612 (2013).

  98. 98.

    et al. Circular RNA ciRS-7 - A promising prognostic biomarker and a potential therapeutic target in colorectal cancer. Clin. Cancer Res. (2017). This study unravels the functional role of the ciRS-7 sponging effect on the tumour suppressor miR-7 in colorectal cancer.

  99. 99.

    et al. Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2. Nucleic Acids Res. 44, 2846–2858 (2016).

  100. 100.

    et al. Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed. Mol. Cell 58, 870–885 (2015).

  101. 101.

    et al. A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell 142, 409–419 (2010).

  102. 102.

    et al. LincRNA-p21 suppresses target mRNA translation. Mol. Cell 47, 648–655 (2012). This study provides an example of a lncRNA that binds to and affects the translation of mRNAs.

  103. 103.

    et al. Suppression of miRNA-708 by polycomb group promotes metastases by calcium-induced cell migration. Cancer Cell 23, 63–76 (2013).

  104. 104.

    & lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3′ UTRs via Alu elements. Nature 470, 284–288 (2011).

  105. 105.

    et al. SNHG5 promotes colorectal cancer cell survival by counteracting STAU1-mediated mRNA destabilization. Nat. Commun. 7, 13875 (2016).

  106. 106.

    et al. The MBNL3 splicing factor promotes hepatocellular carcinoma by increasing PXN expression through the alternative splicing of lncRNA-PXN-AS1. Nat. Cell Biol. 19, 820–832 (2017). This study provides an example of a lncRNA binding to an mRNA and blocking access to a miRNA.

  107. 107.

    , , & Dynamic RNA Modifications in Gene Expression Regulation. Cell 169, 1187–1200 (2017).

  108. 108.

    & The epitranscriptome of noncoding RNAs in cancer. Cancer Discov. 7, 359–368 (2017).

  109. 109.

    et al. Oncogenic role of fusion-circRNAs derived from cancer-associated chromosomal translocations. Cell 166, 1055–1056 (2016). This is an important study that reveals that aberrant translocations observed in various types of cancer may generate fusion circRNAs.

  110. 110.

    , & Synergy against PML-RARa: targeting transcription, proteolysis, differentiation, and self-renewal in acute promyelocytic leukemia. J. Exp. Med. 210, 2793–2802 (2013).

  111. 111.

    et al. EML4-ALK rearrangement in non-small cell lung cancer and non-tumor lung tissues. Am. J. Pathol. 174, 661–670 (2009).

  112. 112.

    A-To-I editing of coding and non-coding RNAs by ADARs. Nat. Rev. Mol. Cell Biol. 17, 83–96 (2016).

  113. 113.

    et al. Widespread RNA editing of embedded alu elements in the human transcriptome. Genome Res. 14, 1719–1725 (2004).

  114. 114.

    , & RNA editing of non-coding RNA and its role in gene regulation. Biochimie 117, 22–27 (2015).

  115. 115.

    & Adenosine-to-inosine RNA editing. Wiley Interdiscip. Rev. Syst. Biol. Med. 1, 202–209 (2009).

  116. 116.

    et al. RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science 349, 1115–1120 (2015).

  117. 117.

    , , & Altered RNA editing in 3′ UTR perturbs microRNA-mediated regulation of oncogenes and tumor-suppressors. Sci. Rep. 6, 23226 (2016). This interesting article suggests that changes to the editing process of miRNA target genes might be selected for as advantageous to cancer cells.

  118. 118.

    et al. ADAR1 forms a complex with Dicer to promote microRNA processing and RNA-induced gene silencing. Cell 153, 575–589 (2013).

  119. 119.

    et al. Modulation of microRNA editing, expression and processing by ADAR2 deaminase in glioblastoma. Genome Biol. 16, 5 (2015).

  120. 120.

    et al. Reduced adenosine-to-inosine miR-455-5p editing promotes melanoma growth and metastasis. Nat. Cell Biol. 17, 311–321 (2015).

  121. 121.

    et al. Gene amplification-associated overexpression of the RNA editing enzyme ADAR1 enhances human lung tumorigenesis. Oncogene 35, 4407–4413 (2016).

  122. 122.

    et al. ADAR1 activation drives leukemia stem cell self-renewal by impairing Let-7 biogenesis. Cell Stem Cell 19, 177–191 (2016). This article describes the inhibitory mechanism of let-7 biogenesis by ADAR1 editase activity.

  123. 123.

    & ADARs edit microRNAs to promote leukemic stem cell activity. Cell Stem Cell 19, 141–142 (2016).

  124. 124.

    , & Alternative cleavage and polyadenylation: extent, regulation and function. Nat. Rev. Genet. 14, 496–506 (2013).

  125. 125.

    , , , & Ubiquitously transcribed genes use alternative polyadenylation to achieve tissue-specific expression. Genes Dev. 27, 2380–2396 (2013).

  126. 126.

    & Widespread shortening of 3′UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell 138, 673–684 (2009). This is an important study about the 3′UTR shortening process in cancer cells as a mechanism to avoid inhibition of oncogenes by miRNAs.

  127. 127.

    & SNPs in microRNA binding sites as prognostic and predictive cancer biomarkers. Crit. Rev. Oncog. 18, 327–340 (2013).

  128. 128.

    et al. Aberrant allele frequencies of the SNPs located in microRNA target sites are potentially associated with human cancers. Nucleic Acids Res. 35, 4535–4541 (2007).

  129. 129.

    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).

  130. 130.

    et al. An illegitimate microRNA target site within the 3′ UTR of MDM4 affects ovarian cancer progression and chemosensitivity. Cancer Res. 70, 9641–9649 (2010).

  131. 131.

    , & Cis-acting elements in its 3′ UTR mediate post-transcriptional regulation of KRAS. Oncotarget 7, 11770–11784 (2016).

  132. 132.

    et al. Pancreatic cancer risk variant in LINC00673 creates a miR-1231 binding site and interferes with PTPN11 degradation. Nat. Genet. 48, 747–757 (2016). This paper provides an example of a SNP in a lncRNA that creates a binding site for a miRNA.

  133. 133.

    , & Dynamics of targeted cancer therapy. Trends Mol. Med. 18, 311–316 (2012).

  134. 134.

    et al. Evolutionary dynamics of cancer in response to targeted combination therapy. eLife 2, e00747 (2013).

  135. 135.

    & Timing and heterogeneity of mutations associated with drug resistance in metastatic cancers. Proc. Natl Acad. Sci. USA 111, 15964–15968 (2014).

  136. 136.

    et al. miRTargetLink—miRNAs, genes and interaction networks. Int. J. Mol. Sci. 17, 564 (2016).

  137. 137.

    et al. Identification of lncRNA-associated competing triplets reveals global patterns and prognostic markers for cancer. Nucleic Acids Res. 43, 3478–3489 (2015).

  138. 138.

    [No authors listed.] The future of cancer genomics. Nat. Med. 21, 99–99 (2015).

  139. 139.

    , & The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge. Contemp. Oncol. 19, A68–A77 (2015).

  140. 140.

    & PROGmiR: a tool for identifying prognostic miRNA biomarkers in multiple cancers using publicly available data. J. Clin. Bioinforma. 2, 23 (2012).

  141. 141.

    & SomamiR 2.0: a database of cancer somatic mutations altering microRNA-ceRNA interactions. Nucleic Acids Res. 44, D1005–D1010 (2016).

  142. 142.

    et al. DoRiNA 2.0—upgrading the doRiNA database of RNA interactions in post-transcriptional regulation. Nucleic Acids Res. 43, D160–D167 (2015).

  143. 143.

    et al. DIANA-mirExTra v2.0: uncovering microRNAs and transcription factors with crucial roles in NGS expression data. Nucleic Acids Res. 44, W128–W134 (2016).

  144. 144.

    et al. circRNADb: a comprehensive database for human circular RNAs with protein-coding annotations. Sci. Rep. 6, 34985 (2016).

  145. 145.

    , & circBase: a database for circular RNAs. RNA 20, 1666–1670 (2014).

  146. 146.

    et al. Biomarker discovery: quantification of microRNAs and other small non-coding RNAs using next generation sequencing. BMC Med. Genomics 8, 35 (2015).

  147. 147.

    & Long noncoding RNAs: a potential novel class of cancer biomarkers. Front. Genet. 6, 145 (2015).

  148. 148.

    et al. Targeting non-coding RNAs with the CRISPR/Cas9 system in human cell lines. Nucleic Acids Res. 43, e17 (2015).

  149. 149.

    & Non-coding RNAs as drug targets. Nat. Rev. Drug Discov. 16, 167–179 (2016).

  150. 150.

    , & Managing microRNAs with vector-encoded decoy-type inhibitors. Mol. Ther. 21, 1478–1485 (2013).

  151. 151.

    , & In vivo delivery of miRNAs for cancer therapy: challenges and strategies. Adv. Drug Deliv. Rev. 81, 128–141 (2015).

  152. 152.

    , , & Long noncoding RNAs in development and cancer: potential biomarkers and therapeutic targets. Mol. Cell. Therap. 3, 5 (2015).

  153. 153.

    et al. Nanoparticle-based therapy in an in vivo microRNA-155 (miR-155)-dependent mouse model of lymphoma. Proc. Natl Acad. Sci. USA 109, E1695–E1704 (2012).

  154. 154.

    et al. MicroRNA silencing for cancer therapy targeted to the tumor microenvironment. Nature 518, 107–110 (2015).

  155. 155.

    et al. The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res. 73, 1180–1189 (2013).

  156. 156.

    et al. Epigenetic inactivation of the p53-induced long noncoding RNA TP53 target 1 in human cancer. Proc. Natl Acad. Sci. USA 113, E7535–E7544 (2016).

  157. 157.

    et al. CpG island hypermethylation-associated silencing of non-coding RNAs transcribed from ultraconserved regions in human cancer. Oncogene 29, 6390–6401 (2010).

  158. 158.

    et al. A microRNA DNA methylation signature for human cancer metastasis. Proc. Natl Acad. Sci. USA 105, 13556–13561 (2008).

  159. 159.

    et al. Genetic unmasking of an epigenetically silenced microRNA in human cancer cells. Cancer Res. 67, 1424–1429 (2007).

  160. 160.

    et al. Genome-wide profiles of methylation, microRNAs, and gene expression in chemoresistant breast cancer. Sci. Rep. 6, 24706 (2016).

  161. 161.

    et al. Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs. Nat. Commun. 7, 11215 (2016).

  162. 162.

    et al. Identification and characterization of hypoxia-regulated endothelial circular RNA. Circ. Res. 117, 884–890 (2015).

Download references

Acknowledgements

The authors thank A. L. Jiao and P. Trivedi for helpful comments on this manuscript. The authors acknowledge support from the Ludwig Center at Harvard, Boston, Massachusetts, USA, and grants from the US National Institutes of Health (R01 CA157749; P50 CA177444).

Author information

Author notes

    • Eleni Anastasiadou
    •  & Leni S. Jacob

    These authors contributed equally to this work.

Affiliations

  1. Harvard Medical School Initiative for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.

    • Eleni Anastasiadou
    • , Leni S. Jacob
    •  & Frank J. Slack

Authors

  1. Search for Eleni Anastasiadou in:

  2. Search for Leni S. Jacob in:

  3. Search for Frank J. Slack in:

Contributions

E.A. and L.S.J. researched the data for the article. E.A., L.S.J. and F.J.S. provided substantial contributions to discussions of its content, wrote the article and undertook review and/or editing of the manuscript before submission.

Competing interests

F.J.S. is a founder and adviser to Mira Dx and 28/7 Rx. The other authors have no conflict of interest.

Corresponding author

Correspondence to Frank J. Slack.

Glossary

Network motifs

Patterns of interactions between nodes in a network that occur more often than by chance.

Supergene

A locus that produces multiple functional RNAs.

Endogenous small interfering RNAs

(Endo-siRNAs). Small RNAs that, unlike microRNAs, are derived from perfectly complementary sense–antisense RNA hybrids (double-stranded RNA).

Mirtrons

MicroRNAs derived from short hairpin introns and processed by the splicing machinery but not by ribonuclease 3 (Drosha).

Pseudogene

A nucleotide sequence that resembles a gene but does not lead to any protein expression.

Nuclear paraspeckles

Nuclear domains within interchromatin spaces, enriched in RNA processing factors.

Crosslinking immunoprecipitation followed by sequencing

(CLIP-seq). A method to study RNA–protein interactions by ultraviolet crosslinking followed by immunoprecipitation.

Staufen1-mediated mRNA decay

(SMD). A process that degrades mRNA through binding of double-stranded RNA-binding protein Staufen homologue 1 (STAU1) to its binding site in the 3′ untranslated regions of target mRNA.

Alu element

A short interspersed element, 300 bp in length, that is repeated in the human genome and forms a characteristic double-stranded RNA embedded in the precursor mRNA.

Alternative polyadenylation signals

When more than one site within a gene locus codes for the signal that allows a string of adenosine bases (poly(A) tail) to be added to the end of the transcript.