Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Long noncoding RNAs in cancer metastasis

Nature Reviews Cancer volume 21, pages 446–460 (2021)Cite this article

Subjects

Abstract

Metastasis is a major contributor to cancer-associated deaths. It is characterized by a multistep process that occurs through the acquisition of molecular and phenotypic changes enabling cancer cells from a primary tumour to disseminate and colonize at distant organ sites. Over the past decade, the discovery and characterization of long noncoding RNAs (lncRNAs) have revealed the diversity of their regulatory roles, including key contributions throughout the metastatic cascade. Here, we review how lncRNAs promote metastasis by functioning in discrete pro-metastatic steps including the epithelial–mesenchymal transition, invasion and migration and organotrophic colonization, and by influencing the metastatic tumour microenvironment, often by interacting within ribonucleoprotein complexes or directly with other nucleic acid entities. We discuss well-characterized lncRNAs with in vivo phenotypes and highlight mechanistic commonalities such as convergence with the TGFβ–ZEB1/ZEB2 axis or the nuclear factor-κB pathway, in addition to lncRNAs with controversial mechanisms and the influence of methodologies on mechanistic interpretation. Furthermore, some lncRNAs can help identify tumours with increased metastatic risk and spur novel therapeutic strategies, with several lncRNAs having shown potential as novel targets for antisense oligonucleotide therapy in animal models. In addition to well-characterized examples of lncRNAs functioning in metastasis, we discuss controversies and ongoing challenges in lncRNA biology. Finally, we present areas for future study for this rapidly evolving field.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Long noncoding RNAs in cancer.
Fig. 2: Long noncoding RNAs involved in the multiple processes of the invasion–metastasis cascade.
Fig. 3: Long noncoding RNAs regulate metastasis via various pathways using diverse mechanisms.
Fig. 4: Metastasis-associated long noncoding RNAs are regulated by various upstream mechanisms.
Fig. 5: Long noncoding RNAs in metastasis site-specific tropism.
Fig. 6: Long noncoding RNAs and tumour microenvironment.

Similar content being viewed by others

References

  1. Amin, M. B. AJCC Cancer Staging Manual. 8th Edn. (Springer, 2017).

  2. Lambert, A. W., Pattabiraman, D. R. & Weinberg, R. A. Emerging biological principles of metastasis. Cell 168, 670–691 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Valastyan, S. & Weinberg, R. A. Tumor metastasis: molecular insights and evolving paradigms. Cell 147, 275–292 (2011). Seminal primer on invasion–metastasis cascade and pathogenesis of tumour metastasis.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Gupta, G. P. & Massagué, J. Cancer metastasis: building a framework. Cell 127, 679–695 (2006).

    CAS  PubMed  Google Scholar 

  5. Ulitsky, I. & Bartel, D. P. lincRNAs: genomics, evolution, and mechanisms. Cell 154, 26–46 (2013). Comprehensive review of lncRNA concepts.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Kopp, F. & Mendell, J. T. Functional classification and experimental dissection of long noncoding RNAs. Cell 172, 393–407 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Guttman, M. et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458, 223–227 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. St Laurent, G., Wahlestedt, C. & Kapranov, P. The landscape of long noncoding RNA classification. Trends Genet. 31, 239–251 (2015).

    Google Scholar 

  9. Cabili, M. N. et al. Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev. 25, 1915–1927 (2011). Establishes the widespread and cell type-specific nature of lncRNA expression.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Iyer, M. K. et al. The landscape of long noncoding RNAs in the human transcriptome. Nat. Genet. 47, 199–208 (2015).

    CAS  PubMed  Google Scholar 

  12. FANTOM Consortium and the RIKEN PMI and CLST (DGT). A promoter-level mammalian expression atlas. Nature 507, 462–470 (2014).

    Google Scholar 

  13. Rinn, J. L. & Chang, H. Y. Genome regulation by long noncoding RNAs. Annu. Rev. Biochem. 81, 145–166 (2012).

    CAS  PubMed  Google Scholar 

  14. Engreitz, J. M. et al. Local regulation of gene expression by lncRNA promoters, transcription and splicing. Nature 539, 452–455 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Barr, M. L. & Bertram, E. G. A morphological distinction between neurones of the male and female, and the behaviour of the nucleolar satellite during accelerated nucleoprotein synthesis. Nature 163, 676–677 (1949).

    CAS  PubMed  Google Scholar 

  16. Chen, C.-K. et al. Xist recruits the X chromosome to the nuclear lamina to enable chromosome-wide silencing. Science 354, 468–472 (2016).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Willingham, A. T. et al. A strategy for probing the function of noncoding RNAs finds a repressor of NFAT. Science 309, 1570–1573 (2005).

    CAS  PubMed  Google Scholar 

  19. Carrieri, C. et al. Long non-coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat. Nature 491, 454–457 (2012).

    CAS  PubMed  Google Scholar 

  20. Lee, S. et al. Noncoding RNA NORAD regulates genomic stability by sequestering PUMILIO proteins. Cell 164, 69–80 (2016).

    CAS  PubMed  Google Scholar 

  21. Gupta, R. A. et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464, 1071–1076 (2010). Establishes HOTAIR as an important epigenetic regulator in breast cancer metastasis.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Rinn, J. L. et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129, 1311–1323 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Tsai, M.-C. et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science 329, 689–693 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Bond, A. M. et al. Balanced gene regulation by an embryonic brain ncRNA is critical for adult hippocampal GABA circuitry. Nat. Neurosci. 12, 1020–1027 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Berghoff, E. G. et al. Evf2 (Dlx6as) lncRNA regulates ultraconserved enhancer methylation and the differential transcriptional control of adjacent genes. Development 140, 4407–4416 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Tay, Y., Rinn, J. & Pandolfi, P. P. The multilayered complexity of ceRNA crosstalk and competition. Nature 505, 344–352 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Trimarchi, T. et al. Genome-wide mapping and characterization of notch-regulated long noncoding RNAs in acute leukemia. Cell 158, 593–606 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Xiang, J.-F. et al. Human colorectal cancer-specific CCAT1-L lncRNA regulates long-range chromatin interactions at the MYC locus. Cell Res. 24, 513–531 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Ma, W. et al. Fine-scale chromatin interaction maps reveal the cis-regulatory landscape of human lincRNA genes. Nat. Methods 12, 71–78 (2015).

    PubMed  Google Scholar 

  30. Latos, P. A. et al. Airn transcriptional overlap, but not its lncRNA products, induces imprinted Igf2r silencing. Science 338, 1469–1472 (2012).

    CAS  PubMed  Google Scholar 

  31. Kornienko, A. E., Guenzl, P. M., Barlow, D. P. & Pauler, F. M. Gene regulation by the act of long non-coding RNA transcription. BMC Biol. 11, 59 (2013).

    PubMed  PubMed Central  Google Scholar 

  32. Li, W. et al. Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature 498, 516–520 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Mele, M. & Rinn, J. L. ‘Cat’s cradling’ the 3D genome by the act of LncRNA transcription. Mol. Cell 62, 657–664 (2016).

    CAS  PubMed  Google Scholar 

  34. Yao, R.-W., Wang, Y. & Chen, L.-L. Cellular functions of long noncoding RNAs. Nat. Cell Biol. 21, 542–551 (2019).

    CAS  PubMed  Google Scholar 

  35. Kim, J. et al. Long noncoding RNA MALAT1 suppresses breast cancer metastasis. Nat. Genet. 50, 1705–1715 (2018). Challenges the concept of MALAT1 as a pro-metastasis lncRNA by revealing an alternative molecular mechanism.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Cho, S. W. et al. Promoter of lncRNA gene PVT1 is a tumor-suppressor DNA boundary element. Cell 173, 1398–1412.e22 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Schmitt, A. M. & Chang, H. Y. Long noncoding RNAs in cancer pathways. Cancer Cell 29, 452–463 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Slack, F. J. & Chinnaiyan, A. M. The role of non-coding RNAs in oncology. Cell 179, 1033–1055 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Hu, X. et al. A functional genomic approach identifies FAL1 as an oncogenic long noncoding RNA that associates with BMI1 and represses p21 expression in cancer. Cancer Cell 26, 344–357 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Tseng, Y.-Y. et al. PVT1 dependence in cancer with MYC copy-number increase. Nature 512, 82–86 (2014). Establishes genomic alterations of lncRNA loci as important features in cancer.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. McCleland, M. L. et al. CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J. Clin. Invest. 126, 639–652 (2016).

    PubMed  PubMed Central  Google Scholar 

  43. Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Yin, Y. et al. Opposing roles for the lncRNA haunt and its genomic locus in regulating HOXA gene activation during embryonic stem cell differentiation. Cell Stem Cell 16, 504–516 (2015).

    CAS  PubMed  Google Scholar 

  45. Paralkar, V. R. et al. Unlinking an lncRNA from its associated cis element. Mol. Cell 62, 104–110 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Groff, A. F. et al. In vivo characterization of Linc-p21 reveals functional cis-regulatory DNA elements. Cell Rep. 16, 2178–2186 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Dimitrova, N. et al. LincRNA-p21 activates p21 in cis to promote Polycomb target gene expression and to enforce the G1/S checkpoint. Mol. Cell 54, 777–790 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Weidle, U. H., Birzele, F., Kollmorgen, G. & Rüger, R. Long non-coding RNAs and their role in metastasis. Cancer Genomics Proteom. 14, 143–160 (2017).

    CAS  Google Scholar 

  50. Huang, Q., Yan, J. & Agami, R. Long non-coding RNAs in metastasis. Cancer Metastasis Rev. 37, 75–81 (2018).

    CAS  PubMed  Google Scholar 

  51. Li, J., Meng, H., Bai, Y. & Wang, K. Regulation of lncRNA and its role in cancer metastasis. Oncol. Res. 23, 205–217 (2016).

    PubMed  PubMed Central  Google Scholar 

  52. Raab, J. R. et al. SWI/SNF remains localized to chromatin in the presence of SCHLAP1. Nat. Genet. 51, 26–29 (2019).

    CAS  PubMed  Google Scholar 

  53. Liu, S. J. & Lim, D. A. Modulating the expression of long non-coding RNAs for functional studies. EMBO Rep. 19, e46955 (2018).

    PubMed  PubMed Central  Google Scholar 

  54. Liu, S. J. et al. CRISPRi-based genome-scale identification of functional long noncoding RNA loci in human cells. Science 355, eaah7111 (2017).

    Google Scholar 

  55. Liu, Y. et al. Genome-wide screening for functional long noncoding RNAs in human cells by Cas9 targeting of splice sites. Nat. Biotechnol. 1656, 175–1210 (2018).

    Google Scholar 

  56. Zhu, S. et al. Genome-scale deletion screening of human long non-coding RNAs using a paired-guide RNA CRISPR–Cas9 library. Nat. Biotechnol. 34, 1279–1286 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Boettcher, M. et al. Dual gene activation and knockout screen reveals directional dependencies in genetic networks. Nat. Biotechnol. 36, 170–178 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Liu, S. J. et al. CRISPRi-based radiation modifier screen identifies long non-coding RNA therapeutic targets in glioma. Genome Biol. 21, 83 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Thiery, J. P., Acloque, H., Huang, R. Y. J. & Nieto, M. A. Epithelial-mesenchymal transitions in development and disease. Cell 139, 871–890 (2009).

    CAS  PubMed  Google Scholar 

  60. Nieto, M. A., Huang, R. Y. J., Jackson, R. A. & Thiery, J. P. EMT: 2016. Cell 166, 21–45 (2016).

    CAS  PubMed  Google Scholar 

  61. Yang, J. et al. Guidelines and definitions for research on epithelial–mesenchymal transition. Nat. Rev. Mol. Cell Biol. 21, 341–352 (2020).

    PubMed  PubMed Central  Google Scholar 

  62. De Craene, B. & Berx, G. Regulatory networks defining EMT during cancer initiation and progression. Nat. Rev. Cancer 13, 97–110 (2013).

    PubMed  Google Scholar 

  63. Brannan, C. I., Dees, E. C. & Ingram, R. S. The product of the H19 gene may function as an RNA. Mol. Cell. 10, 28–36 (1990).

    CAS  Google Scholar 

  64. Rainier, S. et al. Relaxation of imprinted genes in human cancer. Nature 362, 747–749 (1993). One of the earliest reports of a noncoding RNA involved in cancer.

    CAS  PubMed  Google Scholar 

  65. Luo, M. et al. Long non-coding RNA H19 increases bladder cancer metastasis by associating with EZH2 and inhibiting E-cadherin expression. Cancer Lett. 333, 213–221 (2013).

    CAS  PubMed  Google Scholar 

  66. Davidovich, C., Zheng, L., Goodrich, K. J. & Cech, T. R. Promiscuous RNA binding by Polycomb repressive complex 2. Nat. Struct. Mol. Biol. 20, 1250–1257 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Liang, W.-C. et al. The lncRNA H19 promotes epithelial to mesenchymal transition by functioning as miRNA sponges in colorectal cancer. Oncotarget 6, 22513–22525 (2015).

    PubMed  PubMed Central  Google Scholar 

  68. Zhou, W. 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). Demonstrates the role of H19 in a stepwise cascade of metastasis initiation and colonization, with alternative molecular mechanisms based on the cellular context.

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  70. Chen, W.-Y. et al. Loss of SPDEF and gain of TGFBI activity after androgen deprivation therapy promote EMT and bone metastasis of prostate cancer. Sci. Signal 10, eaam6826 (2017).

    PubMed  Google Scholar 

  71. Liang, H. et al. LncRNA PTAR promotes EMT and invasion-metastasis in serous ovarian cancer by competitively binding miR-101-3p to regulate ZEB1 expression. Mol. Cancer 17, 119–13 (2018).

    PubMed  PubMed Central  Google Scholar 

  72. Grelet, S. et al. A regulated PNUTS mRNA to lncRNA splice switch mediates EMT and tumour progression. Nat. Cell Biol. 19, 1105–1115 (2017). A well dissected example of a lncRNA acting as a ceRNA to regulate the EMT.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Yuan, J.-H. et al. A long noncoding RNA activated by TGF-β promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell 25, 666–681 (2014).

    CAS  PubMed  Google Scholar 

  74. Shi, S.-J. et al. LncRNA-ATB promotes trastuzumab resistance and invasion-metastasis cascade in breast cancer. Oncotarget 6, 11652–11663 (2015).

    PubMed  PubMed Central  Google Scholar 

  75. Wu, N. et al. LINC00941 promotes CRC metastasis through preventing SMAD4 protein degradation and activating the TGF-β/SMAD2/3 signaling pathway. Cell Death Differ. 65, 87–14 (2020).

    Google Scholar 

  76. Li, T. et al. Amplification of long noncoding RNA ZFAS1 promotes metastasis in hepatocellular carcinoma. Cancer Res. 75, 3181–3191 (2015).

    CAS  PubMed  Google Scholar 

  77. Liu, F. et al. Long noncoding RNA FTX inhibits hepatocellular carcinoma proliferation and metastasis by binding MCM2 and miR-374a. Oncogene 35, 5422–5434 (2016).

    CAS  PubMed  Google Scholar 

  78. Wang, H. et al. STAT3-mediated upregulation of lncRNA HOXD-AS1 as a ceRNA facilitates liver cancer metastasis by regulating SOX4. Mol. Cancer 16, 136 (2017).

    PubMed  PubMed Central  Google Scholar 

  79. Li, Y. et al. Long noncoding RNA HOXD-AS1 induces epithelial-mesenchymal transition in breast cancer by acting as a competing endogenous RNA of miR-421. J. Cell. Biochem. 120, 10633–10642 (2019).

    CAS  PubMed  Google Scholar 

  80. Terashima, M., Tange, S., Ishimura, A. & Suzuki, T. MEG3 long noncoding RNA contributes to the epigenetic regulation of epithelial-mesenchymal transition in lung cancer cell lines. J. Biol. Chem. 292, 82–99 (2017).

    CAS  PubMed  Google Scholar 

  81. Mondal, T. et al. MEG3 long noncoding RNA regulates the TGF-β pathway genes through formation of RNA-DNA triplex structures. Nat. Commun. 6, 7743–17 (2015).

    CAS  PubMed  Google Scholar 

  82. Yan, X. et al. Mesenchymal stem cells promote hepatocarcinogenesis via lncRNA-MUF interaction with ANXA2 and miR-34a. Cancer Res. 77, 6704–6716 (2017).

    CAS  PubMed  Google Scholar 

  83. Mitra, R. et al. Decoding critical long non-coding RNA in ovarian cancer epithelial-to-mesenchymal transition. Nat. Commun. 8, 1604–1612 (2017).

    PubMed  PubMed Central  Google Scholar 

  84. Li, Z. et al. The degradation of EZH2 mediated by lncRNA ANCR attenuated the invasion and metastasis of breast cancer. Cell Death Differ. 24, 59–71 (2017).

    PubMed  Google Scholar 

  85. Li, W. et al. The FOXN3-NEAT1-SIN3A repressor complex promotes progression of hormonally responsive breast cancer. J. Clin. Invest. 127, 3421–3440 (2017).

    PubMed  PubMed Central  Google Scholar 

  86. Liang, W.-C. et al. LncRNA-NEF antagonized epithelial to mesenchymal transition and cancer metastasis via cis-regulating FOXA2 and inactivating Wnt/β-catenin signaling. Oncogene 37, 1445–1456 (2018).

    CAS  PubMed  Google Scholar 

  87. Tichon, A. et al. A conserved abundant cytoplasmic long noncoding RNA modulates repression by Pumilio proteins in human cells. Nat. Commun. 7, 12209 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Tan, B.-S. et al. LncRNA NORAD is repressed by the YAP pathway and suppresses lung and breast cancer metastasis by sequestering S100P. Oncogene 38, 5612–5626 (2019).

    CAS  PubMed  Google Scholar 

  89. Ling, H. et al. CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer. Genome Res. 23, 1446–1461 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Redis, R. S. et al. Allele-specific reprogramming of cancer metabolism by the long non-coding RNA CCAT2. Mol. Cell 61, 520–534 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Silva-Fisher, J. M. et al. Long non-coding RNA RAMS11 promotes metastatic colorectal cancer progression. Nat. Commun. 11, 2156–13 (2020). A lncRNA that is both prognostic of survival in metastatic colon cancer and predictive of response to chemotherapy and targeted molecular therapy.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Ji, P. et al. MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene 22, 8031–8041 (2003).

    PubMed  Google Scholar 

  93. Arun, G. et al. Differentiation of mammary tumors and reduction in metastasis upon Malat1 lncRNA loss. Genes Dev. 30, 34–51 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Gutschner, T. et al. The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res. 73, 1180–1189 (2013). Seminal loss of function study of MALAT1 as a lncRNA regulator of cancer metastasis.

    CAS  PubMed  Google Scholar 

  95. Zhang, B. et al. The lncRNA Malat1 is dispensable for mouse development but its transcription plays a cis-regulatory role in the adult. Cell Rep. 2, 111–123 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Sterling, J. A. et al. The hedgehog signaling molecule Gli2 induces parathyroid hormone-related peptide expression and osteolysis in metastatic human breast cancer cells. Cancer Res. 66, 7548–7553 (2006).

    CAS  PubMed  Google Scholar 

  97. Xing, Z. et al. lncRNA directs cooperative epigenetic regulation downstream of chemokine signals. Cell 159, 1110–1125 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Meijer, D., van Agthoven, T., Bosma, P. T., Nooter, K. & Dorssers, L. C. J. Functional screen for genes responsible for tamoxifen resistance in human breast cancer cells. Mol. Cancer Res. 4, 379–386 (2006).

    CAS  PubMed  Google Scholar 

  99. Calon, A. et al. Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation. Cancer Cell 22, 571–584 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Kogo, R. et al. Long noncoding RNA HOTAIR regulates Polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers. Cancer Res. 71, 6320–6326 (2011).

    CAS  PubMed  Google Scholar 

  101. Ren, Y. et al. Paracrine and epigenetic control of CAF-induced metastasis: the role of HOTAIR stimulated by TGF-ß1 secretion. Mol. Cancer 17, 5–14 (2018).

    PubMed  PubMed Central  Google Scholar 

  102. Gupta, G. P. et al. Identifying site-specific metastasis genes and functions. Cold Spring Harb. Symposia Quant. Biol. 70, 149–158 (2005).

    CAS  PubMed  Google Scholar 

  103. Minn, A. J. et al. Genes that mediate breast cancer metastasis to lung. Nature 436, 518–524 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Yuzhalin, A. E. & Yu, D. Brain metastasis organotropism. Cold Spring Harb. Perspect. Med. 10, a037242 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Weidle, U. H., Birzele, F., Kollmorgen, G. & Rüger, R. Molecular basis of lung tropism of metastasis. Cancer Genomics Proteom. 13, 129–139 (2016).

    CAS  Google Scholar 

  106. Shimo, T. et al. Pathogenic role of connective tissue growth factor (CTGF/CCN2) in osteolytic metastasis of breast cancer. J. Bone Miner. Res. 21, 1045–1059 (2006).

    CAS  PubMed  Google Scholar 

  107. Chen, W., Hoffmann, A. D., Liu, H. & Liu, X. Organotropism: new insights into molecular mechanisms of breast cancer metastasis. NPJ Precis. Oncol. 2, 4 (2018).

    PubMed  PubMed Central  Google Scholar 

  108. Guy, C. T., Cardiff, R. D. & Muller, W. J. Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol. Cell. Biol. 12, 954–961 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Muller, W. J., Sinn, E., Pattengale, P. K., Wallace, R. & Leder, P. Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell 54, 105–115 (1988).

    CAS  PubMed  Google Scholar 

  110. Annunziato, S., Barazas, M., Rottenberg, S. & Jonkers, J. Genetic dissection of cancer development, therapy response, and resistance in mouse models of breast cancer. Cold Spring Harb. Symposia Quant. Biol. 81, 141–150 (2016).

    PubMed  Google Scholar 

  111. Li, C. et al. A ROR1-HER3-lncRNA signalling axis modulates the Hippo-YAP pathway to regulate bone metastasis. Nat. Cell Biol. 19, 106–119 (2017). Studies the role of MAYA in directing organ-specific tropism towards bone metastases and demonstrates therapeutic in vivo targeting of this lncRNA in mice.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Valiente, M. et al. Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell 156, 1002–1016 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Wang, S. et al. JAK2-binding long noncoding RNA promotes breast cancer brain metastasis. J. Clin. Invest. 127, 4498–4515 (2017). Demonstrates how lnc-BM promotes brain metastases through activation of cell adhesion molecules and cytokine release.

    PubMed  PubMed Central  Google Scholar 

  114. Lee, J. T. Gracefully ageing at 50, X-chromosome inactivation becomes a paradigm for RNA and chromatin control. Nat. Rev. Mol. Cell Biol. 12, 815–826 (2011).

    CAS  PubMed  Google Scholar 

  115. Xing, F. et al. Loss of XIST in breast cancer activates MSN-c-Met and reprograms microglia via exosomal miRNA to promote brain metastasis. Cancer Res. 78, 4316–4330 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. De Palma, M., Biziato, D. & Petrova, T. V. Microenvironmental regulation of tumour angiogenesis. Nat. Rev. Cancer 17, 457–474 (2017).

    PubMed  Google Scholar 

  117. Kitamura, T., Qian, B.-Z. & Pollard, J. W. Immune cell promotion of metastasis. Nat. Rev. Immunol. 15, 73–86 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Karki, R. & Kanneganti, T.-D. Diverging inflammasome signals in tumorigenesis and potential targeting. Nat. Rev. Cancer 19, 197–214 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Huntington, N. D., Cursons, J. & Rautela, J. The cancer-natural killer cell immunity cycle. Nat. Rev. Cancer 7, 703–718 (2020).

    Google Scholar 

  120. Peinado, H. et al. Pre-metastatic niches: organ-specific homes for metastases. Nat. Rev. Cancer 17, 302–317 (2017).

    CAS  PubMed  Google Scholar 

  121. Zanconato, F., Cordenonsi, M. & Piccolo, S. YAP and TAZ: a signalling hub of the tumour microenvironment. Nat. Rev. Cancer 19, 454–464 (2019).

    CAS  PubMed  Google Scholar 

  122. Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Liu, B. et al. A cytoplasmic NF-κB interacting long noncoding RNA blocks IκB phosphorylation and suppresses breast cancer metastasis. Cancer Cell 27, 370–381 (2015).

    CAS  PubMed  Google Scholar 

  124. Huang, D. et al. NKILA lncRNA promotes tumor immune evasion by sensitizing T cells to activation-induced cell death. Nat. Immunol. 19, 1112–1125 (2018). Broadens the role of NKILA toinclude both tumour-intrinsic and tumour microenvironment factors.

    CAS  PubMed  Google Scholar 

  125. Ji, J. et al. Long non-coding RNA Lnc-Tim3 exacerbates CD8 T cell exhaustion via binding to Tim-3 and inducing nuclear translocation of Bat3 in HCC. Cell Death Dis. 9, 478 (2018).

    PubMed  PubMed Central  Google Scholar 

  126. Sang, L.-J. et al. LncRNA CamK-A regulates Ca2+-signaling-mediated tumor microenvironment remodeling. Mol. Cell 72, 71–83.e7 (2018).

    CAS  PubMed  Google Scholar 

  127. Jiang, R. et al. The long noncoding RNA lnc-EGFR stimulates T-regulatory cells differentiation thus promoting hepatocellular carcinoma immune evasion. Nat. Commun. 8, 15129 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Chen, C. et al. LNMAT1 promotes lymphatic metastasis of bladder cancer via CCL2 dependent macrophage recruitment. Nat. Commun. 9, 3826–18 (2018).

    PubMed  PubMed Central  Google Scholar 

  129. Chen, Y. G., Satpathy, A. T. & Chang, H. Y. Gene regulation in the immune system by long noncoding RNAs. Nat. Immunol. 18, 962–972 (2017).

    CAS  PubMed  Google Scholar 

  130. Fatica, A. & Bozzoni, I. Long non-coding RNAs: new players in cell differentiation and development. Nat. Rev. Genet. 15, 7–21 (2014).

    CAS  PubMed  Google Scholar 

  131. Sauvageau, M. et al. Multiple knockout mouse models reveal lincRNAs are required for life and brain development. eLife 2, e01749 (2013). Genetic deletion of multiple lncRNAs in mouse models demonstrating essential phenotypes.

    PubMed  PubMed Central  Google Scholar 

  132. Roobol, M. J. et al. Performance of the prostate cancer antigen 3 (PCA3) gene and prostate-specific antigen in prescreened men: exploring the value of PCA3 for a first-line diagnostic test. Eur. Urol. 58, 475–481 (2010).

    CAS  PubMed  Google Scholar 

  133. Prensner, J. R. et al. RNA biomarkers associated with metastatic progression in prostate cancer: a multi-institutional high-throughput analysis of SChLAP1. Lancet Oncol. 15, 1469–1480 (2014). Large-scale translational study establishing SChLAP1 as a prognostic marker for metastatic prostate cancer risk.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Reyes, D. K. & Pienta, K. J. The biology and treatment of oligometastatic cancer. Oncotarget 6, 8491–8524 (2015).

    PubMed  PubMed Central  Google Scholar 

  136. Palma, D. A. et al. The oligometastatic state - separating truth from wishful thinking. Nat. Publ. Group. 11, 549–557 (2014).

    Google Scholar 

  137. Qu, L. et al. Exosome-transmitted lncARSR promotes sunitinib resistance in renal cancer by acting as a competing endogenous RNA. Cancer Cell 29, 653–668 (2016). Demonstrates paracrine transfer of lncRNAs through exosomes leading to drug resistance.

    CAS  PubMed  Google Scholar 

  138. Yoshida, T. et al. Estimated number of off-target candidate sites for antisense oligonucleotides in human mRNA sequences. Genes Cell 23, 448–455 (2018).

    CAS  Google Scholar 

  139. Yoshida, T. et al. Evaluation of off-target effects of gapmer antisense oligonucleotides using human cells. Genes Cell 24, 827–835 (2019).

    CAS  Google Scholar 

  140. Lee, J.-S. & Mendell, J. T. Antisense-mediated transcript knockdown triggers premature transcription termination. Mol. Cell 77, 1044–1054.e3 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Lai, F., Damle, S. S., Ling, K. K. & Rigo, F. Directed RNase H cleavage of nascent transcripts causes transcription termination. Mol. Cell 77, 1032–1043.e4 (2020).

    CAS  PubMed  Google Scholar 

  142. Swayze, E. E. et al. Antisense oligonucleotides containing locked nucleic acid improve potency but cause significant hepatotoxicity in animals. Nucleic Acids Res. 35, 687–700 (2007).

    CAS  PubMed  Google Scholar 

  143. Meng, L. et al. Towards a therapy for Angelman syndrome by targeting a long non-coding RNA. Nature 518, 409–412 (2015).

    CAS  PubMed  Google Scholar 

  144. Scharner, J. et al. Hybridization-mediated off-target effects of splice-switching antisense oligonucleotides. Nucleic Acids Res. 48, 802–816 (2020).

    CAS  PubMed  Google Scholar 

  145. Zielinski, R. & Chi, K. N. Custirsen (OGX-011): a second-generation antisense inhibitor of clusterin in development for the treatment of prostate cancer. Future Oncol. 8, 1239–1251 (2012).

    CAS  PubMed  Google Scholar 

  146. Yamamoto, Y. et al. Generation 2.5 antisense oligonucleotides targeting the androgen receptor and its splice variants suppress enzalutamide-resistant prostate cancer cell growth. Clin. Cancer Res. 21, 1675–1687 (2015).

    CAS  PubMed  Google Scholar 

  147. Finkel, R. S. et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N. Engl. J. Med. 377, 1723–1732 (2017). Randomized clinical trial of an antisense oligonucleotide-based therapeutic in human patients demonstrating successful clinical response.

    CAS  PubMed  Google Scholar 

  148. Hong, D. et al. AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer. Sci. Transl. Med. 7, 314ra185 (2015).

    PubMed  PubMed Central  Google Scholar 

  149. Monteleone, G. et al. Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn’s disease. N. Engl. J. Med. 372, 1104–1113 (2015).

    CAS  PubMed  Google Scholar 

  150. Cornelis, G., Souquere, S., Vernochet, C., Heidmann, T. & Pierron, G. Functional conservation of the lncRNA NEAT1 in the ancestrally diverged marsupial lineage: evidence for NEAT1 expression and associated paraspeckle assembly during late gestation in the opossum Monodelphis domestica. RNA Biol. 13, 826–836 (2016).

    PubMed  PubMed Central  Google Scholar 

  151. Karner, H. et al. Functional conservation of LncRNA JPX despite sequence and structural divergence. J. Mol. Biol. 432, 283–300 (2020).

    CAS  PubMed  Google Scholar 

  152. Long, Y. et al. RNA is essential for PRC2 chromatin occupancy and function in human pluripotent stem cells. Nat. Genet. 52, 931–938 (2020).

    CAS  PubMed  Google Scholar 

  153. Fares, J., Fares, M. Y., Khachfe, H. H., Salhab, H. A. & Fares, Y. Molecular principles of metastasis: a hallmark of cancer revisited. Signal. Transduct. Target. Ther. 5, 28–17 (2020).

    PubMed  PubMed Central  Google Scholar 

  154. Bassett, A. R. et al. Considerations when investigating lncRNA function in vivo. eLife 3, e03058 (2014).

    PubMed  PubMed Central  Google Scholar 

  155. Wurster, C. D. & Ludolph, A. C. Antisense oligonucleotides in neurological disorders. Ther. Adv. Neurol. Disord. 11, 1756286418776932 (2018).

    PubMed  PubMed Central  Google Scholar 

  156. Thomson, D. W. & Dinger, M. E. Endogenous microRNA sponges: evidence and controversy. Nat. Rev. Genet. 17, 272–283 (2016).

    CAS  PubMed  Google Scholar 

  157. Denzler, R., Agarwal, V., Stefano, J., Bartel, D. P. & Stoffel, M. Assessing the ceRNA hypothesis with quantitative measurements of miRNA and target abundance. Mol. Cell 54, 766–776 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Ala, U. et al. Integrated transcriptional and competitive endogenous RNA networks are cross-regulated in permissive molecular environments. Proc. Natl Acad. Sci. USA 110, 7154–7159 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Figliuzzi, M., Marinari, E. & De Martino, A. MicroRNAs as a selective channel of communication between competing RNAs: a steady-state theory. Biophys. J. 104, 1203–1213 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Hausser, J. & Zavolan, M. Identification and consequences of miRNA-target interactions–beyond repression of gene expression. Nat. Rev. Genet. 15, 599–612 (2014).

    CAS  PubMed  Google Scholar 

  161. Thomson, D. W., Bracken, C. P. & Goodall, G. J. Experimental strategies for microRNA target identification. Nucleic Acids Res. 39, 6845–6853 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Gennarino, V. A. et al. Identification of microRNA-regulated gene networks by expression analysis of target genes. Genome Res. 22, 1163–1172 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Du, Z. et al. Integrative analyses reveal a long noncoding RNA-mediated sponge regulatory network in prostate cancer. Nat. Commun. 7, 10982–10 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Paraskevopoulou, M. D. et al. DIANA-LncBase: experimentally verified and computationally predicted microRNA targets on long non-coding RNAs. Nucleic Acids Res. 41, D239–D245 (2013).

    CAS  PubMed  Google Scholar 

  165. Wang, P. et al. miRSponge: a manually curated database for experimentally supported miRNA sponges and ceRNAs. Database 2015, bav098 (2015).

    PubMed  PubMed Central  Google Scholar 

  166. Hoffmann, M. et al. SPONGEdb: a pan-cancer resource for competing endogenous RNA interactions. NAR Cancer https://doi.org/10.1093/narcan/zcaa042 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Li, J.-H., Liu, S., Zhou, H., Qu, L.-H. & Yang, J.-H. starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res. 42, D92–D97 (2014).

    CAS  PubMed  Google Scholar 

  168. Karreth, F. A. et al. The BRAF pseudogene functions as a competitive endogenous RNA and induces lymphoma in vivo. Cell 161, 319–332 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Piwecka, M. et al. Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function. Science 357, eaam8526 (2017).

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA

    S. John Liu & Felix Y. Feng

  2. Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA

    S. John Liu & Daniel A. Lim

  3. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA

    S. John Liu & Felix Y. Feng

  4. Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA

    S. John Liu & Daniel A. Lim

  5. Department of Internal Medicine, Washington University in St Louis, St Louis, MO, USA

    Ha X. Dang & Christopher A. Maher

  6. Siteman Cancer Center, Washington University in St Louis, St Louis, MO, USA

    Ha X. Dang & Christopher A. Maher

  7. McDonnell Genome Institute, Washington University in St Louis, St Louis, MO, USA

    Ha X. Dang & Christopher A. Maher

  8. San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA

    Daniel A. Lim

  9. Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA

    Felix Y. Feng

  10. Department of Urology, University of California, San Francisco, San Francisco, CA, USA

    Felix Y. Feng

  11. Department of Biomedical Engineering, Washington University in St Louis, St Louis, MO, USA

    Christopher A. Maher

Authors
  1. S. John Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ha X. Dang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniel A. Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Felix Y. Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christopher A. Maher
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Christopher A. Maher.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Cancer thanks M. Huarte, L. Ma and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

Invasion–metastasis cascade

A stepwise succession of events whereby primary tumour cells adopt a phenotype that promotes local invasion, intravasation into the bloodstream, extravasation and migration to distant organ sites, and colonization of those sites, which often involves physiological adaptation.

Long noncoding RNAs

(lncRNAs). Noncoding RNA transcripts longer than 200 nucleotides, which are frequently polyadenylated, and that show no evidence that they encode proteins.

Competing endogenous RNAs

(ceRNAs). RNA transcripts (which may be lncRNAs, mRNAs or pseudogenes) that are capable of binding and influencing the activity of microRNAs through complementary base pairing.

Organ-specific tropism

The propensity for disseminated cancer cells to colonize and proliferate at specific organ sites due to diverse physiological and molecular factors.

Antisense oligonucleotides

(ASOs). Exogenous oligonucleotides, often chemically modified to resist degradation, that alter the amount, stability or activity of complementary RNA transcripts, usually through RNase-based mechanisms.

Epithelial–mesenchymal transition

(EMT). A set of molecular processes that convert cancer cells of polarized epithelial phenotypes into more invasive mesenchymal phenotypes.

Anoikis

A subtype of programmed cell death triggered by inappropriate cellular or extracellular matrix interactions, often in the setting of tumour cells escaping their primary environment.

Micrometastases

Collections of metastasized tumour cells that are clinically detectable but typically under 2 mm in diameter in human patients.

Comprehensive identification of RNA-binding proteins by mass spectrometry

(ChIRP-MS). A method of identifying endogenous RNA–protein interactions with high specificity, using in vivo crosslinking, RNA pulldown and mass spectrometry.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, S.J., Dang, H.X., Lim, D.A. et al. Long noncoding RNAs in cancer metastasis. Nat Rev Cancer 21, 446–460 (2021). https://doi.org/10.1038/s41568-021-00353-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41568-021-00353-1

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer