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Long noncoding RNA: an emerging paradigm of cancer research

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Tumor Biology

Abstract

Recent studies have demonstrated the importance of non-protein coding part of human genome in carcinogenesis and metastasis. Among numerous kinds of non-protein coding RNAs, long noncoding RNAs (lncRNAs) play a key regulatory role in cancer biology. LncRNAs are dysregulated in different kinds of cancer and the expression levels of certain lncRNAs are associated with recurrence, metastasis, and prognosis of cancer. It is also proved that overexpression of certain lncRNAs, behaving like oncogenes, can promote matrix invasion of cancer cells and tumor growth. In this review, we focus our attention on lncRNAs those have been validated in human cancer tissues to suggest reasonable strategies for future research. We introduce an update view of lncRNA, extract cancer-related lncRNAs from literature, and describe the known functions and possible underlying molecular mechanisms of some well investigated lncRNAs (MALAT1, HOX antisense intergenic RNA, and highly upregulated in hepatocellular cancer), as well as their current and potential future application in cancer diagnosis (PCA3) and treatment (H19).

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References

  1. Birney E, Stamatoyannopoulos JA, Dutta A, Guigo R, Gingeras TR, Margulies EH, et al. Identification and analysis of functional elements in 1 % of the human genome by the encode pilot project. Nature. 2007;447(7146):799–816.

    Article  PubMed  CAS  Google Scholar 

  2. Esteller M. Non-coding RNAs in human disease. Nat Rev Genet. 2011;12(12):861–74.

    Article  PubMed  CAS  Google Scholar 

  3. Carthew RW, Sontheimer EJ. Origins and mechanisms of miRNAs and siRNAs. Cell. 2009;136(4):642–55.

    Article  PubMed  CAS  Google Scholar 

  4. Dinger ME, Amaral PP, Mercer TR, Pang KC, Bruce SJ, Gardiner BB, et al. Long noncoding RNAs in mouse embryonic stem cell pluripotency and differentiation. Genome Res. 2008;18(9):1433–45.

    Article  PubMed  CAS  Google Scholar 

  5. Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464(7291):1071–6.

    Article  PubMed  CAS  Google Scholar 

  6. Ji P, Diederichs S, Wang W, Boing S, Metzger R, Schneider PM, et al. MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene. 2003;22(39):8031–41.

    Article  PubMed  Google Scholar 

  7. Schmidt LH, Spieker T, Koschmieder S, Schaffers S, Humberg J, Jungen D, et al. The long noncoding MALAT-1 RNA indicates a poor prognosis in non-small cell lung cancer and induces migration and tumor growth. J Thorac Oncol. 2011;6(12):1984–92.

    Article  PubMed  Google Scholar 

  8. Ponting CP, Oliver PL, Reik W. Evolution and functions of long noncoding RNAs. Cell. 2009;136(4):629–41.

    Article  PubMed  CAS  Google Scholar 

  9. Kapranov P, Cheng J, Dike S, Nix DA, Duttagupta R, Willingham AT, et al. RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science. 2007;316(5830):1484–8.

    Article  PubMed  CAS  Google Scholar 

  10. Martick M, Horan LH, Noller HF, Scott WG. A discontinuous hammerhead ribozyme embedded in a mammalian messenger RNA. Nature. 2008;454(7206):899–902.

    Article  PubMed  CAS  Google Scholar 

  11. Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ, Pandolfi PP. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature. 2010;465(7301):1033–8.

    Article  PubMed  CAS  Google Scholar 

  12. Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: insights into functions. Nat Rev Genet. 2009;10(3):155–9.

    Article  PubMed  CAS  Google Scholar 

  13. Spizzo R, Almeida MI, Colombatti A, Calin GA. Long non-coding RNAs and cancer: a new frontier of translational research? Oncogene. 2012;31(43):4577–87.

    Article  PubMed  CAS  Google Scholar 

  14. Matouk IJ, Abbasi I, Hochberg A, Galun E, Dweik H, Akkawi M. Highly upregulated in liver cancer noncoding RNA is overexpressed in hepatic colorectal metastasis. Eur J Gastroenterol Hepatol. 2009;21(6):688–92.

    Article  PubMed  CAS  Google Scholar 

  15. Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell. 2007;129(7):1311–23.

    Article  PubMed  CAS  Google Scholar 

  16. Wang J, Liu X, Wu H, Ni P, Gu Z, Qiao Y, et al. CREB up-regulates long non-coding RNA, HULC expression through interaction with microRNA-372 in liver cancer. Nucleic Acids Res. 2010;38(16):5366–83.

    Article  PubMed  CAS  Google Scholar 

  17. Reis EM, Verjovski-Almeida S. Perspectives of long non-coding RNAs in cancer diagnostics. Front Genet. 2012;3:32.

    PubMed  Google Scholar 

  18. Wang XS, Zhang Z, Wang HC, Cai JL, Xu QW, Li MQ, et al. Rapid identification of UCA1 as a very sensitive and specific unique marker for human bladder carcinoma. Clin Cancer Res. 2006;12(16):4851–8.

    Article  PubMed  CAS  Google Scholar 

  19. Zhu Y, Yu M, Li Z, Kong C, Bi J, Li J, et al. NcRAN, a newly identified long noncoding RNA, enhances human bladder tumor growth, invasion, and survival. Urology. 2011;77(2):510. e1–5.

    Article  PubMed  Google Scholar 

  20. Korneev SA, Korneeva EI, Lagarkova MA, Kiselev SL, Critchley G, O’Shea M. Novel noncoding antisense RNA transcribed from human anti-NOS2A locus is differentially regulated during neuronal differentiation of embryonic stem cells. RNA. 2008;14(10):2030–7.

    Article  PubMed  CAS  Google Scholar 

  21. Geng YJ, Xie SL, Li Q, Ma J, Wang GY. Large intervening non-coding RNA HOTAIR is associated with hepatocellular carcinoma progression. J Int Med Res. 2011;39(6):2119–28.

    PubMed  CAS  Google Scholar 

  22. Niinuma T, Suzuki H, Nojima M, Nosho K, Yamamoto H, Takamaru H, et al. Upregulation of miR-196a and HOTAIR drive malignant character in gastrointestinal stromal tumors. Cancer Res. 2012;72(5):1126–36.

    Article  PubMed  CAS  Google Scholar 

  23. Mourtada-Maarabouni M, Pickard MR, Hedge VL, Farzaneh F, Williams GT. GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer. Oncogene. 2009;28(2):195–208.

    Article  PubMed  CAS  Google Scholar 

  24. Silva JM, Boczek NJ, Berres MW, Ma X, Smith DI. LSINCT5 is over expressed in breast and ovarian cancer and affects cellular proliferation. RNA Biol. 2011;8(3):496–505.

    Article  PubMed  CAS  Google Scholar 

  25. Iacoangeli A, Lin Y, Morley EJ, Muslimov IA, Bianchi R, Reilly J, et al. BC200 RNA in invasive and preinvasive breast cancer. Carcinogenesis. 2004;25(11):2125–33.

    Article  PubMed  CAS  Google Scholar 

  26. Panzitt K, Tschernatsch MM, Guelly C, Moustafa T, Stradner M, Strohmaier HM, et al. Characterization of HULC, a novel gene with striking up-regulation in hepatocellular carcinoma, as noncoding RNA. Gastroenterology. 2007;132(1):330–42.

    Article  PubMed  CAS  Google Scholar 

  27. Yang F, Zhang L, Huo XS, Yuan JH, Xu D, Yuan SX, et al. Long noncoding RNA high expression in hepatocellular carcinoma facilitates tumor growth through enhancer of zeste homolog 2 in humans. Hepatology. 2011;54(5):1679–89.

    Article  PubMed  CAS  Google Scholar 

  28. Braconi C, Kogure T, Valeri N, Huang N, Nuovo G, Costinean S, et al. MicroRNA-29 can regulate expression of the long non-coding RNA gene MEG3 in hepatocellular cancer. Oncogene. 2011;30(47):4750–6.

    Article  PubMed  CAS  Google Scholar 

  29. Braconi C, Valeri N, Kogure T, Gasparini P, Huang N, Nuovo GJ, et al. Expression and functional role of a transcribed noncoding RNA with an ultraconserved element in hepatocellular carcinoma. Proc Natl Acad Sci U S A. 2011;108(2):786–91.

    Article  PubMed  CAS  Google Scholar 

  30. Pasmant E, Sabbagh A, Masliah-Planchon J, Ortonne N, Laurendeau I, Melin L, et al. Role of noncoding RNA ANRIL in genesis of plexiform neurofibromas in neurofibromatosis type 1. J Natl Cancer Inst. 2011;103(22):1713–22.

    Article  PubMed  CAS  Google Scholar 

  31. Khaitan D, Dinger ME, Mazar J, Crawford J, Smith MA, Mattick JS, et al. The melanoma-upregulated long noncoding RNA SPRY4-IT1 modulates apoptosis and invasion. Cancer Res. 2011;71(11):3852–62.

    Article  PubMed  CAS  Google Scholar 

  32. Chung S, Nakagawa H, Uemura M, Piao L, Ashikawa K, Hosono N, et al. Association of a novel long non-coding RNA in 8q24 with prostate cancer susceptibility. Cancer Sci. 2011;102(1):245–52.

    Article  PubMed  CAS  Google Scholar 

  33. Srikantan V, Zou Z, Petrovics G, Xu L, Augustus M, Davis L, et al. PCGEM1, a prostate-specific gene, is overexpressed in prostate cancer. Proc Natl Acad Sci U S A. 2000;97(22):12216–21.

    Article  PubMed  CAS  Google Scholar 

  34. Bussemakers MJ, van Bokhoven A, Verhaegh GW, Smit FP, Karthaus HF, Schalken JA, et al. DD3: a new prostate-specific gene, highly overexpressed in prostate cancer. Cancer Res. 1999;59(23):5975–9.

    PubMed  CAS  Google Scholar 

  35. Prensner JR, Iyer MK, Balbin OA, Dhanasekaran SM, Cao Q, Brenner JC, et al. Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression. Nat Biotechnol. 2011;29(8):742–9.

    Article  PubMed  CAS  Google Scholar 

  36. Cui Z, Ren S, Lu J, Wang F, Xu W, Sun Y, et al. The prostate cancer-up-regulated long noncoding RNA plncRNA-1 modulates apoptosis and proliferation through reciprocal regulation of androgen receptor. Urol Oncol. 2012. doi:10.1016/j.urolonc.2011.11.030.

  37. Graham LD, Pedersen SK, Brown GS, Ho T, Kassir Z, Moynihan AT, et al. Colorectal neoplasia differentially expressed (CRNDE), a novel gene with elevated expression in colorectal adenomas and adenocarcinomas. Genes Cancer. 2011;2(8):829–40.

    Article  PubMed  CAS  Google Scholar 

  38. Ellis BC, Molloy PL, Graham LD. CRNDE: a long non-coding RNA involved in cancer, neurobiology, and development. Front Genet. 2012;3:270.

    Article  PubMed  Google Scholar 

  39. Moran VA, Perera RJ, Khalil AM. Emerging functional and mechanistic paradigms of mammalian long non-coding RNAs. Nucleic Acids Res. 2012;40(14):6391–400.

    Article  PubMed  CAS  Google Scholar 

  40. Gibb EA, Vucic EA, Enfield KS, Stewart GL, Lonergan KM, Kennett JY, et al. Human cancer long non-coding RNA transcriptomes. PLoS One. 2011;6(10):e25915.

    Article  PubMed  CAS  Google Scholar 

  41. Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol Cell. 2011;43(6):904–14.

    Article  PubMed  CAS  Google Scholar 

  42. Wilusz JE, Sunwoo H, Spector DL. Long noncoding RNAs: functional surprises from the RNA world. Genes Dev. 2009;23(13):1494–504.

    Article  PubMed  CAS  Google Scholar 

  43. Xu C, Yang M, Tian J, Wang X, Li Z. MALAT-1: a long non-coding RNA and its important 3′ end functional motif in colorectal cancer metastasis. Int J Oncol. 2011;39(1):169–75.

    PubMed  Google Scholar 

  44. Guo F, Li Y, Liu Y, Wang J, Li G. Inhibition of metastasis-associated lung adenocarcinoma transcript 1 in CaSki human cervical cancer cells suppresses cell proliferation and invasion. Acta Biochim Biophys Sin (Shanghai). 2010;42(3):224–9.

    Article  CAS  Google Scholar 

  45. Yang L, Lin C, Liu W, Zhang J, Ohgi KA, Grinstein JD, et al. NcRNA- and PC2 methylation-dependent gene relocation between nuclear structures mediates gene activation programs. Cell. 2011;147(4):773–88.

    Article  PubMed  CAS  Google Scholar 

  46. Wilusz JE, Freier SM, Spector DL. 3′ end processing of a long nuclear-retained noncoding RNA yields a tRNA-like cytoplasmic RNA. Cell. 2008;135(5):919–32.

    Article  PubMed  CAS  Google Scholar 

  47. Hallegger M, Llorian M, Smith CW. Alternative splicing: global insights. FEBS J. 2010;277(4):856–66.

    Article  PubMed  CAS  Google Scholar 

  48. Pan Q, Shai O, Lee LJ, Frey BJ, Blencowe BJ. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet. 2008;40(12):1413–5.

    Article  PubMed  CAS  Google Scholar 

  49. Long JC, Caceres JF. The SR protein family of splicing factors: master regulators of gene expression. Biochem J. 2009;417(1):15–27.

    Article  PubMed  CAS  Google Scholar 

  50. Tripathi V, Ellis JD, Shen Z, Song DY, Pan Q, Watt AT, et al. The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol Cell. 2010;39(6):925–38.

    Article  PubMed  CAS  Google Scholar 

  51. Lin R, Roychowdhury-Saha M, Black C, Watt AT, Marcusson EG, Freier SM, et al. Control of RNA processing by a large non-coding RNA over-expressed in carcinomas. FEBS Lett. 2011;585(4):671–6.

    Article  PubMed  CAS  Google Scholar 

  52. Lin R, Maeda S, Liu C, Karin M, Edgington TS. A large noncoding RNA is a marker for murine hepatocellular carcinomas and a spectrum of human carcinomas. Oncogene. 2007;26(6):851–8.

    Article  PubMed  CAS  Google Scholar 

  53. Yang Z, Zhou L, Wu LM, Lai MC, Xie HY, Zhang F, et al. Overexpression of long non-coding RNA HOTAIR predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation. Ann Surg Oncol. 2011;18(5):1243–50.

    Article  PubMed  Google Scholar 

  54. Sparmann A, van Lohuizen M. Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer. 2006;6(11):846–56.

    Article  PubMed  CAS  Google Scholar 

  55. Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science. 2010;329(5992):689–93.

    Article  PubMed  CAS  Google Scholar 

  56. Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP. A ceRNA hypothesis: the Rosetta stone of a hidden RNA language? Cell. 2011;146(3):353–8.

    Article  PubMed  CAS  Google Scholar 

  57. Marks LS, Fradet Y, Deras IL, Blase A, Mathis J, Aubin SM, et al. PCA3 molecular urine assay for prostate cancer in men undergoing repeat biopsy. Urology. 2007;69(3):532–5.

    Article  PubMed  Google Scholar 

  58. Tinzl M, Marberger M, Horvath S, Chypre C. DD3PCA3 RNA analysis in urine—a new perspective for detecting prostate cancer. Eur Urol. 2004;46(2):182–6. discussion 7.

    Article  PubMed  CAS  Google Scholar 

  59. Hessels D, Klein Gunnewiek JM, van Oort I, Karthaus HF, van Leenders GJ, van Balken B, et al. DD3(PCA3)-based molecular urine analysis for the diagnosis of prostate cancer. Eur Urol. 2003;44(1):8–15. discussion 6.

    Article  PubMed  CAS  Google Scholar 

  60. van Gils MP, Hessels D, van Hooij O, Jannink SA, Peelen WP, Hanssen SL, et al. The time-resolved fluorescence-based PCA3 test on urinary sediments after digital rectal examination; a Dutch multicenter validation of the diagnostic performance. Clin Cancer Res. 2007;13(3):939–43.

    Article  PubMed  Google Scholar 

  61. Roobol MJ, Schroder FH, van Leeuwen P, Wolters T, van den Bergh RC, van Leenders GJ, 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. 2010;58(4):475–81.

    Article  PubMed  CAS  Google Scholar 

  62. Ploussard G, Durand X, Xylinas E, Moutereau S, Radulescu C, Forgue A, et al. Prostate cancer antigen 3 score accurately predicts tumour volume and might help in selecting prostate cancer patients for active surveillance. Eur Urol. 2011;59(3):422–9.

    Article  PubMed  Google Scholar 

  63. Pachnis V, Brannan CI, Tilghman SM. The structure and expression of a novel gene activated in early mouse embryogenesis. EMBO J. 1988;7(3):673–81.

    PubMed  CAS  Google Scholar 

  64. Scaiewicz V, Sorin V, Fellig Y, Birman T, Mizrahi A, Galula J, et al. Use of H19 gene regulatory sequences in DNA-based therapy for pancreatic cancer. J Oncol. 2010;2010:178174.

    Article  PubMed  CAS  Google Scholar 

  65. Ohana P, Bibi O, Matouk I, Levy C, Birman T, Ariel I, et al. Use of H19 regulatory sequences for targeted gene therapy in cancer. Int J Cancer. 2002;98(5):645–50.

    Article  PubMed  CAS  Google Scholar 

  66. Hanna N, Ohana P, Konikoff FM, Leichtmann G, Hubert A, Appelbaum L, et al. Phase 1/2a, dose-escalation, safety, pharmacokinetic and preliminary efficacy study of intratumoral administration of BC-819 in patients with unresectable pancreatic cancer. Cancer Gene Ther. 2012;19(6):374–81.

    Article  PubMed  CAS  Google Scholar 

  67. Tsai MC, Spitale RC, Chang HY. Long intergenic noncoding RNAs: new links in cancer progression. Cancer Res. 2011;71(1):3–7.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Rong Yin or Lin Xu.

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Qiu, MT., Hu, JW., Yin, R. et al. Long noncoding RNA: an emerging paradigm of cancer research. Tumor Biol. 34, 613–620 (2013). https://doi.org/10.1007/s13277-013-0658-6

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