Advertisement

Computational Analysis of lncRNA Function in Cancer

  • Xu ZhangEmail author
  • Tsui-Ting Ho
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1878)

Abstract

Long noncoding RNAs (lncRNAs) have been shown to play crucial roles in cancer biology. With the help of computational analysis illustrated here, the joint effects of lncRNAs and clinical variables can be quantified in a Cox model on cancer recurrence. Of importance, the predictive accuracy was then validated with the prognostic scores computed based on the suggested model. Further investigation of these potential lncRNAs would provide useful insights following the study of the mechanisms underlying the differential expression of these lncRNAs in association with and possibly contributing to cancer recurrence. Ultimately, the expanding knowledge of the function of lncRNAs curated by computational analysis will suggest new targets for cancer treatment.

Key words

lncRNA Cancer Cox model Lasso method Model validation Experimental validation 

References

  1. 1.
    Consortium EP, Birney E, Stamatoyannopoulos JA, Dutta A, Guigo R, Gingeras TR, Margulies EH, Weng Z, Snyder M, Dermitzakis ET, Thurman RE, Kuehn MS, Taylor CM, Neph S, Koch CM, Asthana S, Malhotra A, Adzhubei I, Greenbaum JA, Andrews RM, Flicek P, Boyle PJ, Cao H, Carter NP, Clelland GK, Davis S, Day N, Dhami P, Dillon SC, Dorschner MO, Fiegler H, Giresi PG, Goldy J, Hawrylycz M, Haydock A, Humbert R, James KD, Johnson BE, Johnson EM, Frum TT, Rosenzweig ER, Karnani N, Lee K, Lefebvre GC, Navas PA, Neri F, Parker SC, Sabo PJ, Sandstrom R, Shafer A, Vetrie D, Weaver M, Wilcox S, Yu M, Collins FS, Dekker J, Lieb JD, Tullius TD, Crawford GE, Sunyaev S, Noble WS, Dunham I, Denoeud F, Reymond A, Kapranov P, Rozowsky J, Zheng D, Castelo R, Frankish A, Harrow J, Ghosh S, Sandelin A, Hofacker IL, Baertsch R, Keefe D, Dike S, Cheng J, Hirsch HA, Sekinger EA, Lagarde J, Abril JF, Shahab A, Flamm C, Fried C, Hackermuller J, Hertel J, Lindemeyer M, Missal K, Tanzer A, Washietl S, Korbel J, Emanuelsson O, Pedersen JS, Holroyd N, Taylor R, Swarbreck D, Matthews N, Dickson MC, Thomas DJ, Weirauch MT, Gilbert J, Drenkow J, Bell I, Zhao X, Srinivasan KG, Sung WK, Ooi HS, Chiu KP, Foissac S, Alioto T, Brent M, Pachter L, Tress ML, Valencia A, Choo SW, Choo CY, Ucla C, Manzano C, Wyss C, Cheung E, Clark TG, Brown JB, Ganesh M, Patel S, Tammana H, Chrast J, Henrichsen CN, Kai C, Kawai J, Nagalakshmi U, Wu J, Lian Z, Lian J, Newburger P, Zhang X, Bickel P, Mattick JS, Carninci P, Hayashizaki Y, Weissman S, Hubbard T, Myers RM, Rogers J, Stadler PF, Lowe TM, Wei CL, Ruan Y, Struhl K, Gerstein M, Antonarakis SE, Fu Y, Green ED, Karaoz U, Siepel A, Taylor J, Liefer LA, Wetterstrand KA, Good PJ, Feingold EA, Guyer MS, Cooper GM, Asimenos G, Dewey CN, Hou M, Nikolaev S, Montoya-Burgos JI, Loytynoja A, Whelan S, Pardi F, Massingham T, Huang H, Zhang NR, Holmes I, Mullikin JC, Ureta-Vidal A, Paten B, Seringhaus M, Church D, Rosenbloom K, Kent WJ, Stone EA, Program NCS, Baylor College of Medicine Human Genome Sequencing Center, Washington University Genome Sequencing Center, Broad Institute, Children’s Hospital Oakland Research Institute, Batzoglou S, Goldman N, Hardison RC, Haussler D, Miller W, Sidow A, Trinklein ND, Zhang ZD, Barrera L, Stuart R, King DC, Ameur A, Enroth S, Bieda MC, Kim J, Bhinge AA, Jiang N, Liu J, Yao F, Vega VB, Lee CW, Ng P, Shahab A, Yang A, Moqtaderi Z, Zhu Z, Xu X, Squazzo S, Oberley MJ, Inman D, Singer MA, Richmond TA, Munn KJ, Rada-Iglesias A, Wallerman O, Komorowski J, Fowler JC, Couttet P, Bruce AW, Dovey OM, Ellis PD, Langford CF, Nix DA, Euskirchen G, Hartman S, Urban AE, Kraus P, Van Calcar S, Heintzman N, Kim TH, Wang K, Qu C, Hon G, Luna R, Glass CK, Rosenfeld MG, Aldred SF, Cooper SJ, Halees A, Lin JM, Shulha HP, Zhang X, Xu M, Haidar JN, Yu Y, Ruan Y, Iyer VR, Green RD, Wadelius C, Farnham PJ, Ren B, Harte RA, Hinrichs AS, Trumbower H, Clawson H, Hillman-Jackson J, Zweig AS, Smith K, Thakkapallayil A, Barber G, Kuhn RM, Karolchik D, Armengol L, Bird CP, de Bakker PI, Kern AD, Lopez-Bigas N, Martin JD, Stranger BE, Woodroffe A, Davydov E, Dimas A, Eyras E, Hallgrimsdottir IB, Huppert J, Zody MC, Abecasis GR, Estivill X, Bouffard GG, Guan X, Hansen NF, Idol JR, Maduro VV, Maskeri B, JC MD, Park M, Thomas PJ, Young AC, Blakesley RW, Muzny DM, Sodergren E, Wheeler DA, Worley KC, Jiang H, Weinstock GM, Gibbs RA, Graves T, Fulton R, Mardis ER, Wilson RK, Clamp M, Cuff J, Gnerre S, Jaffe DB, Chang JL, Lindblad-Toh K, Lander ES, Koriabine M, Nefedov M, Osoegawa K, Yoshinaga Y, Zhu B, de Jong PJ (2007) Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447(7146):799–816CrossRefGoogle Scholar
  2. 2.
    Cech TR, Steitz JA (2014) The noncoding RNA revolution-trashing old rules to forge new ones. Cell 157(1):77–94CrossRefGoogle Scholar
  3. 3.
    Kapranov P, Cheng J, Dike S, Nix DA, Duttagupta R, Willingham AT, Stadler PF, Hertel J, Hackermuller J, Hofacker IL, Bell I, Cheung E, Drenkow J, Dumais E, Patel S, Helt G, Ganesh M, Ghosh S, Piccolboni A, Sementchenko V, Tammana H, Gingeras TR (2007) RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science 316(5830):1484–1488CrossRefGoogle Scholar
  4. 4.
    Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, Guernec G, Martin D, Merkel A, Knowles DG, Lagarde J, Veeravalli L, Ruan X, Ruan Y, Lassmann T, Carninci P, Brown JB, Lipovich L, Gonzalez JM, Thomas M, Davis CA, Shiekhattar R, Gingeras TR, Hubbard TJ, Notredame C, Harrow J, Guigo R (2012) The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res 22(9):1775–1789CrossRefGoogle Scholar
  5. 5.
    Ulitsky I, Bartel DP (2013) lncRNAs: genomics, evolution, and mechanisms. Cell 154(1):26–46CrossRefGoogle Scholar
  6. 6.
    Prensner JR, Chinnaiyan AM (2011) The emergence of lncRNAs in cancer biology. Cancer Discov 1(5):391–407CrossRefGoogle Scholar
  7. 7.
    Prensner JR, Iyer MK, Balbin OA, Dhanasekaran SM, Cao Q, Brenner JC, Laxman B, Asangani IA, Grasso CS, Kominsky HD, Cao X, Jing X, Wang X, Siddiqui J, Wei JT, Robinson D, Iyer HK, Palanisamy N, Maher CA, Chinnaiyan AM (2011) Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lncRNA implicated in disease progression. Nat Biotechnol 29(8):742–749CrossRefGoogle Scholar
  8. 8.
    Lee GL, Dobi A, Srivastava S (2011) Prostate cancer: diagnostic performance of the PCA3 urine test. Nat Rev Urol 8(3):123–124CrossRefGoogle Scholar
  9. 9.
    Iyer MK, Niknafs YS, Malik R, Singhal U, Sahu A, Hosono Y, Barrette TR, Prensner JR, Evans JR, Zhao S, Poliakov A, Cao X, Dhanasekaran SM, Wu YM, Robinson DR, Beer DG, Feng FY, Iyer HK, Chinnaiyan AM (2015) The landscape of long noncoding RNAs in the human transcriptome. Nat Genet 47(3):199–208CrossRefGoogle Scholar
  10. 10.
    Liu Q, Huang J, Zhou N, Zhang Z, Zhang A, Lu Z, Wu F, Mo YY (2013) LncRNA loc285194 is a p53-regulated tumor suppressor. Nucleic Acids Res 41(9):4976–4987CrossRefGoogle Scholar
  11. 11.
    Zhang Z, Zhu Z, Watabe K, Zhang X, Bai C, Xu M, Wu F, Mo YY (2013) Negative regulation of lncRNA GAS5 by miR-21. Cell Death Differ 20(11):1558–1568CrossRefGoogle Scholar
  12. 12.
    Zhang A, Zhou N, Huang J, Liu Q, Fukuda K, Ma D, Lu Z, Bai C, Watabe K, Mo YY (2013) The human long non-coding RNA-RoR is a p53 repressor in response to DNA damage. Cell Res 23(3):340–350CrossRefGoogle Scholar
  13. 13.
    Huang J, Zhang A, Ho TT, Zhang Z, Zhou N, Ding X, Zhang X, Xu M, Mo YY (2016) Linc-RoR promotes c-Myc expression through hnRNP I and AUF1. Nucleic Acids Res 44(7):3059–3069CrossRefGoogle Scholar
  14. 14.
    Huang J, Zhou N, Watabe K, Lu Z, Wu F, Xu M, Mo YY (2014) Long non-coding RNA UCA1 promotes breast tumor growth by suppression of p27 (Kip1). Cell Death Dis 5:e1008CrossRefGoogle Scholar
  15. 15.
    Singh R, Gupta SC, Peng WX, Zhou N, Pochampally R, Atfi A, Watabe K, Lu Z, Mo YY (2016) Regulation of alternative splicing of Bcl-x by BC200 contributes to breast cancer pathogenesis. Cell Death Dis 7(6):e2262CrossRefGoogle Scholar
  16. 16.
    Zhang Z, Zhou N, Huang J, Ho TT, Zhu Z, Qiu Z, Zhou X, Bai C, Wu F, Xu M, Mo YY (2016) Regulation of androgen receptor splice variant AR3 by PCGEM1. Oncotarget 7(13):15481–15491PubMedPubMedCentralGoogle Scholar
  17. 17.
    Quek XC, Thomson DW, Maag JL, Bartonicek N, Signal B, Clark MB, Gloss BS, Dinger ME (2015) lncRNAdb v2.0: expanding the reference database for functional long noncoding RNAs. Nucleic Acids Res 43(Database issue):D168–D173CrossRefGoogle Scholar
  18. 18.
    Zhao Y, Li H, Fang S, Kang Y, Wu W, Hao Y, Li Z, Bu D, Sun N, Zhang MQ, Chen R (2016) NONCODE 2016: an informative and valuable data source of long non-coding RNAs. Nucleic Acids Res 44(D1):D203–D208CrossRefGoogle Scholar
  19. 19.
    Mercer TR, Dinger ME, Mattick JS (2009) Long non-coding RNAs: insights into functions. Nat Rev Genet 10(3):155–159CrossRefGoogle Scholar
  20. 20.
    Ma H, Hao Y, Dong X, Gong Q, Chen J, Zhang J, Tian W (2012) Molecular mechanisms and function prediction of long noncoding RNA. Scientific World Journal 2012:541786PubMedGoogle Scholar
  21. 21.
    Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C, Schultz N (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2(5):401–404CrossRefGoogle Scholar
  22. 22.
    Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, Cerami E, Sander C, Schultz N (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6(269):pl1CrossRefGoogle Scholar
  23. 23.
    Mantel N (1966) Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50(3):163–170Google Scholar
  24. 24.
    Cox DR (1972) Regression models and life-tables. J R Stat Soc B 34:187–220Google Scholar
  25. 25.
    Akaike H (1973) Information theory and an extension of the maximum likelihood principle. 2nd International Symposium on Information Theory, Tsaghkadzor, Armenia, USSR, Budapest: Akadémiai Kiadó, pp 267–281Google Scholar
  26. 26.
    Cox DR (1975) Partial likelihood. Biometrika 62(2):269–276CrossRefGoogle Scholar
  27. 27.
    Hoerl AE, Kennard RW (1970) Ridge regression: biased estimation for nonorthogonal problems. Technometrics 12(1):55–67CrossRefGoogle Scholar
  28. 28.
    Tibshirani R (1996) Regression shrinkage and selection via the lasso. J R Stat Soc B 58:267–288Google Scholar
  29. 29.
    Tibshirani R (1997) The lasso method for variable selection in the Cox model. Stat Med 16(4):385–395CrossRefGoogle Scholar
  30. 30.
    Zhang HH, Lu W (2007) Adaptive lasso for Cox’s proportional hazards model. Biometrika 94(3):691–703CrossRefGoogle Scholar
  31. 31.
    Friedman J, Hastie T, Tibshirani R (2016) glmnet: Lasso and elastic-net regularized generalized linear models. R package version 2.0-5. http://CRAN.R-project.org/package=glmnet
  32. 32.
    Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481CrossRefGoogle Scholar
  33. 33.
    Ho TT, Zhou N, Huang J, Koirala P, Xu M, Fung R, Wu F, Mo YY (2015) Targeting non-coding RNAs with the CRISPR/Cas9 system in human cell lines. Nucleic Acids Res 43(3):e17CrossRefGoogle Scholar
  34. 34.
    Liu H, Li J, Koirala P, Ding X, Chen B, Wang Y, Wang Z, Wang C, Zhang X, Mo YY (2016) Long non-coding RNAs as prognostic markers in human breast cancer. Oncotarget 7(15):20584–20596PubMedPubMedCentralGoogle Scholar
  35. 35.
    Chen X, Liu B, Yang R, Guo Y, Li F, Wang L, Hu H (2016) Integrated analysis of long non-coding RNAs in human colorectal cancer. Oncotarget.  https://doi.org/10.18632/oncotarget.8192
  36. 36.
    Guttman M, Amit I, Garber M, French C, Lin MF, Feldser D, Huarte M, Zuk O, Carey BW, Cassady JP, Cabili MN, Jaenisch R, Mikkelsen TS, Jacks T, Hacohen N, Bernstein BE, Kellis M, Regev A, Rinn JL, Lander ES (2009) Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458(7235):223–227CrossRefGoogle Scholar
  37. 37.
    Liao Q, Liu C, Yuan X, Kang S, Miao R, Xiao H, Zhao G, Luo H, Bu D, Zhao H, Skogerbo G, Wu Z, Zhao Y (2011) Large-scale prediction of long non-coding RNA functions in a coding-non-coding gene co-expression network. Nucleic Acids Res 39(9):3864–3878CrossRefGoogle Scholar
  38. 38.
    Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP (2011) A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell 146(3):353–358CrossRefGoogle Scholar
  39. 39.
    Du Z, Sun T, Hacisuleyman E, Fei T, Wang X, Brown M, Rinn JL, Lee MG, Chen Y, Kantoff PW, Liu XS (2016) Integrative analyses reveal a long noncoding RNA-mediated sponge regulatory network in prostate cancer. Nat Commun 7:10982CrossRefGoogle Scholar
  40. 40.
    Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G (2000) Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25(1):25–29CrossRefGoogle Scholar
  41. 41.
    Ogata H, Goto S, Sato K, Fujibuchi W, Bono H, Kanehisa M (1999) KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res 27(1):29–34CrossRefGoogle Scholar
  42. 42.
    Lin XC, Zhu Y, Chen WB, Lin LW, Chen DH, Huang JR, Pan K, Lin Y, Wu BT, Dai Y, Tu ZG (2014) Integrated analysis of long non-coding RNAs and mRNA expression profiles reveals the potential role of lncRNAs in gastric cancer pathogenesis. Int J Oncol 45(2):619–628CrossRefGoogle Scholar
  43. 43.
    Xu J, Gao C, Zhang F, Ma X, Peng X, Zhang R, Kong D, Simard AR, Hao J (2016) Differentially expressed lncRNAs and mRNAs identified by microarray analysis in GBS patients vs healthy controls. Sci Rep 6:21819CrossRefGoogle Scholar
  44. 44.
    Dong R, Jia D, Xue P, Cui X, Li K, Zheng S, He X, Dong K (2014) Genome-wide analysis of long noncoding RNA (lncRNA) expression in hepatoblastoma tissues. PLoS One 9(1):e85599CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Center of Clinical and Translational Sciences and Department of Internal MedicineThe University of Texas Health Science Center at HoustonHoustonUSA
  2. 2.Cancer Institute, Department of Radiation OncologyUniversity of Mississippi Medical CenterJacksonUSA

Personalised recommendations