Hesna Begüm AKMAN, Ayşe Elif Erson BENSAN

Noncoding RNAs and cancer

New and diverse groups of noncoding RNAs are beginning to be discovered. These noncoding RNAs are grouped based on their sizes, genomic positions, or distinctive functions ranging from the regulation of chromatin structure and gene expression to genome stability maintenance. Among noncoding RNAs, microRNAs are the best studied and understood small RNAs with direct and indirect roles in normal and in cancer cells. Given the high rate of transcription from noncoding parts of the genome, other noncoding elements are also of great interest. It is also of interest to understand that there may be interesting cases of crosstalk and/or coregulation between the noncoding and the coding portion of the genome. Therefore, deregulated expression of noncoding RNAs can be considered to cause significant alterations in cancer cells. The complexities of the genome and transcriptome still remain mesmerizing. As we better understand these complexities, we will be able to improve our understanding of human conditions and will hopefully develop tools to improve the ways in which we deal with diseases, particularly cancer. Here, based on recent findings, we provide a descriptive profile of noncoding RNA classes, their roles, and their potential contributions to the complex events of tumorigenesis.

Anahtar Kelimeler:

Noncoding RNAs, cancer, long noncoding RNAs, small noncoding RNAs, microRNAs

Noncoding RNAs and cancer

Keywords:

Noncoding RNAs, cancer, long noncoding RNAs, small noncoding RNAs, microRNAs,

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Akman BH, Can T, Erson-Bensan AE (2012). Estrogen-induced upregulation and 3’-UTR shortening of CDC6. Nucleic Acids Res 40: 10679–10688.
Akman BH, Erson-Bensan AE (2014). Alternative polyadenylation and its impact on cellular processes. MicroRNA 3: 2–9.
Aravin AA, Lagos-Quintana M, Yalcin A, Zavolan M, Marks D, Snyder B, Gaasterland T, Meyer J, Tuschl T (2003). The small RNA profile during Drosophila melanogaster development. Dev Cell 5: 337–350.
Asangani IA, Rasheed SA, Nikolova DA, Leupold JH, Colburn NH, Post S, Allgayer H (2008). MicroRNA-21 (miR-21) post- transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene 27: 2128–2136.
Bader AG (2012). miR-34 - a microRNA replacement therapy is headed to the clinic. Front Genet 3:120.
Bailey SM, Brenneman MA, Goodwin EH (2004). Frequent recombination in telomeric DNA may extend the proliferative life of telomerase-negative cells. Nucleic Acids Res 32: 3743– 3751.
Baranwal S, Alahari SK (2010). miRNA control of tumor cell invasion and metastasis. Int J Cancer 126: 1283–1290.
Beckedorff FC, Amaral MS, Deocesano-Pereira C, Verjovski-Almeida S (2013a). Long non-coding RNAs and their implications in cancer epigenetics. Biosci Rep 33: 667–675.
Beckedorff FC, Ayupe AC, Crocci-Souza R, Amaral MS, Nakaya HI, Soltys DT, Menck CF, Reis EM, Verjovski-Almeida S (2013b). The intronic long noncoding RNA ANRASSF1 recruits PRC2 to the RASSF1A promoter, reducing the expression of RASSF1A and increasing cell proliferation. PLoS Genet 9: e1003705.
Bernstein BE, Birney E, Dunham I, Green ED, Gunter C, Snyder M (2012). An integrated encyclopedia of DNA elements in the human genome. Nature 489: 57–74.
Borchert GM, Lanier W, Davidson BL (2006). RNA polymerase III transcribes human microRNAs. Nat Struct Mol Biol 13: 1097– 1101.
Bouchie A (2013). First microRNA mimic enters clinic. Nat Biotechnol 31: 577.
Brennecke J, Aravin AA, Stark A, Dus M, Kellis M, Sachidanandam R, Hannon GJ (2007). Discrete small RNA-generating loci as master regulators of transposon activity in Drosophila. Cell
Cai X, Hagedorn CH, Cullen BR (2004). Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA 10: 1957–1966.
Calin GA, Liu CG, Ferracin M, Hyslop T, Spizzo R, Sevignani C, Fabbri M, Cimmino A, Lee EJ, Wojcik SE et al. (2007). Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas. Cancer Cell 3: 215–229.
Chambers AF, Groom AC, MacDonald IC (2002). Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2: 563–572.
Chang LS, Lin SY, Lieu AS, Wu TL (2002). Differential expression of human 5S snoRNA genes. Biochem Biophys Res Commun 299: 196–200.
Chen L, Dahlstrom JE, Lee SH, Rangasamy D (2012). Naturally occurring endo-siRNA silences LINE-1 retrotransposons in human cells through DNA methylation. Epigenetics 7: 758– 771.
Chiyomaru T, Fukuhara S, Saini S, Majid S, Deng G, Shahryary V, Chang I, Tanaka Y, Enokida H, Nakagawa M et al. (2014). Long non-coding RNA HOTAIR is targeted and regulated by miR- 141 in human cancer cells. J Biol Chem 18: 12550–12565.
Curtale G, Citarella F (2013). Dynamic nature of noncoding RNA regulation of adaptive immune response. Int J Mol Sci 14: 17347–17377.
Davison GM (2007). Telomeres and telomerase in leukaemia and lymphoma. Transfus Apher Sci 37: 43–47.
Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, Guernec G, Martin D, Merkel A, Knowles DG et al. (2012). The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res 22: 1775–1789.
Eichner LJ, Perry MC, Dufour CR, Bertos N, Park M, St-Pierre J, Giguere V (2010). miR-378( *) mediates metabolic shift in breast cancer cells via the PGC-1β/ERRγ transcriptional pathway. Cell Metab 12: 352–361.
Erson AE, Petty EM (2008). MicroRNAs in development and disease. Clin Genet 74: 296–306.
Esteller M (2011). Non-coding RNAs in human disease. Nat Rev Genet 12: 861–874.
Faghihi MA, Modarresi F, Khalil AM, Wood DE, Sahagan BG, Morgan TE, Finch CE, St Laurent G 3rd, Kenny PJ, Wahlestedt C (2008). Expression of a noncoding RNA is elevated in Alzheimer’s disease and drives rapid feed-forward regulation of beta-secretase. Nat Med 14: 723–730.
Filipowicz W, Pogacic V (2002). Biogenesis of small nucleolar ribonucleoproteins. Curr Opin Cell Biol 14: 319–327.
Fish JE, Santoro MM, Morton SU, Yu S, Yeh RF, Wythe JD, Ivey KN, Bruneau BG, Stainier DY, Srivastava D (2008). miR-126 regulates angiogenic signaling and vascular integrity. Dev Cell 15: 272–284.
Fitzgerald KA, Caffrey DR (2014). Long noncoding RNAs in innate and adaptive immunity. Curr Opin Immunol 26: 140–146.
Garzon R, Garofalo M, Martelli MP, Briesewitz R, Wang L, Fernandez- Cymering C, Volinia S, Liu CG, Schnittger S, Haferlach T et al. (2008). Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin. P Natl Acad Sci USA 105: 3945–3950.
Gregory RI, Yan KP, Amuthan G, Chendrimada T, Doratotaj B, Cooch N, Shiekhattar R (2004). The Microprocessor complex mediates the genesis of microRNAs. Nature 432: 235–240.
Gutschner T, Hammerle M, Eissmann M, Hsu J, Kim Y, Hung G, Revenko A, Arun G, Stentrup M, Gross M et al. (2013). The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res 73: 1180–1189.
Hah N, Murakami S, Nagari A, Danko CG, Kraus WL (2013). Enhancer transcripts mark active estrogen receptor binding sites. Genome Res 23: 1210–1223.
Han J, Lee Y, Yeom KH, Kim YK, Jin H, Kim VN (2004). The Drosha- DGCR8 complex in primary microRNA processing. Genes Dev 18: 3016–3027.
Hanahan D, Weinberg RA (2011). Hallmarks of cancer: the next generation. Cell 5: 646–674.
Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J (2013). Natural RNA circles function as efficient microRNA sponges. Nature 495: 384–388.
Hutvagner G, McLachlan J, Pasquinelli AE, Balint E, Tuschl T, Zamore PD (2001). A cellular function for the RNA- interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science 293: 834–838.
Ji P, Diederichs S, Wang W, Boing S, Metzger R, Schneider PM, Tidow N, Brandt B, Buerger H, Bulk E et al. (2003). 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.
Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, Reinert KL, Brown D, Slack FJ (2005). RAS is regulated by the let-7 microRNA family. Cell 5: 635–647.
Katzman S, Kern AD, Bejerano G, Fewell G, Fulton L, Wilson RK, Salama SR, Haussler D (2007). Human genome ultraconserved elements are ultraselected. Science 317: 915.
Kumarswamy R, Volkmann I, Thum T (2011). Regulation and function of miRNA-21 in health and disease. RNA Biol 8: 706–713.
Kwon C, Tak H, Rho M, Chang HR, Kim YH, Kim KT, Balch C, Lee EK, Nam S (2014). Detection of PIWI and piRNAs in the mitochondria of mammalian cancer cells. Biochem Biophys Res Commun 446: 218–223.
Lawrie CH, Larrea E, Larrinaga G, Goicoechea I, Arestin M, Fernandez-Mercado M, Hes O, Caceres F, Manterola L, Lopez JI (2014). Targeted next-generation sequencing and non- coding RNA expression analysis of clear cell papillary renal cell carcinoma suggests distinct pathological mechanisms from other renal tumour subtypes. J Pathol 232: 32–42.
Lee E, Iskow R, Yang L, Gokcumen O, Haseley P, Luquette LJ 3rd, Lohr JG, Harris CC, Ding L, Wilson RK et al. (2012). Landscape of somatic retrotransposition in human cancers. Science 337: 967–971.
Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P, Radmark O, Kim S et al. (2003). The nuclear RNase III Drosha initiates microRNA processing. Nature 425: 415–419.
Lee Y, Kim M, Han J, Yeom KH, Lee S, Baek SH, Kim VN (2004). MicroRNA genes are transcribed by RNA polymerase II. EMBO J 23: 4051–4060.
Li S, Liang Z, Xu L, Zou F (2012). MicroRNA-21: a ubiquitously expressed pro-survival factor in cancer and other diseases. Mol Cell Biochem 360: 147–158.
Li W, Notani D, Ma Q, Tanasa B, Nunez E, Chen AY, Merkurjev D, Zhang J, Ohgi K, Song X et al. (2013). Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature 498: 516–520.
Ling H, Fabbri M, Calin GA (2013). MicroRNAs and other non- coding RNAs as targets for anticancer drug development. Nat Rev Drug Discov 12: 847–865.
Lujambio A, Portela A, Liz J, Melo SA, Rossi S, Spizzo R, Croce CM, Calin GA, Esteller M (2010). CpG island hypermethylation- associated silencing of non-coding RNAs transcribed from ultraconserved regions in human cancer. Oncogene 29: 6390– 6401.
Ma L, Teruya-Feldstein J, Weinberg RA (2007). Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 449: 682–688.
Mannoor K, Liao J, Jiang F (2012). Small nucleolar RNAs in cancer. Biochim Biophys Acta 1826: 121–128.
Marton S, Garcia MR, Robello C, Persson H, Trajtenberg F, Pritsch O, Rovira C, Naya H, Dighiero G, Cayota A (2008). Small RNAs analysis in CLL reveals a deregulation of miRNA expression and novel miRNA candidates of putative relevance in CLL pathogenesis. Leukemia 22: 330–338.
Mayr C, Bartel DP (2009). Widespread shortening of 3’UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell 138: 673–684.
Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, Mackowiak SD, Gregersen LH, Munschauer M et al. (2013). Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495: 333–338.
Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T (2007). MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 133: 647–658.
Mitomo S, Maesawa C, Ogasawara S, Iwaya T, Shibazaki M, Yashima- Abo A, Kotani K, Oikawa H, Sakurai E, Izutsu N et al. (2008). Downregulation of miR-138 is associated with overexpression of human telomerase reverse transcriptase protein in human anaplastic thyroid carcinoma cell lines. Cancer Sci 99: 280–286.
Nahkuri S, Paro R (2012). The role of noncoding RNAs in chromatin regulation during differentiation. WIREs Dev Biol 1: 743–752.
Nana-Sinkam SP, Croce CM (2013). Clinical applications for microRNAs in cancer. Clin Pharmacol Ther 93: 98–104.
Ohhata T, Senner CE, Hemberger M, Wutz A (2011). Lineage-specific function of the noncoding Tsix RNA for Xist repression and Xi reactivation in mice. Genes Dev 25: 1702–1715.
Okamura K, Chung WJ, Ruby JG, Guo H, Bartel DP, Lai EC (2008). The Drosophila hairpin RNA pathway generates endogenous short interfering RNAs. Nature 453: 803–806.
Okamura K, Lai EC (2008). Endogenous small interfering RNAs in animals. Nat Rev Mol Cell Biol 9: 673–678.
Orom UA, Derrien T, Beringer M, Gumireddy K, Gardini A, Bussotti G, Lai F, Zytnicki M, Notredame C, Huang Q et al. (2010). Long noncoding RNAs with enhancer-like function in human cells. Cell 143: 46–58.
Orom UA, Nielsen FC, Lund AH (2008). MicroRNA-10a binds the 5’UTR of ribosomal protein mRNAs and enhances their translation. Mol Cell 30: 460–471.
Panzitt K, Tschernatsch MM, Guelly C, Moustafa T, Stradner M, Strohmaier HM, Buck CR, Denk H, Schroeder R, Trauner M et al. (2007). Characterization of HULC, a novel gene with striking up-regulation in hepatocellular carcinoma, as noncoding RNA. Gastroenterology 132: 330–342.
Pedersen I, David M (2008). MicroRNAs in the immune response. Cytokine 43: 391–394.
Poliseno L, Salmena L, Riccardi L, Fornari A, Song MS, Hobbs RM, Sportoletti P, Varmeh S, Egia A, Fedele G et al. (2010). Identification of the miR-106b~25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation. Sci Signal 3: ra29.
Rapicavoli NA, Qu K, Zhang J, Mikhail M, Laberge RM, Chang HY (2013). A mammalian pseudogene lncRNA at the interface of inflammation and anti-inflammatory therapeutics. eLife 2: e00762.
Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, Soond DR, van Dongen S, Grocock RJ, Das PP, Miska EA et al. (2007). Requirement of bic/microRNA-155 for normal immune function. Science 316: 608–611.
Ronchetti D, Mosca L, Cutrona G, Tuana G, Gentile M, Fabris S, Agnelli L, Ciceri G, Matis S, Massucco C et al. (2013). Small nucleolar RNAs as new biomarkers in chronic lymphocytic leukemia. BMC Med Genomics 6: 27.
Ross RJ, Weiner MM, Lin H (2014). PIWI proteins and PIWI- interacting RNAs in the soma. Nature 505: 353–359.
Ruggero D, Pandolfi PP (2003). Does the ribosome translate cancer? Nat Rev Cancer 3: 179–192.
Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP (2011). A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell 146: 353–358.
Sandberg R, Neilson JR, Sarma A, Sharp PA, Burge CB (2008). Proliferating cells express mRNAs with shortened 3’ untranslated regions and fewer microRNA target sites. Science
Sartori DA, Chan DW (2014). Biomarkers in prostate cancer: what’s new? Curr Opin Oncol 26: 259–264.
Scaruffi P (2011). The transcribed-ultraconserved regions: a novel class of long noncoding RNAs involved in cancer susceptibility. ScientificWorldJournal 11: 340–352.
Selcuklu SD, Yakicier MC, Erson AE (2009). An investigation of microRNAs mapping to breast cancer related genomic gain and loss regions. Cancer Genet Cytogenet 189: 15–23.
Siomi MC, Sato K, Pezic D, Aravin AA (2011). PIWI-interacting small RNAs: the vanguard of genome defence. Nat Rev Mol Cell Biol 12: 246–258.
St Laurent G, Shtokalo D, Tackett MR, Yang Z, Eremina T, Wahlestedt C, Urcuqui-Inchima S, Seilheimer B, McCaffrey TA, Kapranov P (2012). Intronic RNAs constitute the major fraction of the non-coding RNA in mammalian cells. BMC Genomics 13: 504.
Su H, Xu T, Ganapathy S, Shadfan M, Long M, Huang TH, Thompson I, Yuan ZM (2014). Elevated snoRNA biogenesis is essential in breast cancer. Oncogene 33: 1348–1358.
Tripathi V, Ellis JD, Shen Z, Song DY, Pan Q, Watt AT, Freier SM, Bennett CF, Sharma A, Bubulya PA et al. (2010). The nuclear- retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol Cell 39: 925–938.
Volders PJ, Helsens K, Wang X, Menten B, Martens L, Gevaert K, Vandesompele J, Mestdagh P (2013). LNCipedia: a database for annotated human lncRNA transcript sequences and structures. Nucleic Acids Res 41: D246–D251.
Wang J, Liu X, Wu H, Ni P, Gu Z, Qiao Y, Chen N, Sun F, Fan Q (2010). CREB up-regulates long non-coding RNA, HULC expression through interaction with microRNA-372 in liver cancer. Nucleic Acids Res 38: 5366–5383.
Wang S, Olson EN (2009). AngiomiRs--key regulators of angiogenesis. Curr Opin Genet Dev 19: 205–211.
Watanabe T, Tomizawa S, Mitsuya K, Totoki Y, Yamamoto Y, Kuramochi-Miyagawa S, Iida N, Hoki Y, Murphy PJ, Toyoda A et al. (2011). Role for piRNAs and noncoding RNA in de novo DNA methylation of the imprinted mouse Rasgrf1 locus. Science 332: 848–852.
Xu H, Cheung IY, Guo HF, Cheung NK (2009). MicroRNA miR-29 modulates expression of immunoinhibitory molecule B7-H3: potential implications for immune based therapy of human solid tumors. Cancer Res 69: 6275–6281.
Yang L, Duff MO, Graveley BR, Carmichael GG, Chen LL (2011a). Genomewide characterization of non-polyadenylated RNAs. Genome Biol 12: R16.
Yang L, Lin C, Jin C, Yang JC, Tanasa B, Li W, Merkurjev D, Ohgi KA, Meng D, Zhang J et al. (2013). lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs. Nature 500: 598–602.
Yang L, Lin C, Liu W, Zhang J, Ohgi KA, Grinstein JD, Dorrestein PC, Rosenfeld MG (2011b). ncRNA- and Pc2 methylation- dependent gene relocation between nuclear structures mediates gene activation programs. Cell 147: 773–788.
Yang R, Frank B, Hemminki K, Bartram CR, Wappenschmidt B, Sutter C, Kiechle M, Bugert P, Schmutzler RK, Arnold N et al. (2008). SNPs in ultraconserved elements and familial breast cancer risk. Carcinogenesis 29: 351–355.
Yap KL, Li S, Munoz-Cabello AM, Raguz S, Zeng L, Mujtaba S, Gil J, Walsh MJ, Zhou MM (2010). Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Mol Cell 38: 662–674.
Yi R, Qin Y, Macara IG, Cullen BR (2003). Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev 24: 3011–3016.
Yildirim E, Kirby JE, Brown DE, Mercier FE, Sadreyev RI, Scadden DT, Lee JT (2013). Xist RNA is a potent suppressor of hematologic cancer in mice. Cell 152: 727–742.
Yin QF, Yang L, Zhang Y, Xiang JF, Wu YW, Carmichael GG, Chen LL (2012). Long noncoding RNAs with snoRNA ends. Mol Cell 48: 219–230.
Yu W, Gius D, Onyango P, Muldoon-Jacobs K, Karp J, Feinberg AP, Cui H (2008). Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA. Nature 451: 202–206.
Zhang Y, Yang L, Chen LL (2013a). Life without A tail: New formats of long noncoding RNAs. Int J Biochem Cell Biol 13: 326.
Zhang Y, Zhang XO, Chen T, Xiang JF, Yin QF, Xing YH, Zhu S, Yang L, Chen LL (2013b). Circular intronic long noncoding RNAs. Mol Cell 51: 792–806.