Contreras Planesas, Beatriz

Universitat Autònoma de Barcelona. Facultat de Biociències

Diposit Digital de Documents de la UAB

Nowadays there are many cancer studies in progress with the aim of finding better treatments, diagnostic markers and depth knowledge of the tumor progress. Considering factors involvedin cancer regulation is also essential.The role of transposable elements such as LINE-1 is gaining prominence. There has been an important step on the understanding: from being considered 'junk DNA' to find out about theirinvolvement in cell regulation, in addition to realize the ectopic recombination and transposition effects.The disruption of the tumor suppressor gene APC by a LINE-1 has been known since 1992, revealing their possible role in cancer.For these reasons a literature review was made with the aim of learning the biology of LINE-1 and its involvement in cancer as a regulator, insights in different regulation levels.Regulation of LINE-1 in human cancersBeatriz Contreras PlanesasGenetics Degree. Universitat Autònoma de Barcelona (UAB). 08193 Bellaterra, Catalonia, Spain.1. IntroductionCancer is an uncontrolled cells proliferation.OncogeneTumor SupressorGeneKeywords: LINE-1 , cancer regulation, methylation, histone modification, iRNA, helicase.2. Cancer and LINE-1Cell divisionCell growthDNA repairApoptosisHanahan et al. (2011)3. ResultsDNA methylation leads to gene silencing. Cells control LINE-1 transpositionby DNA hypermethylation. In cancer, this pattern is lost and it can be seenhypomethylated LINE-1. Hypomethylation of LINE-1 in cancer enablestransposition and leads an increase on genomic instability.Currently the level of LINE-1 methylation is used as a biomarker in cancer todetermine the state of the cell global methylation, and as a diagnosticmarker.Association was found between the degree of LINE-1 methylation andfactors such as tumor progression, poor prognosis, metastasis and lowsurvival, even though this association is not the same for all types ofcancers. The correlation was also studied with factors such as age of onset,sex, diet or alcohol intake, but the results are very different depending onthe type of cancer studied.Histones are nucleosomes proteins that regulate geneexpression due to its interaction with chromatin whichmodulates its compactness. Different modifications ofhistone tails lead to compaction changes, andtherefore, expression changes.The histones’ repression as a regulation of LINE-1 isknown as a genomic defence mechanism, although ithas been observed a more relaxed repression in cancer,acting together with methylation. Even an upregulationhas been observed in some LINE-1 which acts asoncogenes' regulators. Moreover, cell lineage-specificor tissue differences in histones repression have beenseen.A) Methylation B) Histone modificationsWolff et al. (2010)The iRNA are small interfering RNA that act on RNA - protein complexes. They canrepress expression in the post transcriptional step by producing cuts in the mRNA orblocking at translational level.23% of miRNA, a type of iRNA, were originated from transposable elements, so theyC) iRNARecent studies point to MOV10 helicase as a LINE-1 regulator. It has been seen that thehelicase reduces the average life of the LINE-1 transcript, thus being the regulator.Some studies are currently being carried out to find out the molecular mechanism andits possible application on cancer knowledge.D) Helicase MOV10Singer et al. (2010)Beck et al. (2011)All studies do not deepen because they observe a regulatory role of LINE-1 but the molecular mechanism is unknown. This leads tounderestimate their participation in cancer. It should be taken into account that they are also the support for other types of transpositions.It might be an issue of great concern in oncology to know the participation of LINE-1 in the regulation, because it is known its involvement ingenomic instability, in regulation of oncogenes and tumor suppressor genes, and lately, participation with the inmune system is intuited.It has been observed, therefore, inconsistencies between studies, probably due to not taking into account the differences among types ofcancers due to the origins of cell types or tumor heterogeneity.Another important factor is the coordinated regulation, the participation of more than one type of regulation at the same time.Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–74 (2011).Beck, C. R. et al. LINE-1 elements in structural variation and disease. Annu. Rev. Genomics Hum. Genet. 12, 187–215 (2011).Carreira, P. E.et al. L1 retrotransposons, cancer stem cells and oncogenesis. FEBS J. 281, 63–73 (2014).Shalgi, R. et al. Repression of transposable-elements - a microRNA anti-cancer defense mechanism? Trends Genet. 26, 253–9 (2010).Schulz, W. A. L1 retrotransposons in human cancers. J. Biomed. Biotechnol. (2006).Slotkin, R. K. & Martienssen, R. Transposable elements and the epigenetic regulation of the genome. Nat. Rev. Genet. 8, 272–85 (2007).Wolff, E. M. et al. Hypomethylation of a LINE-1 promoter activates an alternate transcript of the MET oncogene in bladders with cancer.PLoS Genet. 6,(2010).share a high degree of complementarity with LINE- 1 and are their regulators.In the tumor process a reduction of miRNA is observed, a fact that prevents themfrom regulating LINE-1. As a result there is an increase on transposition and ectopicrecombination leading to deregulation of oncogenes and tumor suppressor genes,ending as genomic instability.Besides, it has been shown a regulatory role of LINE-1 in mRNA transcription. SomeLINE-1 are close to or within genes sequences and affect its regulation findingchimeric mRNA, splicing variants and premature polyA sites. Moreover a deregulationof cancer genes is caused by an antisense RNA that controls post transcriptional level.This antisense RNA is transcribed through the antisense promoter of a near LINE- 1and has enough complementarity with the mRNA that cause gene silencing.Shalgi et al. (2010)5. References4. ConclusionsCarreira et al. (2014)

Regulation of LINE-1 in human cancers

http://ddd.uab.cat/pub/tfg/2014/126252/TFG_beatrizcontrerasplanesas.pdf

Regulation of LINE-1 in human cancers

Abstract

Similar works

Full text

Available Versions

Diposit Digital de Documents de la UAB