MicroRNAs in disease and health: aberrant regulation in lung cancer and association with genomic variation
Date
2016-07-01
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Abstract
Viimaste aastate geneetilised uuringud on näidanud et suur osa inimese genoomilt transkribeeritavast RNAst ei kodeeri keha “ehituskivideks” olevaid valke, vaid omab eelkõige regulatoorset rolli, mõjutades kuidas valke kodeerivad geenid oma funktsioone täidavad. Enim uuritud klass mittekodeerivaid RNAsid on väikesed ~20 nukleotiidi pikkused mikroRNAd, mis reguleerivad geenide aktiivsust, seondudes sihtmärgiks olevate RNAdega. MikroRNAd on olulised enamikes bioloogilistes protsessides ja on seotud paljude haiguste, sealhulgas vähkkasvajatega. Vähis omavad need potentsiaali võimalike ravimisihtmärkidena ja biomarkeritena mida saaks tulevikus kasutada kasvajate varasemaks avastamiseks ning täpsemaks dignoosimiseks.
Käesoleva töös uuriti, milliste mikroRNAde ekspressioonitasemed on muutunud mitteväikerakulises kopsuvähis. Selleks määrati kopsuvähi proovidest 858 mikroRNA tasemed. Analüüsi tulemusena leiti 72 mikroRNAd mille tase oli vähis muutunud ja mis võivad seetõttu olla seotud vähitekkega või omada potentsiaali biomarkerina. Ühe mikroRNA puhul leiti seos ka patsiendi operatsioonijärgse elulemusega. Kuna selle ja teiste sarnaste uuringute tulemused on üsna varieeruvad, viidi läbi süstemaatiline meta-analüüs, kasutades spetsiaalset järjestatud geeninimekirjade analüüsimiseks loodud meetodit. Kahtekümmet uuringut hõlmava analüüsi tulemusena leiti kopsuvähis seitse üles- ja kaheksa allareguleeritud mikroRNAd.
Kuna paljude RNAde taset rakus mõjutavad varieeruvad positsioonid inimese genoomis, siis järgmisena uuriti kas selline geenide avaldumise kontroll võib toimuda mikroRNAde seondumise kaudu. Selleks analüüsiti inimese genoomset varieeruvust bioinformaatiliselt ennustatud mikroRNA sihtmärkides ja tuvastati mitu geeni, mille regulatsioonis sellised variandid tõenäoliselt olulist rolli mängivad. Samas kinnitavad tulemused, et mikroRNAd on ainult üks võimalik osa geenide avaldumise kontrollist.
Käesolev töö andis uusi teadmisi mikroRNAde kohta kopsuvähis, aitas süstematiseerida eelnevat informatsiooni ning sidus mikroRNAde regulatoorse potentsiaali normaalse geneetilise varieeruvusega.
Recent discoveries have demonstrated that the lion's share of RNA transcribed from human genome is not encoding structural proteins but instead regulates the action of protein-coding genes. The most widely studied class of non-coding RNAs are microRNAs, small ~20 nucleotide long molecules which regulate the activity of genes by binding the targeted RNAs. MicroRNAs are important in most biological processes and are involved in pathogenesis of several diseases, for example cancers. They can serve as potential drug targets and biomarkers which could be used for earlier detection and better diagnosis. In this thesis, microRNA expression changes in non-small cell lung cancer were investigated. Cancer samples were collected from lung cancer patients and the expression levels of 858 microRNAs were measured. The analysis revealed 72 microRNAs with changed expression pattern in cancer which could be involved in the formation of tumor or serve as potential biomarkers. One microRNA showed association with patient post-operative survival. Because results of this and other similar studies are quite variable, systematic meta-analysis was conducted by special method enabling the comparison of ranked gene lists. Meta-analysis of twenty studies revealed the robust set of seven up- and eight down-regulated microRNAs in lung cancer. Variable positions in human genome influence the expression levels of thousands of RNAs. In this thesis, the hypothesis that variants mapping into microRNA binding sites may influence the expression of mRNAs via microRNA binding was tested. For that, variable genomic positions were intersected with bioinformatically predicted microRNA target sites. Several genes were prioritized in which those variants are likely to play regulatory role. However, there was no global overrepresentation of associations that agree with the logic of microRNA action mechanism, suggesting that additional mechanisms may be involved in this process. This thesis widened our knowledge about microRNA aberrations in lung cancer, helped to systematize the previous knowledge and connected the regulatory potential of microRNAs with normal genetic variation.
Recent discoveries have demonstrated that the lion's share of RNA transcribed from human genome is not encoding structural proteins but instead regulates the action of protein-coding genes. The most widely studied class of non-coding RNAs are microRNAs, small ~20 nucleotide long molecules which regulate the activity of genes by binding the targeted RNAs. MicroRNAs are important in most biological processes and are involved in pathogenesis of several diseases, for example cancers. They can serve as potential drug targets and biomarkers which could be used for earlier detection and better diagnosis. In this thesis, microRNA expression changes in non-small cell lung cancer were investigated. Cancer samples were collected from lung cancer patients and the expression levels of 858 microRNAs were measured. The analysis revealed 72 microRNAs with changed expression pattern in cancer which could be involved in the formation of tumor or serve as potential biomarkers. One microRNA showed association with patient post-operative survival. Because results of this and other similar studies are quite variable, systematic meta-analysis was conducted by special method enabling the comparison of ranked gene lists. Meta-analysis of twenty studies revealed the robust set of seven up- and eight down-regulated microRNAs in lung cancer. Variable positions in human genome influence the expression levels of thousands of RNAs. In this thesis, the hypothesis that variants mapping into microRNA binding sites may influence the expression of mRNAs via microRNA binding was tested. For that, variable genomic positions were intersected with bioinformatically predicted microRNA target sites. Several genes were prioritized in which those variants are likely to play regulatory role. However, there was no global overrepresentation of associations that agree with the logic of microRNA action mechanism, suggesting that additional mechanisms may be involved in this process. This thesis widened our knowledge about microRNA aberrations in lung cancer, helped to systematize the previous knowledge and connected the regulatory potential of microRNAs with normal genetic variation.
Description
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Keywords
micro RNA, kopsuvähk, geneetilised markerid, kromosoommutatsioonid, metaanalüüs, micro RNA, lung cancer, genetic markers, chromosomal aberrations, meta-analysis