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Piciocchi, Marika (2013) Danno ossidativo nucleare e mitocondriale e disfunzione telomerica nel processo di carcinogenesi epatica. [Tesi di dottorato]

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Abstract (inglese)

Induction of chronic oxidative stress by hepatitis C (HCV) and B (HBV) virus is one of the molecular events leading to hepatocellular carcinoma (HCC) development. Telomeres are prone to oxidative modifications, that induce a progressive telomere shortening and a consequent chromosomal instability. Telomerase activity plays a crucial role in telomeres maintenance and cell immortalization. TERT, the rate limiting factor for telomerase transcription, is regulated by epigenetic mechanism and under oxidative stress migrates to mitochondria, where it ameliorates the membrane stability and exerts an anti-apoptotic role. The aim of the study was to investigate the complexmolecular networkunderlying virus-related liver carcinogenesis, evaluating: 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidative DNA damage, and OGG1 gene, telomere length, telomerase activity, TERT promoter methylation and mitochondrial TERT translocation.
One hundred sixty-two patients were investigated: 21with HCC (bothtumor and peritumoral tissue samples), 71 with chronic hepatitis HCV-related and 35 with chronic hepatitis HBV-related and 15 controls. Eight-OHdG was quantified through HPLC-EC, telomerase activity and telomeres length by Real Time PCR, TERT promoter methylation status by Quantitative Methylation Specific PCR and mitochondrial TERT translocation by western blotting. Overall, 8-OHdG levels were significantly higher in tumor tissues than in controls (p=0.02), telomeres were significantly shorter in HCC compared to the less advanced stages of disease (p=0.01), whereas telomerase activity was significantly higher in tumor tissues than in controls (p=0.01). Eight-OHdG levels inversely correlated with telomere length in HCC. Overall, TERT promoter was hypermethylated in HCC and peritumoral tissue samples (p=0.0001). When the patients were subgrouped on the basis of etiology, HBV-related liver damage progression was characterized by later 8-OHdG accumulation and a pronounced telomerase activation limited to HCC tissue. TERT was localized in mitochondria in all the investigated HCC samples and, in mitochondria DNA, 8-OHdG levels were significantly lower than in genomic DNA (p=0.0003).
These data describe a complex network in which oxidative DNA damage is linked to changes in telomeres length, extent of telomerase activation and higher methylation of TERT promoter in HBV/HCV related carcinogenesis. The role of mitochondrial TERT in HCC is open to debate, but an intriguing work hypothesis is that it could down-regulate apoptosis.

Abstract (italiano)

Lo stress ossidativo e le specie reattive dell’ossigeno (ROS), la cui sintesi è indotta dal danno epatico causato dai virus delle epatiti C (HCV) e B (HBV), sono in grado di scatenare la cascata di eventi molecolari che portano allo sviluppo del carcinoma epatocellulare (HCC). I telomeri sono siti elettivi di attacco da parte dei ROS, che inducono un loro progressivo accorciamento e una conseguente instabilità cromosomica. L’attività della telomerasi gioca un ruolo cruciale nel mantenimento dei telomeri e nell’immortalizzazione cellulare. TERT, il fattore limitante per la trascrizione della telomerasi, è regolato da meccanismi epigenetici e in condizioni di stress ossidativo può migrare ai mitocondri, dove sembra migliorare la stabilità della membrana ed esercitare una funzione anti-apoptotico. Lo scopo di questo studio è stato quello di indagare la complessa rete molecolare alla base della carcinogenesi epatica ad eziologia virale mediante la valutazione:
 della presenza dell’8-idrossideossiguanosina (8-OHdG), marker di danno ossidativo al DNA, mediante HPLC-EC, e del polimorfismo del gene di riparazione (OGG1);
 della lunghezza dei telomeri e dell'attività della telomerasi mediante Real-Time-PCR;
 dello stato di metilazione del promotore di TERT mediante PCR quantitativa specifica;
 dell’eventuale traslocazione mitocondriale di TERT mediante western blotting.
In questo studio sono stati esaminati 162 pazienti di cui 21 con HCC (di questi pazienti sono stati analizzati sia i campioni di tessuto tumorale che peritumorale), 71 con epatite cronica HCV-correlata, 35 con epatite cronica HBV-correlata e 15 controlli.
In generale, considerando i pazienti tutti insieme, i dati ottenuti hanno mostrato livelli di 8-OHdG significativamente più alti nei tessuti tumorali rispetto ai controlli (p=0.02); i telomeri sono risultati significativamente più corti negli HCC rispetto agli altri gruppi con stadio di malattia meno avanzato (p=0.01), mentre l'attività della telomerasi è risultata significativamente più elevata nei tessuti tumorali rispetto ai controlli (p=0.01). Negli HCC i livelli di 8-OHdG sono risultati inversamente correlati con la lunghezza telomerica. Nelle nostre analisi il promotore di TERT è risultato essere ipermetilato nel carcinoma epatico e nei campioni di tessuto peritumorale (p=0.0001). Inoltre, è’ interessante notare che, quando i pazienti sono stati suddivisi in base all’eziologia virale, è stato possibile verificare come la progressione del danno epatico correlato all’HBV sia caratterizzato da un accumulo di 8-OHdG più tardivo e che caratterizza le fasi più avanzate, rispetto a quello indotto da HCV e, successivamente, da una attivazione della telomerasi limitata, però, al solo tessuto tumorale. Infine la proteina TERT è stato localizzata nei mitocondri di tutti i campioni di HCC esaminati, dove è stato dimostrato non avere attività telomerasica, e, nel DNA mitocondriale (mtDNA), i livelli di 8-OHdG sono risultati significativamente più bassi rispetto a quelli valutati nel DNA genomico (p=0.0003).
Questi dati descrivono una complessa rete di eventi nella carcinogenesi epatica HBV/HCV correlata in cui il danno ossidativo al DNA è legato a cambiamenti nella lunghezza dei telomeri, all’attivazione della telomerasi e ad un’aumentata metilazione del promotore di TERT. Infine, il ruolo di TERT a livello mitocondriale nell’HCC è ancora argomento di discussione, ma un'ipotesi interessante riguarda il suo potenziale coinvolgimento nella possibile regolazione dell’apoptosi.

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Tipo di EPrint:Tesi di dottorato
Relatore:Farinati, Fabio - Cardin, Romilda
Dottorato (corsi e scuole):Ciclo 25 > Scuole 25 > BIOLOGIA E MEDICINA DELLA RIGENERAZIONE > SCIENZE EPATOLOGICHE E GASTROENTEROLOGICHE
Data di deposito della tesi:24 Gennaio 2013
Anno di Pubblicazione:24 Gennaio 2013
Parole chiave (italiano / inglese):epatiti virali, carcinoma epatocellulare, danno ossidativo al DNA, attività telomerasica, lunghezza dei telomeri, TERT e mitocondri. viral hepatitis, hepatocellular carcinoma, oxidative DNA damage, telomerase activity, telomere length, TERT and mitochondria
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/12 Biochimica clinica e biologia molecolare clinica
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze del Farmaco
Codice ID:5466
Depositato il:22 Ott 2013 12:05
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