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Sinigaglia, Alessandro (2009) Studio del ruolo dei miRNA nella patogenesi dell'epatocarcinoma hcv-correlato. [Ph.D. thesis]

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Abstract (english)

BACKGROUND:
MicroRNAs (miRNAs) are non-coding RNAs whose role in gene regulation has been discovered and gradually clarified in recent years.
The action of miRNAs, like that of other types of non-coding RNA (commonly called RNA-interference), is based on their physical interaction with gene transcripts (mRNA), and the inhibition or decrease of protein production from them. The biological effect of miRNAs depends on the nature of their targets.
Currently, there is not a precise map of the targets for each of about 700 human miRNAs, but some functional genomics studies have already shown for some of them a direct involvement in the pathogenetic mechanisms of many diseases including cancer.
Hepatocellular carcinoma (HCC) is one of the most aggressive human tumors and both its early detection and even more its therapy remain somewhat problematic. On the other hand, factors that cause and promote its development (hepatitis viruses, alcohol abuse are the most common) are also constantly present and potentially increasing in the population.
Many reasons can then advise the search for new strategies that, starting from scientific analysis, can result in midterm improvements in the health management of the disease. In the case of micro-RNA, several studies have already been carried out showing the existence of a clear pattern of specific miRNA expression in liver affected by HCC, though there currently lacks a clear consensus on the issue, as well as the link with the study of those in clinically distinct but biologically related conditions as chronic hepatitis, liver fibrosis, cirrhosis.
Finally, many scientific evidences advice us to develop and implement quantitative and qualitative analysis on miRNA in tissues from patients with HCC, in order to gather data needed to better understand the pathogenesis of the tumor but also to better study its causes. Moreover, these studies can be exploited in the medium term for the generation of useful biological models for the development of new therapeutic approaches.
OBJECTIVES:
Starting from these assumptions and entering specifically in this study, the objectives are:
- For the methodology point-of-view, the definition of a protocol for the analysis of miRNA in tissue samples, in view of the rapid spread of this kind of research in biomedicine.
- For The scientific point-of-view, the monitoring of the panel of a specific miRNA liver potentially useful for identifying the stages of liver disease progression leading to HCC. This kind of analysis is performed in a comparative context (tumor tissue vs normal tissue) and can provide the basis for future studies focused on molecular and functional interactions between genes and specific miRNAs of interest.



DESIGN of the STUDY
1.Investigation on the expression of a panel of liver-specific and cancer-associated miRNAs in a series of samples from liver cancer patients (mainly HCV-related HCC) by mean of RT-realtime PCR.
2. Analysis of the presence of HCV in tissue samples by PCR and analysis of genotype and subtype of HCV by automatic sequencing, with comparison of the expression profile of miRNAs with virological data.
RESULTS
The results of our studies on HCC, obtained by Real Time PCR with primers specific for a small panel of miRNA, have led us to identify differences in the expression of some of these genes between samples of tumor tissue and samples of adjacent normal tissue. In particular, we confirmed a significant down-regulation of mir-199a, present in almost 70% of the cases studied, while others (including: mir-195, mir-122a, mir-199b) have slightly less frequent but still significant deregulations ( 50-65%). One single miRNA in the selected panel, mir-222, presented a deregulation in the sense of a higher expression in tumor tissue than in normal, in over 40% cases. The other examined micro-RNAs do not show significant differences between the two types of tissue. Slightly different considerations can arise from the comparison of data from HCV positive and negative samples.
These data are consistent with those reported in previous literature, demonstrating the reliability of techniques used.
A parallel activity has focused on the search for HCV viral genomes, and the analysis of viral sequences. Combining the results of the study with the clinical data available, 20 patients out of 29 were HCV-positive. About the viral sequences amplified and analyzed, the alignement with bioinformatic databases gives us the result that 70% of HCV-positive patients belong to the group of subtype 1b, 15% to group 1a, and another 15% to Group 2.
CONCLUSIONS
In conclusion, this study allowed us both to test and develop protocols for analysis to be applied also in other scientific studies, and to collect data on the expression of miRNAs in hepatocellular carcinoma which, although requiring further investigation, appear to be interesting hints of a specific genetic de-regulation of this pathological condition.

Abstract (italian)

INTRODUZIONE:
I microRNA (miRNA) sono RNA non codificanti il cui ruolo di regolazione dell’espressione genica è stato scoperto e via via delucidato in anni recenti.
L’azione dei miRNA, non dissimilmente da quella di altre tipologie di RNA non codificanti (comunemente chiamata RNA-interference), si esprime nell’interazione fisica specifica con trascritti genici (mRNA) e nell’impedimento o comunque nella riduzione quantitativa della produzione a partire da questi ultimi di proteine. L’effetto biologico del miRNA dipende pertanto dalla natura del suo bersaglio.
Non è al momento disponibile una mappa precisa dei bersagli di ciascuno dei circa 700 miRNA umani, ma alcuni studi di genomica funzionale hanno già dimostrato per alcuni di essi un coinvolgimento diretto nei meccanismi patogenetici di numerose patologie fra cui il cancro.
L’epatocarcinoma (HCC) è fra i tumori umani uno dei più aggressivi e tanto la sua diagnosi precoce quanto ancor più la sua terapia permangono alquanto problematiche. D’altro canto, i fattori che ne provocano e promuovono l’insorgenza (virus epatitici, abuso di alcool le più comuni) sono a loro volta costantemente presenti nella popolazione e potenzialmente in aumento.
Molte ragioni quindi possono consigliare la ricerca di nuove linee strategiche che, partendo dall’analisi scientifica, possano sfociare nel medio periodo in miglioramenti nella gestione sanitaria della patologia. Nel caso dei micro-RNA, sono già stati effettuati numerosi studi miranti a mostrare l’esistenza di un preciso schema nell’espressione di specifici miRNA nei fegati affetti da HCC, tuttavia manca al momento un chiaro consenso sulla questione, nonché il quanto mai necessario raccordo con lo studio dei medesimi in ambiti clinicamente distinti ma biologicamente attinenti quali epatite cronica , fibrosi epatica, cirrosi.
Concludendo, numerose evidenze scientifiche consigliano di sviluppare e mettere in atto analisi quantitative e qualitative sui miRNA nei tessuti di pazienti affetti da HCC, per poter raccogliere dati necessari ad una miglior comprensione della patogenesi del tumore ma anche per poter studiare meglio le sue cause. Nondimeno, tali studi possono essere sfruttati nel medio periodo per la generazione di modelli biologici utili ai fini dello sviluppo di nuovi approcci terapeutici.
OBIETTIVI:
Partendo da tali presupposti ed entrando nello specifico di questo studio, gli obiettivi sono:
- Sul piano metodologico, la definizione di un protocollo generale per l’analisi dei miRNA in campioni tissutali, nella prospettiva di una rapida diffusione di questo genere di ricerche nell’ambito biomedico.
- Sul piano scientifico, il monitoraggio dell’espressione di un pannello di miRNA specifici per il fegato potenzialmente utili per identificare le tappe della progressione dalla patologia epatica all’HCC. Questo tipo di analisi viene svolta in un contesto comparativo ( tessuto tumorale contro tessuto normale) e può fornire le basi per futuri studi focalizzati su interazioni molecolari e funzionali tra miRNA specifici e geni di interesse.

DISEGNO DELLO STUDIO
1.Indagine sull'espressione di un pannello di miRNA fegato-specifici e associati a tumore in una serie di campioni di pazienti con tumore epatico HCV-associate (principalmente HCC HCV-collegato) tramite metodiche di RT-real time -PCR
2. Analisi della presenza di HCV con PCR nei campioni di tessuto, e analisi del genotipo e sottotipo di HCV mediante sequenziamento automatico; confronto del profilo di espressione di miRNA con i dati virologici.
RISULTATI
I risultati dei nostri studi su HCC, ottenuti mediante Real Time PCR con primers specifici per un ristretto pannello di miRNA, hanno permesso di individuare delle differenze nell’espressione di alcuni di questi geni tra campioni di tessuto tumorale e campioni di tessuto normale adiacente. In particolare abbiamo confermato una significativa sottoespressione di mir-199a, presente in quasi il 70% dei casi analizzati, mentre altri (fra cui: mir-195, mir-122a, mir-199b) presentano deregolazioni leggermente meno frequenti ma pur sempre significative (50-65%). Un solo miRNA del pannello selezionato, mir-222, presenta una deregolazione nel senso di una sovraespressione nel tessuto tumorale rispetto a quello sano, in una percentuale superiore al 40%. Gli altri micro-RNA presi in esame non danno, con questa metodica, differenze significative fra i due tipi di tessuto. Considerazioni leggermente differenti derivano dal confronto dei dati relativi a campioni HCV positivi e negativi.
Questi dati sono compatibili con quelli riferiti nella letteratura pregressa, dimostrando l’attendibilità delle tecniche utilizzate.
L’ attività avviata parallelamente ha riguardato la ricerca di genomi virali di HCV, e successivamente l’analisi delle sequenze virali. Unendo i risultati dell’analisi ai dati clinici disponibili, 20 pazienti su 29 risultano HCV-positivi. Circa le sequenze virali amplificate e analizzate, il confronto coi database bioinformatici ci dà per risultato che il 70% circa dei pazienti HCV-positivi appartiene al gruppo del sottotipo 1b, il 15% al gruppo 1a, e l’altro 15% al gruppo 2.
CONCLUSIONI
In conclusione, questo studio ha permesso sia di testare e mettere a punto protocolli di analisi trasferibili nel breve periodo ad altri studi scientifici, sia di raccogliere dati sull’espressione dei miRNA nell’epatocarcinoma che, pur necessitando di indagini ulteriori, appaiono interessanti indizi di una de-regolazione genetica specifica di questa condizione patologica.

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EPrint type:Ph.D. thesis
Tutor:Farinati, Fabio
Supervisor:Barzon, Luisa
Ph.D. course:Ciclo 21 > Scuole per il 21simo ciclo > BIOLOGIA E MEDICINA DELLA RIGENERAZIONE > SCIENZE EPATOLOGICHE E GASTROENTEROLOGICHE
Data di deposito della tesi:31 January 2009
Anno di Pubblicazione:2009
Key Words:epatocarcinoma micro RNA HCV
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/06 Oncologia medica
Area 06 - Scienze mediche > MED/12 Gastroenterologia
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Scienze Chirurgiche Gastroenterologiche "Pier Giuseppe Cevese"
Codice ID:1395
Depositato il:31 Jan 2009
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