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Ciato, Denis (2016) Novel molecular mechanisms involved in the pathogenesis of GH-secreting pituitary adenomas. [Tesi di dottorato]

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Abstract (inglese)

Pituitary tumors usually show a particular benign nature, with a slow growth potential. Despite these characteristics, they can cause severe complications due to their excessive hormone secretion. Still, further investigations are needed to understand the molecular mechanisms implicated in their development in detail. AHRR (Aryl Hydrocarbon Receptor (AHR) Repressor) and HSP90 (Heat Shock Protein 90) are good candidates for playing a role in pituitary tumorigenesis due to their tumorigenic role reported in different types of tumors and their action in the metabolism of endocrine disruptors (EDs), in which AIP (Aryl Hydrocarbon Receptor Interacting Protein) is also implicated. AHR Repressor (AHRR) is the main regulator of AHR activity through a negative feedback mechanism, which impairment leads to tumor-promoting events. Accordingly, AHRR downregulation was reported in several malignancies including colon, breast and lung cancer and was correlated with a more malignant phenotype (e.g. resistance to apoptosis, increased cellular motility and angiogenic potential) in different tumor cell lines. Although several studies investigated the potential role of AHR signaling in pituitary tumorigenesis, so far no data has been available on the role of AHRR in pituitary tumorigenesis. Therefore, the primary aim of the present study was to evaluate the possible role of AHRR in influencing the tumor phenotype in the somato-lactotroph cell line GH3 in which AHRR was stably silenced or overexpressed. AHRR-silenced cells showed a less aggressive phenotype due to a decreased cell viability and to a more pronounced resistance to apoptosis-inducing stimulus in comparison to the control. Correspondingly, opposite results were obtained for the stable overexpression of AHRR. In addition, AHRR silencing increased senescence-associated beta galactosidase (SA-β Gal) staining in accordance with a slow-growing phenotype observed at proliferation level, without having effect on cell cycle progression. No correlation was observed between AHRR mRNA expression in human pituitary adenomas and tumor aggressiveness, although GH-secreting tumors displayed a higher expression of AHRR in comparison to normal pituitaries.
The second part of this thesis was aimed at the role of HSP90 in the pathogenesis of GH-secreting tumors. In addition to the stabilization of AHR, this protein plays a pivotal role in maturation and stabilization of other proteins implicated in oncogenic signaling and cancer progression, and treatment with HSP90 inhibitors has recently shown promising results in pituitary corticotroph adenomas. Therefore, the function of HSP90 was investigated in GH-secreting pituitary adenomas. An intense HSP90 immunoreactivity was reported in 8 out of 25 GH-secreting pituitary tumors. In order to study the therapeutic potential of HSP90 inhibition in these tumors, the cell line GH3 was treated with different HSP90 inhibitors. The C-terminal HSP90 inhibitors novobiocin and KU174 dose-dependently decreased GH promoter activity, whereas only KU174 decreased GH secretory levels.
Conclusively, the data presented herein provide novel insights in the pathogenesis of GH-secreting pituitary adenomas. AHRR might have an oncogenic role by influencing tumor aggressiveness, as shown in the cellular model. Moreover, the results obtained in the second part suggest that HSP90 might have a role in the tumorigenesis of GH-secreting pituitary tumors and a potential for HSP90 C-terminal inhibitors in managing the excess of GH secretion.

Abstract (italiano)

I tumori ipofisari manifestano normalmente un fenotipo benigno, caratterizzato da un potenziale di crescita ridotto. Anche in assenza di effetti patogenetici dovuti all´espansione della massa tumorale nelle strutture adiacenti, possono causare severe complicazioni a causa della loro eccessiva secrezione ormonale. Studi approfonditi sono ancora necessari per riconoscere nuovi meccanismi molecolari implicati nel loro sviluppo. AHRR (Aryl Hydrocarbon Receptor (AHR) Repressor) e HSP90 (Heat Shock Protein 90), oltre ad avere un ruolo nella tumorigenesi in tessuti di differente origine, potrebbero potenzialmente essere coinvolti nello sviluppo dei tumori ipofisari per via della loro attività nel metabolismo di Endocrine Disruptors (EDs), in cui anche la proteina AIP (Aryl Hydrocarbon Receptor Interacting Protein) è implicata. AHRR é il principale regolatore dell’attività di AHR, e lo sbilanciamento di questo sistema di regolazione può avere effetti tumorigenici. Nella fattispecie, l´espressione ridotta di AHRR è stata descritta in tumori di differente origine anatomica tra i quali colon, seno e polmone; e sembra essere associata ad una maggiore aggressività del fenotipo tumorale (in termini di resistenza all´apoptosi, aumento della proliferazione e potenziale angiogenico) in differenti modelli cellulari. Nonostante diversi studi abbiano investigato il potenziale ruolo della via di segnale di AHR nei tumori ipofisari, non vi sono evidenze riguardo al ruolo specifico di AHRR. Scopo principale di questo lavoro di tesi è stato perciò valutare il possibile ruolo di AHRR nella patogenesi dei tumori ipofisari. La linea cellulare somato-lattotropa GH3 è stata utilizzata come modello per generare cloni stabili in cui AHRR è silenziato o overespresso. Il silenziamento di AHRR ha portato alla manifestazione di un fenotipo meno aggressivo dovuto alla diminuzione della capacità proliferativa e alla maggiore resistenza a stimoli apoptotici rispetto al controllo, mentre risultati opposti sono stati ottenuti overesprimendo stabilmente AHRR. È stato inoltre evidenziato come il silenziamento di AHRR abbia indotto la manifestazione di un fenotipo più senescente rispetto al controllo, in correlazione con la riduzione della proliferazione cellulare. Non sembra però che ciò coinvolga un cambiamento sulla distribuzione del ciclo cellulare. Inoltre, forse a causa del numero ridotto di campioni analizzati, la valutazione quantitativa dell’espressione a livello dell’mRNA di AHRR nei tumori ipofisari non sembra essere in relazione con l’aggressività tumorale, anche se nel sottogruppo adenomi GH-secernenti vi sia una maggiore espressione rispetto a campioni di ipofisi normali.
La seconda parte di questo lavoro di tesi ha avuto come scopo la valutazione del ruolo di HSP90 nella patogenesi dei tumori ipofisari. Oltre alla stabilizzazione di AHR, questa proteina svolge un ruolo fondamentale nella maturazione e nella stabilizzazione di altre proteine implicate nella trasformazione e nella progressione tumorale, e la sua inibizione specifica ha recentemente dimostrato risultati promettenti negli adenomi ACTH-secernenti. Sulla base di queste premesse, la valutazione del ruolo di HSP90 è stata estesa ai tumori GH-secernenti. L´analisi immunoistochimica effettuata su adenomi GH secernenti ha evidenziato una intensa immunoreattivitá di HSP90 in 8/25 casi. Visto il potenziale coinvolgimento di HSP90 in questa tipologia di adenomi ipofisari, la linea cellulare GH3 è stata utilizzata come modello per investigare il potenziale terapeutico di differenti inibitori di HSP90. Nella fattispecie, il trattamento con gli inibitori C-terminali di HSP90 novobiocina e KU174 ha provocato una diminuzione dose-dipendente dell´attivitá promotoriale del GH, mentre solo KU174 ha significativamente diminuito la secrezione di GH.

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Tipo di EPrint:Tesi di dottorato
Relatore:Scaroni, Carla
Dottorato (corsi e scuole):Ciclo 28 > Scuole 28 > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > METODOLOGIA CLINICA, SCIENZE ENDOCRINOLOGICHE, DIABETOLOGICHE E NEFROLOGICHE
Data di deposito della tesi:26 Aprile 2016
Anno di Pubblicazione:26 Aprile 2016
Parole chiave (italiano / inglese):acromegaly, AHRR, HSP90, aggressiveness, GH secretion
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/11 Biologia molecolare
Area 06 - Scienze mediche > MED/13 Endocrinologia
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina
Codice ID:9629
Depositato il:13 Ott 2016 11:10
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