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Morton, Stuart D (2015) Leukaemia inhibitory factor protects cholangiocarcinoma cells from drug-induced apoptosis via a STAT3-independent, PI3K-dependent, Mcl-1 activation. [Tesi di dottorato]

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Abstract (inglese)

Background and Aim. Cholangiocarcinoma (CCA) is an aggressive, chemoresistant liver malignancy characterised by an abundant desmoplasia. Tumour-stromal interactions promote cancer development and thus could be targets of interventional therapies. Leukaemia inhibitory factor (LIF), an IL-6 family cytokine, promotes development and progression of various epithelial cancers, however very little is known about its effects in CCA. We aimed to investigate a possible role of LIF and its receptor (LIFR) in the pathogenesis of CCA.
Methods. LIF, LIFR and gp130 distributions were evaluated by immunohistochemistry in archived human histological samples derived from surgical resection (n=19). LIF secretion (ELISA) and LIFR expression (Western blotting) were assessed in freshly isolated human primary cholangiocytes (n=8) and established CCA cell lines (n=3). Using the two established CCA cell lines that expressed LIFR, we tested LIF’s effects on: proliferation, viability (both MTS) and apoptosis (caspase 3 and 7 activation) with/without chemotherapeutic agents (cisplatin, gemcitabine, paclitaxel or camptothecin), migration (scratch assay), invasion (Boyden chambers), stem cell-like phenotype (Nanog and Oct4 gene expression by real-time PCR), and expression levels of pro-apoptotic (pBax) and anti-apoptotic (Mcl-1 with/without PI3K inhibition) proteins, and pSTAT3 (Western blotting).
Results. LIF and LIFR were more extensive in neoplastic than control bile ducts; LIF was also widespread amongst tumour stromal cells. LIF had minimal effects on cell proliferation, migration, invasion, and induction of a stem cell-like phenotype, whilst it significantly counteracted drug-induced apoptosis. Upon LIF stimulation, decreased caspase 3/7 activation was associated with increased Mcl-1 expression attenuated by PI3K inhibition whereas pBax and pSTAT3 remained unchanged.
Conclusions. Autocrine and paracrine LIF signalling may promote chemoresistance in CCA by up-regulating Mcl-1. This pro-survival capability may be mediated by a novel STAT3-independent, PI3K-dependent pathway.

Abstract (italiano)

Razionale e scopo. Il colangiocarcinoma (CCA) è una neoplasia epatica estremamente aggressiva e chemioresistente, caratterizzata da un’abbondante desmoplasia. Le interazioni stroma-tumore possono promuovere lo sviluppo tumorale e per questo possono risultare dei buoni bersagli per una terapia potenzialmente curativa. Il leukaemia inhibitory factor (LIF), è una citochina appartenente alla famiglia dell’IL-6 ed è in grado di promuovere lo sviluppo e la progressione di un ampio numero di tumori epiteliali, ma poco si sa della sua funzione e dei suoi effetti nel CCA. Il nostro scopo è quello di studiare il ruolo di LIF e del suo recettore (LIFR) nella patogenesi del CCA.
Metodi. La distribuzione di LIF, LIFR e gp130 è stata valutata tramite immunoistochimica su tessuti umani di archivio derivanti da resezioni chirurgiche per CCA (n=19). La secrezione di LIF (ELISA) e l’espressione di LIFR (Western blotting) sono state valutate su colture primarie di colangiociti umani ottenuti da resezioni per CCA (n=8) e su linee stabili di CCA (n=3). Abbiamo quindi testato su due linee stabilizzate di CCA esprimenti LIFR: la proliferazione, la vitalità (entrambi con MTS) e l’apoptosi cellulare (attivazione delle caspasi 3/7) con/senza trattamento con agenti chemioterapici (cis-platino, gemcitabina, paclitaxel o camptotecina), la migrazione (scratch assay), l’invasione (camere di Boyden), l’induzione di un fenotipo simil-staminale (espressione genica di Nanog e Oct4 con real-time PCR) ed infine i livelli di espressione di proteine pro- (pBax) ed anti-apoptotiche (Mcl-1 con/senza inibizione di PI3K) e di pSTAT3 (Western blot).
Risultati. LIF e LIFR risultano maggiormente espressi nelle strutture neoplastiche che nei dotti biliari peritumorali; LIF risulta inoltre espressa da gran parte delle cellule dello stroma tumorale. Gli effetti del LIF su proliferazione, migrazione, invasione e induzione di un fenotipo simil-staminale sono minimi, di contro esso protegge le cellule tumorali dall’apoptosi indotta da farmaci. Dopo la stimolazione con LIF, si osserva una riduzione dell’attivazione delle caspasi 3/7 associata ad un aumento dell’espressione di Mcl-1, la quale viene diminuita dall’inibizione della PI3K; l’espressione di pBax e pSTAT3 non risultano invece modulate.
Conclusioni. Il segnale di LIF può promuovere, sia per via autocrina che paracrina, la chemioresistenza del CCA aumentando i livelli di espressione di Mcl-1. Queste capacità favorenti la sopravvivenza cellulare sono mediate da una nuova via di segnale STAT3-indipendente e PI3K-dipendente.

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Tipo di EPrint:Tesi di dottorato
Relatore:Fabris, Luca
Dottorato (corsi e scuole):Ciclo 27 > scuole 27 > BIOLOGIA E MEDICINA DELLA RIGENERAZIONE
Data di deposito della tesi:27 Gennaio 2015
Anno di Pubblicazione:27 Gennaio 2015
Parole chiave (italiano / inglese):Cholangiocarcinoma; Leukaemia inhibitory factor; Chemoresistance; Mcl-1; Phosphatidylinositol-3 kinase
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/12 Gastroenterologia
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina Molecolare
Codice ID:7585
Depositato il:09 Dic 2015 09:49
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