Pastore, Arianna (2022) ZNF224 is a mediator of TGF-β pro-oncogenic function in melanoma. [Tesi di dottorato]
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| Tipologia del documento: | Tesi di dottorato |
|---|---|
| Lingua: | English |
| Titolo: | ZNF224 is a mediator of TGF-β pro-oncogenic function in melanoma |
| Autori: | Autore Email Pastore, Arianna arianna.pastore@unina.it |
| Data: | 10 Marzo 2022 |
| Numero di pagine: | 64 |
| Istituzione: | Università degli Studi di Napoli Federico II |
| Dipartimento: | Medicina Molecolare e Biotecnologie Mediche |
| Dottorato: | Medicina molecolare e biotecnologie mediche |
| Ciclo di dottorato: | 34 |
| Coordinatore del Corso di dottorato: | nome email Santoro, Massimo massimo.santoro@unina.it |
| Tutor: | nome email Costanzo, Paola [non definito] |
| Data: | 10 Marzo 2022 |
| Numero di pagine: | 64 |
| Parole chiave: | ZNF224; Melanoma; TGF-β pathway. |
| Settori scientifico-disciplinari del MIUR: | Area 05 - Scienze biologiche > BIO/10 - Biochimica |
| Depositato il: | 17 Mar 2022 15:09 |
| Ultima modifica: | 28 Feb 2024 10:42 |
| URI: | http://www.fedoa.unina.it/id/eprint/14463 |
Abstract
ZNF224 is a human pleiotropic KRAB zinc finger protein that plays a crucial role in human cancer. Depending on its cellular context and molecular partners,it can act as both tumour promoter and suppressor.The Transforming Growth Factor-β (TGF-β) is an essential and pleiotropic cytokine involved in several physiological and pathological processes. In particular, it is a crucial regulator of melanoma progression, a highly invasive and metastatic tumour.In this thesis work, we investigated the ZNF224 role in melanoma and its involvement in the TGF-β signaling as a mediator of the TGF-β pro-oncogenic function. We first found that ZNF224 expression is increased in melanoma cell lines compared to non-cancerous cells and that its expression is induced by TGF-β stimulation. Then, we showed that ZNF224 potentiated the acquisition of a mesenchymal phenotype and a metastatic behaviour by promoting epithelial -mesenchymal transition (EMT). Indeed, ZNF224 overexpression activated the EMT-associated genes such as Slug, Snail, Vimentin and N-Cadherin, and it acted synergistically with TGF-β to potentiate their activation. Furthermore,ZNF224 overexpression in melanoma cells promotes proliferation, invasiveness,and metastatic potential, while ZNF224 knockdown had the opposite effect. Intriguingly, we found that ZNF224 could sustain the endogenous TGFβ/Smad signaling. Indeed, ZNF224 overexpression prolonged the phosphorylation of the Smad complex and increased the levels of the TGF-β itself and its type 1 and 2 receptors (TβR1 and TβR2). These results unveil the existence of a positive regulatory loop between ZNF224 and TGF-β and suggest that ZNF224 contributes to the constitutive activation of this pathway, thus supporting melanoma progression. However, other experiments are required to investigate the underlying molecular mechanisms between ZNF224 and TGF-β pathway. Identifying ZNF224 as a modulator of TGF-β signaling in melanoma could represent a new important tool in understanding the complex role of the TGF-β pathway in melanoma and could help to identify novel molecular therapeutic targets and suitable treatment options for this deadly disease
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