Di Stadio, Chiara Stella
(2017)
Epigenetic mechanisms underlying Gastrokine 1 gene silencing
in gastric cancer progression.
[Tesi di dottorato]
| Tipologia del documento: |
Tesi di dottorato
|
| Lingua: |
English |
| Titolo: |
Epigenetic mechanisms underlying Gastrokine 1 gene silencing
in gastric cancer progression |
| Autori: |
| Autore | Email |
|---|
| Di Stadio, Chiara Stella | kstella@hotmail.it |
|
| Data: |
10 Aprile 2017 |
| Numero di pagine: |
53 |
| Istituzione: |
Università degli Studi di Napoli Federico II |
| Dipartimento: |
Medicina Molecolare e Biotecnologie Mediche |
| Dottorato: |
Medicina molecolare e biotecnologie mediche |
| Ciclo di dottorato: |
29 |
| Coordinatore del Corso di dottorato: |
| nome | email |
|---|
| Avvedimento, Vittorio Enrico | avvedim@unina.it |
|
| Tutor: |
| nome | email |
|---|
| ARCARI, PAOLO | [non definito] |
|
| Data: |
10 Aprile 2017 |
| Numero di pagine: |
53 |
| Parole chiave: |
GKN1 |
| Settori scientifico-disciplinari del MIUR: |
Area 05 - Scienze biologiche > BIO/10 - Biochimica |
[error in script]
[error in script]
| Depositato il: |
02 Mag 2017 14:00 |
| Ultima modifica: |
13 Mar 2018 11:26 |
| URI: |
http://www.fedoa.unina.it/id/eprint/11754 |
| DOI: |
10.6093/UNINA/FEDOA/11754 |
Abstract
Gastric cancer (GC) is still one of the leading causes of cancer-related deaths
worldwide and high mortality rate is mainly due to late-stage diagnosis. New
insights show that epigenetic alterations contribute significantly to the
development and progression of GC and if nowadays the role of somatic
mutations as drivers of carcinogenesis in the alimentary tract is well
established, the importance of gene silencing by epigenetic mechanisms is
increasingly recognized. Gastrokine1 (GKN1) is a highly expressed stomach
protein important for maintaining the physiological function of the gastric
mucosa. GKN1 is down-regulated in gastric tumor tissues and derived cell
lines so it has recently emerged as a potential biomarker for gastric cancer. It
has also been demonstrated that GKN1 expression induces apoptosis in
gastric cancer cells thus suggesting a possible role of the protein as tumor
suppressor. The mechanism by which GKN1 gene is inactivated in GC
remains still unknown, so here I have investigated on the possible causes of
GKN1 gene silencing in order to determine if epigenetic mechanisms could
also contribute to its down-regulation. To these aim, chromatin
immunoprecipitation (ChIP) assays for the repressive trimethylation of
histone 3 at lysine 9 (H3K9triMe) and its specific histone-lysine Nmethyltransferase
(SUV39H1) were performed on biopsies of normal and
tumor human gastric tissues. The results showed that GKN1 downregulation
in gastric cancer tissues is associated with high levels of H3K9triMe and
with the recruitment of SUV39H1 on GKN1 promoter, suggesting the
presence of an epigenetic transcriptional complex that negatively regulates
GKN1 expression in gastric tumor.
It was also investigated whether underacetylation might contribute to GKN1
transcriptional inhibition using TSA to increase general histone acetylation.
The results showed that inhibition of HDACs leads to GKN1 restoration at
transcriptional level, but no at traslational level. These findings led to
hypothesize that a second regulatory block occurs at translational level,
perhaps by mechanisms mediated by microRNAs (miRNAs), resulting in
translational repression and gene silencing. So, the possible involvment of
miRNAs in this process was investigated. The results demostrated that GKN1
3’UTR was a direct target of hsa-miR-544a and miR-1245b-3p and showed
an increase of miR-544a expression in the gastric cancer cell lines after TSA
treatment.
The up-regulation of miR-544a could be the cause of the GKN1
translational repression, thus suggesting its potential role as biomarker and
therapeutic target in GC patients.
These findings indicate that epigenetic mechanisms leading to the
inactivation of GKN1 play a key role in the multi-step process of gastric
2
carcinogenesis and would provide an essential starting point for the
development of new therapeutic strategies based on epigenetic targets for
alternatives gene.
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