| dc.description.abstract | Helicobacter pylori is one of the most important pathogenic bacteria associated with
various gastric diseases, including cancer. This pathogen induces an acute mucosal
inflammatory response and, if not eradicated, it could lead to chronic infection and
eventually, in a subset of individuals, to gastric cancer. In response to the infection,
the gastric mucosa releases several protective factors, including TFF1, which binds
Helicobacter in the mucus layer and reduces inflammation caused by the infection.
TFF1 is a gastro-specific tumor suppressor gene upregulated in the acute phase of the
Helicobacter infection but silenced during the chronic infection. This Ph.D. thesis
project aimed to evaluate the role of TFF1 in the context of infection.
First, TFF1 was assayed for its effects on Helicobacter at molecular and morphological
levels. The results showed that H. pylori is more prone to aggregate in a TFF1-
concentration-dependent manner and as consequence its motility through a
physiological mucus layer is compromised.
Since Helicobacter chronic infection promotes TFF1 silencing impairing the mucosal
protection and contributing to the development of malignant transformation, the
second aim of this thesis was to investigate the molecular pathways involved in this
silencing. Our hypothesis was that the cytokines secreted by activated immune cells
during H. pylori chronic infection would cause the silencing of TFF1 in gastric cells.
Based on our results, IFNγ plays the major role in the TFF1 downregulation.
Moreover, examining the TFF1 promoter, this phenotype seems to occur via C/EBPβ
that works as a negative regulator during IFNγ stimulation. According to our evidence,
IFNγ induces the expression of C/EBPβ and favors its binding to the TFF1 promoter,
repressing its transcription. In addition, the involvement of DNA methylation in this
process was evaluated, suggesting that this epigenetic mechanism is also involved in
IFNγ-dependent TFF1 silencing. [edited by Author] | it_IT |
