First name
Valentina
Last name
Buttiglione
Year of Study
Research Center
Thesis Title
The role of miR-340 in post-transcriptional regulation of the uPA-system in breast cancer
Thesis Abstract
The urokinase-type plasminogen activator system (uPA-system), whose main components are the
serine protease uPA (PLAU), the cell surface receptor uPAR (PLAUR) and the uPA inhibitor PAI-1
(SERPINE1), has been extensively studied for its involvement in cancer pathogenesis. Specifically,
nowadays the components of the uPA-system are well-characterised determinants for the prognosis
of breast cancer. The regulation of the gene expression of the uPA-system components is very
complex and depends on a plethora of stimuli acting both at transcriptional and post-transcriptional
level. The uPA-system components are often over expressed in breast cancer but the detailed
molecular mechanisms regulating the expression are still to uncover. In an expression analysis
conducted on a cohort of unselected breast cancer patients, we found that the expression of PLAU
and PLAUR is highly correlated. Meta-analyses of published experimental data and in silico studies
pointed out the possibility that PLAU, PLAUR and also SERPINE1 might be negatively regulated at
post-transcriptional level by a microRNA, the miR-340. We experimentally validated the role of
miR-340 as negative regulator of the expression of the three uPA-system components using MDAMB-
231, a triple negative breast cancer cell line. Microarray experiments, performed to characterise
the global transcriptome changes induced by miR-340 in MDA-MB-231 cells, showed that miR-
340 down regulates also the expression of desmoplastic reaction-related genes underlining a
possible role of miR-340 in regulating tumour-associated genes. Notably, most of the identified
miR-340 target genes were found indeed to be associated with poor clinical outcome in breast
cancer. Functional studies carried out in MDA-MB-231 cells suggested that miR-340 might
modulate cell proliferation, even if this effect was not confirmed in vivo. In order to better define
the functional role of miR-340, we generated a miR-340 deficient mouse model, taken advantage of
the zinc finger nuclease technology. Overall these data identify, for the first time, a single
microRNA that is able to down regulate the expression of the three main components of the uPAsystem
together with desmoplastic reaction and breast cancer prognosis-related genes, thus
representing a new potential player in the pathogenesis of breast cancer.
serine protease uPA (PLAU), the cell surface receptor uPAR (PLAUR) and the uPA inhibitor PAI-1
(SERPINE1), has been extensively studied for its involvement in cancer pathogenesis. Specifically,
nowadays the components of the uPA-system are well-characterised determinants for the prognosis
of breast cancer. The regulation of the gene expression of the uPA-system components is very
complex and depends on a plethora of stimuli acting both at transcriptional and post-transcriptional
level. The uPA-system components are often over expressed in breast cancer but the detailed
molecular mechanisms regulating the expression are still to uncover. In an expression analysis
conducted on a cohort of unselected breast cancer patients, we found that the expression of PLAU
and PLAUR is highly correlated. Meta-analyses of published experimental data and in silico studies
pointed out the possibility that PLAU, PLAUR and also SERPINE1 might be negatively regulated at
post-transcriptional level by a microRNA, the miR-340. We experimentally validated the role of
miR-340 as negative regulator of the expression of the three uPA-system components using MDAMB-
231, a triple negative breast cancer cell line. Microarray experiments, performed to characterise
the global transcriptome changes induced by miR-340 in MDA-MB-231 cells, showed that miR-
340 down regulates also the expression of desmoplastic reaction-related genes underlining a
possible role of miR-340 in regulating tumour-associated genes. Notably, most of the identified
miR-340 target genes were found indeed to be associated with poor clinical outcome in breast
cancer. Functional studies carried out in MDA-MB-231 cells suggested that miR-340 might
modulate cell proliferation, even if this effect was not confirmed in vivo. In order to better define
the functional role of miR-340, we generated a miR-340 deficient mouse model, taken advantage of
the zinc finger nuclease technology. Overall these data identify, for the first time, a single
microRNA that is able to down regulate the expression of the three main components of the uPAsystem
together with desmoplastic reaction and breast cancer prognosis-related genes, thus
representing a new potential player in the pathogenesis of breast cancer.
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