7 research outputs found
Genetic mouse models as in vivo tools for cholangiocarcinoma research
Cholangiocarcinoma (CCA) is a genetically and histologically complex disease with
a highly dismal prognosis. A deeper understanding of the underlying cellular and molecular
mechanisms of human CCA will increase our current knowledge of the disease and expedite
the eventual development of novel therapeutic strategies for this fatal cancer. This endeavor is
effectively supported by genetic mouse models, which serve as sophisticated tools to systematically
investigate CCA pathobiology and treatment response. These in vivo models feature many of the
genetic alterations found in humans, recapitulate multiple hallmarks of cholangiocarcinogenesis
(encompassing cell transformation, preneoplastic lesions, established tumors and metastatic disease)
and provide an ideal experimental setting to study the interplay between tumor cells and the
surrounding stroma. This review is intended to serve as a compendium of CCA mouse models,
including traditional transgenic models but also genetically flexible approaches based on either the
direct introduction of DNA into liver cells or transplantation of pre-malignant cells, and is meant as a
resource for CCA researchers to aid in the selection of the most appropriate in vivo model system
Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease
Previous studies showed that YAP1 is over-expressed in hepatocellular carcinoma
(HCC). Here we observed higher expression of Yap1/Ctgf axis in dysplastic nodules and
HCC chemically-induced in F344 rats, genetically susceptible to hepatocarcinogenesis,
than in lesions induced in resistant BN rats. In BN rats, highest increase in Yap1-
tyr357, p73 phosphorylation and Caspase 3 cleavage occurred. In human HCCs with
poorer prognosis (< 3 years survival after partial liver resection, HCCP), levels of
YAP1, CTGF, 14–3–3, and TEAD proteins, and YAP1-14-3-3 and YAP1-TEAD complexes
were higher than in HCCs with better outcome (> 3 years survival; HCCB). In the
latter, higher levels of phosphorylated YAP1-ser127, YAP1-tyr357 and p73, YAP1
ubiquitination, and Caspase 3 cleavage occurred. Expression of stemness markers
NANOG, OCT-3/4, and CD133 were highest in HCCP and correlated with YAP1 and
YAP1-TEAD levels. In HepG2, Huh7, and Hep3B cells, forced YAP1 over-expression
led to stem cell markers expression and increased cell viability, whereas inhibition
of YAP1 expression by specific siRNA, or transfection of mutant YAP1 which does
not bind to TEAD, induced opposite alterations. These changes were associated, in
Huh7 cells transfected with YAP1 or YAP1 siRNA, with stimulation or inhibition of cell
migration and invasivity, respectively. Furthermore, transcriptome analysis showed
that YAP1 transfection in Huh7 cells induces over-expression of genes involved
in tumor stemness. In conclusion, Yap1 post-translational modifications favoring
its ubiquitination and apoptosis characterize HCC with better prognosis, whereas
conditions favoring the formation of YAP1-TEAD complexes are associated with
aggressiveness and acquisition of stemness features by HCC cells
FOSL1 promotes cholangiocarcinoma via transcriptional effectors that could be therapeutically targeted
Understanding the molecular mechanisms involved in cholangiocarcinoma (bile duct cancer) development and progression stands as a critical step for the development of novel therapies. Through an inter-species approach, this study provides evidence of the clinical and functional role of the transcription factor FOSL1 in cholangiocarcinoma. Moreover, we report that downstream effectors of FOSL1 are susceptible to pharmacological inhibition, thus providing new opportunities for therapeutic intervention
Genetic mouse models as in vivo tools for cholangiocarcinoma research
Cholangiocarcinoma (CCA) is a genetically and histologically complex disease with
a highly dismal prognosis. A deeper understanding of the underlying cellular and molecular
mechanisms of human CCA will increase our current knowledge of the disease and expedite
the eventual development of novel therapeutic strategies for this fatal cancer. This endeavor is
effectively supported by genetic mouse models, which serve as sophisticated tools to systematically
investigate CCA pathobiology and treatment response. These in vivo models feature many of the
genetic alterations found in humans, recapitulate multiple hallmarks of cholangiocarcinogenesis
(encompassing cell transformation, preneoplastic lesions, established tumors and metastatic disease)
and provide an ideal experimental setting to study the interplay between tumor cells and the
surrounding stroma. This review is intended to serve as a compendium of CCA mouse models,
including traditional transgenic models but also genetically flexible approaches based on either the
direct introduction of DNA into liver cells or transplantation of pre-malignant cells, and is meant as a
resource for CCA researchers to aid in the selection of the most appropriate in vivo model system
Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease
Previous studies showed that YAP1 is over-expressed in hepatocellular carcinoma
(HCC). Here we observed higher expression of Yap1/Ctgf axis in dysplastic nodules and
HCC chemically-induced in F344 rats, genetically susceptible to hepatocarcinogenesis,
than in lesions induced in resistant BN rats. In BN rats, highest increase in Yap1-
tyr357, p73 phosphorylation and Caspase 3 cleavage occurred. In human HCCs with
poorer prognosis (< 3 years survival after partial liver resection, HCCP), levels of
YAP1, CTGF, 14–3–3, and TEAD proteins, and YAP1-14-3-3 and YAP1-TEAD complexes
were higher than in HCCs with better outcome (> 3 years survival; HCCB). In the
latter, higher levels of phosphorylated YAP1-ser127, YAP1-tyr357 and p73, YAP1
ubiquitination, and Caspase 3 cleavage occurred. Expression of stemness markers
NANOG, OCT-3/4, and CD133 were highest in HCCP and correlated with YAP1 and
YAP1-TEAD levels. In HepG2, Huh7, and Hep3B cells, forced YAP1 over-expression
led to stem cell markers expression and increased cell viability, whereas inhibition
of YAP1 expression by specific siRNA, or transfection of mutant YAP1 which does
not bind to TEAD, induced opposite alterations. These changes were associated, in
Huh7 cells transfected with YAP1 or YAP1 siRNA, with stimulation or inhibition of cell
migration and invasivity, respectively. Furthermore, transcriptome analysis showed
that YAP1 transfection in Huh7 cells induces over-expression of genes involved
in tumor stemness. In conclusion, Yap1 post-translational modifications favoring
its ubiquitination and apoptosis characterize HCC with better prognosis, whereas
conditions favoring the formation of YAP1-TEAD complexes are associated with
aggressiveness and acquisition of stemness features by HCC cells
FOSL1 promotes cholangiocarcinoma via transcriptional effectors that could be therapeutically targeted
Understanding the molecular mechanisms involved in cholangiocarcinoma (bile duct cancer) development and progression stands as a critical step for the development of novel therapies. Through an inter-species approach, this study provides evidence of the clinical and functional role of the transcription factor FOSL1 in cholangiocarcinoma. Moreover, we report that downstream effectors of FOSL1 are susceptible to pharmacological inhibition, thus providing new opportunities for therapeutic intervention
SUMOylation regulates LKB1 localization and its oncogenic activity in liver cancer
Background: Even though liver kinase B1 (LKB1) is usually described as a tumor suppressor in a wide variety of
tissues, it has been shown that LKB1 aberrant expression is associated with bad prognosis in Hepatocellular
Carcinoma (HCC).
Methods: Herein we have overexpressed LKB1 in human hepatoma cells and by using histidine pull-down assay
we have investigated the role of the hypoxia-related post-translational modification of Small Ubiquitin-related
Modifier (SUMO)ylation in the regulation of LKB1 oncogenic role. Molecular modelling between LKB1 and its
interactors, involved in regulation of LKB1 nucleocytoplasmic shuttling and LKB1 activity, was performed. Finally,
high affinity SUMO binding entities-based technology were used to validate our findings in a pre-clinical mouse
model and in clinical HCC.
Findings: We found that in human hepatoma cells under hypoxic stress, LKB1 overexpression increases cell viability and aggressiveness in association with changes in LKB1 cellular localization. Moreover, by using sitedirected mutagenesis, we have shown that LKB1 is SUMOylated by SUMO-2 at Lys178 hampering LKB1
nucleocytoplasmic shuttling and fueling hepatoma cell growth. Molecular modelling of SUMO modified LKB1 further confirmed steric impedance between SUMOylated LKB1 and the STe20-Related ADaptor cofactor (STRADα),
involved in LKB1 export from the nucleus. Finally, we provide evidence that endogenous LKB1 is modified by
SUMO in pre-clinical mouse models of HCC and clinical HCC, where LKB1 SUMOylation is higher in fast growing
tumors.
Interpretation: Overall, SUMO-2 modification of LKB1 at Lys178 mediates LKB1 cellular localization and its oncogenic role in liver cancer