3 research outputs found
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, 14â3â3, 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
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, 14â3â3, 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
Stoma-free survival after anastomotic leak following rectal cancer resection: worldwide cohort of 2470 patients
Background: The optimal treatment of anastomotic leak after rectal cancer resection is unclear. This worldwide cohort study aimed to provide an overview of four treatment strategies applied. Methods: Patients from 216 centres and 45 countries with anastomotic leak after rectal cancer resection between 2014 and 2018 were included. Treatment was categorized as salvage surgery, faecal diversion with passive or active (vacuum) drainage, and no primary/secondary faecal diversion. The primary outcome was 1-year stoma-free survival. In addition, passive and active drainage were compared using propensity score matching (2: 1). Results: Of 2470 evaluable patients, 388 (16.0 per cent) underwent salvage surgery, 1524 (62.0 per cent) passive drainage, 278 (11.0 per cent) active drainage, and 280 (11.0 per cent) had no faecal diversion. One-year stoma-free survival rates were 13.7, 48.3, 48.2, and 65.4 per cent respectively. Propensity score matching resulted in 556 patients with passive and 278 with active drainage. There was no statistically significant difference between these groups in 1-year stoma-free survival (OR 0.95, 95 per cent c.i. 0.66 to 1.33), with a risk difference of -1.1 (95 per cent c.i. -9.0 to 7.0) per cent. After active drainage, more patients required secondary salvage surgery (OR 2.32, 1.49 to 3.59), prolonged hospital admission (an additional 6 (95 per cent c.i. 2 to 10) days), and ICU admission (OR 1.41, 1.02 to 1.94). Mean duration of leak healing did not differ significantly (an additional 12 (-28 to 52) days). Conclusion: Primary salvage surgery or omission of faecal diversion likely correspond to the most severe and least severe leaks respectively. In patients with diverted leaks, stoma-free survival did not differ statistically between passive and active drainage, although the increased risk of secondary salvage surgery and ICU admission suggests residual confounding