Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease
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Maria M. Simile1,*, Gavinella Latte1,*, Maria I. Demartis1, Stefania Brozzetti2, Diego F. Calvisi1, Alberto Porcu3, Claudio F. Feo3, Maria A. Seddaiu1, Lucia Daino1, Carmen Berasain4,5,6, Maria L. Tomasi7,8, Matias A. Avila4,5,6, Francesco Feo1, Rosa M. Pascale1
1Department of Clinical and Experimental Medicine, Division of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy
2Department of Surgery ‘‘Pietro Valdoni’’, University of Rome ‘Sapienza’’, Rome, Italy
3Department of Clinical and Experimental Medicine, Division of Surgery, University of Sassari, Sassari, Italy
4Division of Hepatology, Centro de Investigación Médica Aplicada (CIMA), University of Navarra, Pamplona, Spain
5CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
6IDISNA, Navarra Institute for Health Research, Pamplona, Spain
7Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
8USC Research Center for Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA
*These authors contributed equally to this work
Rosa M. Pascale, email: [email protected]
Keywords: hepatocarcinogenesis, stem cells, progression, gene expression profile, YAP targets
Received: March 03, 2016 Accepted: May 05, 2016 Published: June 23, 2016
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.
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