title: SMAD4 exerts a tumor-promoting role in hepatocellular carcinoma.
abstract: Further understanding of the molecular biology and pathogenesis of hepatocellular carcinoma (HCC) is crucial for future therapeutic development. SMAD4, recognized as an important tumor suppressor, is a central mediator of transforming growth factor beta (TGFB) and bone morphogenetic protein (BMP) signaling. This study investigated the role of SMAD4 in HCC. Nuclear localization of SMAD4 was observed in a cohort of 140 HCC patients using tissue microarray. HCC cell lines were used for functional assay in vitro and in immune-deficient mice. Nuclear SMAD4 levels were significantly increased in patient HCC tumors as compared with adjacent tissues. Knockdown of SMAD4 significantly reduced the efficiency of colony formation and migratory capacity of HCC cells in vitro and was incompatible with HCC tumor initiation and growth in mice. Knockdown of SMAD4 partially conferred resistance to the anti-growth effects of BMP ligand in HCC cells. Importantly, simultaneous elevation of SMAD4 and phosphorylated SMAD2/3 is significantly associated with poor patient outcome after surgery. Although high levels of SMAD4 can also mediate an antitumor function by coupling with phosphorylated SMAD1/5/8, this signaling, however, is absent in majority of our HCC patients. In conclusion, this study revealed a highly non-canonical tumor-promoting function of SMAD4 in HCC. The drastic elevation of nuclear SMAD4 in sub-population of HCC tumors highlights its potential as an outcome predictor for patient stratification and a target for personalized therapeutic development.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.|Laboratory of Medical Genetics, Biomolecular Research Centre, Wijaya Kusuma University, Surabaya, Indonesia.
authors.forename: P Y
authors.initials: PY
authors.lastname: Hernanda
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.|Bio-X Center, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China.
authors.forename: K
authors.initials: K
authors.lastname: Chen
authors.affiliation: Laboratory of Experimental Surgical Oncology Section Surgical Oncology, Department of Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: A M
authors.initials: AM
authors.lastname: Das
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Sideras
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
authors.forename: W
authors.initials: W
authors.lastname: Cao
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
authors.forename: S J A
authors.initials: SJ
authors.lastname: Bots
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
authors.forename: L L
authors.initials: LL
authors.lastname: Kodach
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
authors.forename: R A
authors.initials: RA
authors.lastname: de Man
authors.affiliation: Department of Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: J N M
authors.initials: JN
authors.lastname: Ijzermans
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.|Division of Gastroenterology, University Health Network, Toronto, Ontario, Canada.
authors.forename: H L A
authors.initials: HL
authors.lastname: Janssen
authors.affiliation: Department of Bioinformatics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: A P
authors.initials: AP
authors.lastname: Stubbs
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: Sprengers
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
authors.forename: M J
authors.initials: MJ
authors.lastname: Bruno
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
authors.forename: H J
authors.initials: HJ
authors.lastname: Metselaar
authors.affiliation: Laboratory of Experimental Surgical Oncology Section Surgical Oncology, Department of Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: T L M
authors.initials: TL
authors.lastname: ten Hagen
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Kwekkeboom
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
authors.forename: M P
authors.initials: MP
authors.lastname: Peppelenbosch
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
authors.forename: Q
authors.initials: Q
authors.lastname: Pan
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D051379:Mice; D010766:Phosphorylation; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D051901:Smad4 Protein / Q000235:genetics / Q000502:physiology*
chemical_list: C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein