title: Regulation and function of the atypical cadherin FAT1 in hepatocellular carcinoma.
abstract: In human cancers, giant cadherin FAT1 may function both, as an oncogene and a tumor suppressor. Here, we investigated the expression and function of FAT1 in hepatocellular carcinoma (HCC). FAT1 expression was increased in human HCC cell lines and tissues compared with primary human hepatocytes and non-tumorous liver tissue as assessed by quantitative PCR and western blot analysis. Combined immunohistochemical and tissue microarray analysis showed a significant correlation of FAT1 expression with tumor stage and proliferation. Suppression of FAT1 expression by short hairpin RNA impaired proliferation and migration as well as apoptosis resistance of HCC cells in vitro. In nude mice, tumors formed by FAT1-suppressed HCC cells showed a delayed onset and more apoptosis compared with tumors of control cells. Both hepatocyte growth factor and hypoxia-mediated hypoxia-inducible factor 1 alpha activation were identified as strong inducers of FAT1 in HCC. Moreover, demethylating agents induced FAT1 expression in HCC cells. Hypoxia lead to reduced levels of the methyl group donor S-adenosyl-L-methionine (SAM) and hypoxia-induced FAT1 expression was inhibited by SAM supplementation in HCC cells. Together, these findings indicate that FAT1 expression in HCC is regulated via promotor methylation. FAT1 appears as relevant mediator of hypoxia and growth receptor signaling to critical tumorigenic pathways in HCC. This knowledge may facilitate the rational design of novel therapeutics against this highly aggressive malignancy.
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, 93053 Regensburg, Germany, Institute of Pharmacy, University of Regensburg, 93053 Regensburg, Germany, Institute of Surgical Pathology, University Hospital Zurich, 8091 Zurich, Switzerland, Institute of Pathology, University Hospital Erlangen, 91054 Erlangen, Germany, Department of Pediatrics and Juvenile Medicine, University Hospital Regensburg, 93053 Regensburg, Germany and Institute of Functional Genomics and Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Valletta
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, 93053 Regensburg, Germany, Institute of Pharmacy, University of Regensburg, 93053 Regensburg, Germany, Institute of Surgical Pathology, University Hospital Zurich, 8091 Zurich, Switzerland, Institute of Pathology, University Hospital Erlangen, 91054 Erlangen, Germany, Department of Pediatrics and Juvenile Medicine, University Hospital Regensburg, 93053 Regensburg, Germany and Institute of Functional Genomics and Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Czech
authors.affiliation: Institute of Pharmacy, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Thilo
authors.initials: T
authors.lastname: Spruss
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Kristian
authors.initials: K
authors.lastname: Ikenberg
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Wild
authors.affiliation: Institute of Pathology, University Hospital Erlangen, 91054 Erlangen, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.affiliation: Department of Pediatrics and Juvenile Medicine, University Hospital Regensburg, 93053 Regensburg, Germany and.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Weiss
authors.affiliation: Institute of Functional Genomics and.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Oefner
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, 93053 Regensburg, Germany, Institute of Pharmacy, University of Regensburg, 93053 Regensburg, Germany, Institute of Surgical Pathology, University Hospital Zurich, 8091 Zurich, Switzerland, Institute of Pathology, University Hospital Erlangen, 91054 Erlangen, Germany, Department of Pediatrics and Juvenile Medicine, University Hospital Regensburg, 93053 Regensburg, Germany and Institute of Functional Genomics and Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Müller
authors.affiliation: Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Anja-Katrin
authors.initials: AK
authors.lastname: Bosserhoff
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, 93053 Regensburg, Germany, Institute of Pharmacy, University of Regensburg, 93053 Regensburg, Germany, Institute of Surgical Pathology, University Hospital Zurich, 8091 Zurich, Switzerland, Institute of Pathology, University Hospital Erlangen, 91054 Erlangen, Germany, Department of Pediatrics and Juvenile Medicine, University Hospital Regensburg, 93053 Regensburg, Germany and Institute of Functional Genomics and Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany claus.hellerbrand@ukr.de.
authors.forename: Claus
authors.initials: C
authors.lastname: Hellerbrand
mesh_terms: D000328:Adult; D000368:Aged; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D047368:Tumor Burden
chemical_list: D015820:Cadherins; C502403:FAT1 protein, human