Canonical Wnt signaling is antagonized by noncanonical Wnt5a in hepatocellular carcinoma cells

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  • Yuzugullu, Haluk
    • Other Affiliation: Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800, Ankara, Turkey; Centre de Recherche INSERM-Université Joseph Fourrier U823, Institut Albert Bonniot, 38706 La Tronche Cedex, France
  • Benhaj, Khemais
    • Other Affiliation: Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800, Ankara, Turkey; >Centre de Biotechnologie de Sfax, B.P "1177", 3038 Sfax, Tunisia
  • Ozturk, Nuri
    • Other Affiliation: Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800, Ankara, Turkey
  • Senturk, Serif
    • Other Affiliation: Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800, Ankara, Turkey
  • Celik, Emine
    • Other Affiliation: Department of Medical Biology and Genetics, Dokuz Eylul University School of Medicine, Izmir, 35340 Turkey
  • Toylu, Asli
    • Other Affiliation: Department of Medical Biology and Genetics, Dokuz Eylul University School of Medicine, Izmir, 35340 Turkey
  • Tasdemir, Nilgun
    • Other Affiliation: Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800, Ankara, Turkey
  • Yilmaz, Mustafa
    • Other Affiliation: Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800, Ankara, Turkey
  • Erdal, Esra
    • Other Affiliation: Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800, Ankara, Turkey; Department of Medical Biology and Genetics, Dokuz Eylul University School of Medicine, Izmir, 35340 Turkey
  • Akcali, Kamil
    • Other Affiliation: Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800, Ankara, Turkey
  • Atabey, Nese
    • Other Affiliation: Department of Medical Biology and Genetics, Faculty of Science, Bilkent University, 06800, Ankara, Turkey
  • Ozturk, Mehmet
    • Other Affiliation: Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800, Ankara, Turkey; Centre de Recherche INSERM-Université Joseph Fourrier U823, Institut Albert Bonniot, 38706 La Tronche Cedex, France
Abstract
  • Abstract: Background: β-catenin mutations that constitutively activate the canonical Wnt signaling have been observed in a subset of hepatocellular carcinomas (HCCs). These mutations are associated with chromosomal stability, low histological grade, low tumor invasion and better patient survival. We hypothesized that canonical Wnt signaling is selectively activated in well-differentiated, but repressed in poorly differentiated HCCs. To this aim, we characterized differentiation status of HCC cell lines and compared their expression status of Wnt pathway genes, and explored their activity of canonical Wnt signaling. Results: We classified human HCC cell lines into "well-differentiated" and "poorly differentiated" subtypes, based on the expression of hepatocyte lineage, epithelial and mesenchymal markers. Poorly differentiated cell lines lost epithelial and hepatocyte lineage markers, and overexpressed mesenchymal markers. Also, they were highly motile and invasive. We compared the expression of 45 Wnt pathway genes between two subtypes. TCF1 and TCF4 factors, and LRP5 and LRP6 co-receptors were ubiquitously expressed. Likewise, six Frizzled receptors, and canonical Wnt3 ligand were expressed in both subtypes. In contrast, canonical ligand Wnt8b and noncanonical ligands Wnt4, Wnt5a, Wnt5b and Wnt7b were expressed selectively in well- and poorly differentiated cell lines, respectively. Canonical Wnt signaling activity, as tested by a TCF reporter assay was detected in 80% of well-differentiated, contrary to 14% of poorly differentiated cell lines. TCF activity generated by ectopic mutant β-catenin was weak in poorly differentiated SNU449 cell line, suggesting a repressive mechanism. We tested Wnt5a as a candidate antagonist. It strongly inhibited canonical Wnt signaling that is activated by mutant β-catenin in HCC cell lines. Conclusion: Differential expression of Wnt ligands in HCC cells is associated with selective activation of canonical Wnt signaling in well-differentiated, and its repression in poorly differentiated cell lines. One potential mechanism of repression involved Wnt5a, acting as an antagonist of canonical Wnt signaling. Our observations support the hypothesis that Wnt pathway is selectively activated or repressed depending on differentiation status of HCC cells. We propose that canonical and noncanonical Wnt pathways have complementary roles in HCC, where the canonical signaling contributes to tumor initiation, and noncanonical signaling to tumor progression.
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DOI
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Resource type
  • Article
Rights statement
  • In Copyright
Rights holder
  • Haluk Yuzugullu et al.; licensee BioMed Central Ltd.
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Journal title
  • Molecular Cancer
Journal volume
  • 8
Journal issue
  • 1
Page start
  • 90
Language
  • English
Is the article or chapter peer-reviewed?
  • Yes
ISSN
  • 1476-4598
Bibliographic citation
  • Molecular Cancer. 2009 Oct 22;8(1):90
Publisher
  • BioMed Central Ltd
Access right
  • Open Access
Date uploaded
  • August 23, 2012

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