Diverse basis of β-catenin activation in human hepatocellular carcinoma: Implications in biology and prognosis

Hirohisa Okabe, Hiroki Kinoshita, Katsunori Imai, Shigeki Nakagawa, Takaaki Higashi, Kota Arima, Hideaki Uchiyama, Toru Ikegami, Norifumi Harimoto, Shinji Itoh, Takatoshi Ishiko, Tomoharu Yoshizumi, Toru Beppu, Satdarshan P.S. Monga, Hideo Baba, Yoshihiko Maehara

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Abstract

Aim: β-catenin signaling is a major oncogenic pathway in hepatocellular carcinoma (HCC). Since β-catenin phosphorylation by glycogen synthase kinase 3β (GSK3β) and casein kinase 1ϵ (CK1ϵ) results in its degradation, mutations affecting these phosphorylation sites cause β-catenin stabilization. However, the relevance of missense mutations in non-phosphorylation sites in exon 3 remains unclear. The current study explores significance of such mutations in addition to addressing the clinical and biological implications of β-catenin activation in human HCC. Methods: Gene alteration in exon3 of CTNNB1, gene expression of β-catenin targets such as glutamate synthetase (GS), axin2, lect2 and regucalcin (RGN), and protein expression of β-catenin were examined in 125 human HCC tissues. Results: Sixteen patients (12.8%) showed conventional missense mutations affecting codons 33, 37, 41, and 45. Fifteen additional patients (12.0%) had other missense mutations in codon 32, 34, and 35. Induction of exon3 mutation caused described β-catenin target gene upregulation in HCC cell line. Interestingly, conventional and non-phosphorylation site mutations were equally associated with upregulation of β-catenin target genes. Nuclear localization of β-catenin was associated with poor overall survival (p = 0.0461). Of these patients with nuclear β-catenin localization, loss of described β-catenin target gene upregulation showed significant poorer overall survival than others (p = 0.0001). Conclusion: This study suggests that both conventional and other missense mutations in exon 3 of CTNNB1 lead to β-catenin activation in human HCC. Additionally, the mechanism of nuclear β-catenin localization without upregulation of described β-catenin target genes might be of clinical importance depending on distinct mechanism.

Original languageEnglish
Article numbere0152695
JournalPloS one
Volume11
Issue number4
DOIs
Publication statusPublished - Apr 2016

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All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Okabe, H., Kinoshita, H., Imai, K., Nakagawa, S., Higashi, T., Arima, K., ... Maehara, Y. (2016). Diverse basis of β-catenin activation in human hepatocellular carcinoma: Implications in biology and prognosis. PloS one, 11(4), [e0152695]. https://doi.org/10.1371/journal.pone.0152695