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

Okabe, H and Kinoshita, H and Imai, K and Nakagawa, S and Higashi, T and Arima, K and Uchiyama, H and Ikegami, T and Harimoto, N and Itoh, S and Ishiko, T and Yoshizumi, T and Beppu, T and Monga, SPS and Baba, H and Maehara, Y (2016) Diverse basis of β-catenin activation in human hepatocellular carcinoma: Implications in biology and prognosis. PLoS ONE, 11 (4).

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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.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Okabe, H
Kinoshita, H
Imai, K
Nakagawa, S
Higashi, T
Arima, K
Uchiyama, H
Ikegami, T
Harimoto, N
Itoh, S
Ishiko, T
Yoshizumi, T
Beppu, T
Monga, SPSsmonga@pitt.eduSMONGA
Baba, H
Maehara, Y
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorCalvisi, DiegoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 1 April 2016
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS ONE
Volume: 11
Number: 4
DOI or Unique Handle: 10.1371/journal.pone.0152695
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Medicine
School of Medicine > Pathology
Refereed: Yes
Date Deposited: 31 Aug 2016 18:08
Last Modified: 03 Apr 2021 09:55
URI: http://d-scholarship.pitt.edu/id/eprint/28267

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