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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

© 2016 Okabe et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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: 26 Jan 2019 10:55
URI: http://d-scholarship.pitt.edu/id/eprint/28267

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