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).
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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Item Type: |
Article
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Status: |
Published |
Creators/Authors: |
Creators | Email | Pitt Username | ORCID  |
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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, SPS | smonga@pitt.edu | SMONGA | | Baba, H | | | | Maehara, Y | | | |
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Contributors: |
Contribution | Contributors Name | Email | Pitt Username | ORCID  |
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Editor | Calvisi, Diego | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED |
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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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