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:	Creators Email Pitt Username ORCID 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
Contributors:	Contribution Contributors Name Email Pitt Username ORCID Editor Calvisi, Diego UNSPECIFIED UNSPECIFIED UNSPECIFIED
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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