FRAT1 overexpression leads to aberrant activation of ?-catenin/TCF pathway in esophageal squamous cell carcinoma
FRAT1 overexpression leads to aberrant activation of ?-catenin/TCF pathway in esophageal squamous cell carcinoma
Esophageal squamous cell carcinoma (ESCC) is an aggressive tumor with a poor prognosis. Although aberrant activation of ?-catenin/T-cell factor (TCF) pathway has been observed in ESCC, mechanisms underlying this phenomenon remain unknown. Frequently rearranged in advanced T-cell lymphomas-1 (FRAT1), overexpressed in some ESCC lines, is a positive regulator of ?-catenin/TCF pathway. However, little is known about the molecular relationship between FRAT1 and ?-catenin/TCF in ESCC. In this study, we analyzed freshly resected ESCC specimens and demonstrated that FRAT1 was overexpressed in approximately 74% of tumor samples compared with matched normal tissue. Overexpression of FRAT1 significantly promoted esophageal cancer cells growth, whereas suppression of FRAT1 level by RNAi markedly inhibited their growth. In addition, FRAT1 overexpression induced the nuclear accumulation of ?-catenin and promoted the transcriptional activity of ?-catenin/TCF. These effects were reversed by coexpression of GSK 3? or ?N TCF4. Furthermore, accumulation of ?-catenin was correlated with FRAT1 overexpression in ESCC and the basal layer of normal esophageal epithelium. Finally, continued expression of c-Myc is necessary and sufficient for maintenance of the growth state in cells expressing FRAT1. Taken together, these results support the novel hypothesis that aberrant activation of ?-catenin/TCF pathway in esophageal cancer appears to be due to upstream events such as FRAT1 overexpression, and c-Myc may be an important element in oncogenesis of human ESCC induced by FRAT1.
FRAT1, ESCC, ?-catenin, c-Myc, overexpression
561-568
Wang, Yihua
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Liu, Shuang
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Zhu, Hongxia
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Zhang, Wei
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Zhang, Guo
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Zhou, Xiaobo
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Zhou, Cuiqi
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Quan, Lanping
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Bai, Jinfeng
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Xue, Liyan
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Lu, Ning
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Xu, Ningzhi
7e2ddae3-ef56-4e9e-9ccb-4fddbcdf045f
1 August 2008
Wang, Yihua
f5044a95-60a7-42d2-87d6-5f1f789e3a7e
Liu, Shuang
f136b833-cd10-476d-80e2-8e8c69ee69bc
Zhu, Hongxia
34c74461-aab8-4886-8ed4-f80438fa2083
Zhang, Wei
fa6d7061-bfce-48c0-879c-925302213c1a
Zhang, Guo
7bce7bd5-04a3-48ac-8330-6f3521fab734
Zhou, Xiaobo
0deca180-bc8a-42d6-b6a6-237e04cae0e1
Zhou, Cuiqi
a79cddd5-12f5-41fd-af17-f553062f6d70
Quan, Lanping
75ae7877-e353-41d9-ba4b-c3ad47e5a69c
Bai, Jinfeng
66033867-936e-4551-96db-61c624e804f1
Xue, Liyan
d396faa2-726e-4672-aec4-7f56d9e186b0
Lu, Ning
8d60125f-c459-4a0e-8d87-c8e0123d40a5
Xu, Ningzhi
7e2ddae3-ef56-4e9e-9ccb-4fddbcdf045f
Wang, Yihua, Liu, Shuang, Zhu, Hongxia, Zhang, Wei, Zhang, Guo, Zhou, Xiaobo, Zhou, Cuiqi, Quan, Lanping, Bai, Jinfeng, Xue, Liyan, Lu, Ning and Xu, Ningzhi
(2008)
FRAT1 overexpression leads to aberrant activation of ?-catenin/TCF pathway in esophageal squamous cell carcinoma.
International Journal of Cancer, 123 (3), .
(doi:10.1002/ijc.23600).
(PMID:18498136)
Abstract
Esophageal squamous cell carcinoma (ESCC) is an aggressive tumor with a poor prognosis. Although aberrant activation of ?-catenin/T-cell factor (TCF) pathway has been observed in ESCC, mechanisms underlying this phenomenon remain unknown. Frequently rearranged in advanced T-cell lymphomas-1 (FRAT1), overexpressed in some ESCC lines, is a positive regulator of ?-catenin/TCF pathway. However, little is known about the molecular relationship between FRAT1 and ?-catenin/TCF in ESCC. In this study, we analyzed freshly resected ESCC specimens and demonstrated that FRAT1 was overexpressed in approximately 74% of tumor samples compared with matched normal tissue. Overexpression of FRAT1 significantly promoted esophageal cancer cells growth, whereas suppression of FRAT1 level by RNAi markedly inhibited their growth. In addition, FRAT1 overexpression induced the nuclear accumulation of ?-catenin and promoted the transcriptional activity of ?-catenin/TCF. These effects were reversed by coexpression of GSK 3? or ?N TCF4. Furthermore, accumulation of ?-catenin was correlated with FRAT1 overexpression in ESCC and the basal layer of normal esophageal epithelium. Finally, continued expression of c-Myc is necessary and sufficient for maintenance of the growth state in cells expressing FRAT1. Taken together, these results support the novel hypothesis that aberrant activation of ?-catenin/TCF pathway in esophageal cancer appears to be due to upstream events such as FRAT1 overexpression, and c-Myc may be an important element in oncogenesis of human ESCC induced by FRAT1.
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Accepted/In Press date: 3 March 2008
e-pub ahead of print date: 3 May 2008
Published date: 1 August 2008
Keywords:
FRAT1, ESCC, ?-catenin, c-Myc, overexpression
Organisations:
Centre for Biological Sciences
Identifiers
Local EPrints ID: 385912
URI: http://eprints.soton.ac.uk/id/eprint/385912
ISSN: 0020-7136
PURE UUID: 9b7baeb8-7421-4d46-9760-8f85c19eeba1
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Date deposited: 26 Jan 2016 10:16
Last modified: 15 Mar 2024 03:52
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Author:
Shuang Liu
Author:
Hongxia Zhu
Author:
Wei Zhang
Author:
Guo Zhang
Author:
Xiaobo Zhou
Author:
Cuiqi Zhou
Author:
Lanping Quan
Author:
Jinfeng Bai
Author:
Liyan Xue
Author:
Ning Lu
Author:
Ningzhi Xu
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