Premium
FRAT1 overexpression leads to aberrant activation of β‐catenin/TCF pathway in esophageal squamous cell carcinoma
Author(s) -
Wang Yihua,
Liu Shuang,
Zhu Hongxia,
Zhang Wei,
Zhang Guo,
Zhou Xiaobo,
Zhou Cuiqi,
Quan Lanping,
Bai Jinfeng,
Xue Liyan,
Lu Ning,
Xu Ningzhi
Publication year - 2008
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.23600
Subject(s) - cancer research , carcinogenesis , catenin , cell growth , beta catenin , biology , esophageal squamous cell carcinoma , cell , wnt signaling pathway , cancer , signal transduction , medicine , microbiology and biotechnology , genetics
Esophageal squamous cell carcinoma (ESCC) is an aggressive tumor with a poor prognosis. Although aberrant activation of β‐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 β‐catenin/TCF pathway. However, little is known about the molecular relationship between FRAT1 and β‐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 β‐catenin and promoted the transcriptional activity of β‐catenin/TCF. These effects were reversed by coexpression of GSK 3β or ΔN TCF4. Furthermore, accumulation of β‐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 β‐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. © 2008 Wiley‐Liss, Inc.