FRAT1 overexpression leads to aberrant activation of beta-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 beta-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 beta-catenin/TCF pathway. However, little is known about the molecular relationship between FRAT1 and beta-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 beta-catenin and promoted the transcriptional activity of beta-catenin/TCF. These effects were reversed by coexpression of GSK 3beta or DeltaN TCF4. Furthermore, accumulation of beta-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 beta-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.
Wang
Yihua
Y
Laboratory of Cell and Molecular Biology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
Liu
Shuang
S
Zhu
Hongxia
H
Zhang
Wei
W
Zhang
Guo
G
Zhou
Xiaobo
X
Zhou
Cuiqi
C
Quan
Lanping
L
Bai
Jinfeng
J
Xue
Liyan
L
Lu
Ning
N
Xu
Ningzhi
N
D048868:Adaptor Proteins, Signal Transducing; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D010957:Plasmids; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation; D051176:beta Catenin / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C491819:FRAT1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C116115:MYCBP protein, human; D011518:Proto-Oncogene Proteins; D051820:TCF Transcription Factors; D014157:Transcription Factors; D051176:beta Catenin