Visit our Expo - Redox and Inflammation signaling 2012

Session II : Receptor signaling and G proteins Poster II, 50
Aberrant activation of Wnt/#-catenin pathway in esophageal squamous cell carcinoma
(ESCC): evidence of FRAT1 overexpression
Yihua Wang1, Shuang Liu1, Wei Zhang1, Hongxia Zhu1, Xiaobo Zhou1, Cuiqi Zhou1,
Guo Zhang1, Lanping Quan1, Jinfeng Bai1, Liyan Xue2, Ning Lu2 and Ningzhi Xu1
1Laboratory of Cell and Molecular Biology; 2Department of Pathology; Cancer
Institute & Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union
Medical College, Beijing 100021, China. E-mail: xningzhi@public.bta.net.cn
Esophageal squamous cell carcinoma (ESCC) ranks among one of the most frequent cause of
cancer death in the world. Despite recent advances in therapy and management, esophageal
cancer remains a killer. Therefore, new therapies based on a better understanding of the
biology of esophageal cancer are most required. Recently, accumulation of nuclear and
cytoplasmic #-catenin has been observed in ESCC. However, mechanisms underlying this
phenomenon remain unknown. Frequently rearranged in advanced T-cell lymphomas-1
(FRAT1), strikingly overexpressed in some human esophageal cancer cell lines, is a positive
regulator of the Wnt/#-catenin pathway. Whereas FRAT1 is a regulator of cytoplamsic #catenin,
little is known with regard to the molecular relationship between FRAT1 and #catenin
in human cancers, including ESCC.
In this study, FRAT1 cDNA was cloned and transfected into human ESCC cells. The effects
of FRAT1 overexpression on cellular growth and transcriptional activity of #-catenin/T-cell
factor (TCF) were analyzed. RNA interference (RNAi) was also used to determine the
functions of FRAT1. In situ hybridization and immunohistochemical analysis were performed
to identify the level of FRAT1 mRNA expression and localization of #-catenin in surgical
specimens of ESCC respectively.
We observe that FRAT1 is overexpressed in ESCC and speculate that aberrant activation of
Wnt/#-catenin pathway in esophageal cancer appears to be due to upstream events such as
FRAT1 overexpression. Analysis of freshly resected ESCC specimens showed that FRAT1
was overexpressed in approximately 74% of tumor samples compared to matched normal
ones. We found that overexpression of FRAT1 in ESCC cell line KYSE150 significantly
promoted cell growth, whereas suppression of FRAT1 level by RNAi markedly inhibited
growth of esophageal tumor cells. 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 GSK3# or &NTCF4. Furthermore, aberrant
expression of #-catenin was correlated with FRAT1 overexpression in primary human ESCC.
Taken together, our data support the novel hypothesis that FRAT1 overexpression is critical
to Wnt/#-catenin pathway activation in ESCC. These findings identify components of Wnt/#catenin
pathway, such as FRAT1 overexpression, as possible therapeutic targets for the
development of novel molecular treatments for human esophageal cancer.
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