Premium
Wnt pathway is involved in pleomorphic adenomas induced by overexpression of PLAG1 in transgenic mice
Author(s) -
Zhao Xudong,
Ren Weihua,
Yang Wenjun,
Wang Yi,
Kong Hui,
Wang Long,
Yan Lanzhen,
Xu Guojiang,
Fei Jian,
Fu Jiliang,
Zhang Chenping,
Wang Zhugang
Publication year - 2005
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.21400
Subject(s) - wnt signaling pathway , salivary gland , pleomorphic adenoma , biology , carcinogenesis , genetically modified mouse , catenin , transgene , ectopic expression , transcription factor , cancer research , downregulation and upregulation , signal transduction , pathology , endocrinology , microbiology and biotechnology , gene , medicine , genetics , biochemistry
Pleomorphic adenoma gene 1 ( PLAG1 ) was found frequently rearranged and activated in human salivary gland pleomorphic adenomas. It encodes a developmentally regulated transcription factor. Ectopic overexpression of PLAG1 has been proposed to play a crucial role in tumorigenesis of salivary gland pleomorphic adenomas. It was reported that PLAG1 can activate the transcription of insulin‐like growth factor 2 ( IGF2 ), functioning as a protooncogene. In this report, we show that the salivary gland tumors developed in PLAG1 transgenic mice share major histopathologic features with human pleomorphic adenomas. It was found that β‐catenin, the key component of Wnt signaling pathway, was upregulated at transcriptional level in tumors developed in 3 independent transgenic mouse lines. Immunohistochemical staining revealed that expression of β‐catenin as well as c‐myc, downstream of β‐catenin in Wnt signaling pathway, was highly upregulated with overexpression of PLAG1 transgene in tumor and normal transgenic salivary gland tissues. Moreover, we found that PLAG1 can activate the transcription of mouse but not human β‐catenin in the 3T3 cells cotransfected with reporter constructs. Sequence analysis shows there are 4 PLAG1 consensus binding sites in mouse β‐catenin promoter region but not in human. Our findings provide the first in vivo evidence for the oncogenic activity of PLAG1 in pleomorphic adenoma tumorigenesis, reveal a valued animal model for human salivary gland tumors and suggest that Wnt signaling pathway may also contribute to the development of pleomorphic adenomas in transgenic mice. © 2005 Wiley‐Liss, Inc.