Wnt pathway is involved in pleomorphic adenomas induced by overexpression of PLAG1 in transgenic mice.
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 beta-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 beta-catenin as well as c-myc, downstream of beta-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 beta-catenin in the 3T3 cells cotransfected with reporter constructs. Sequence analysis shows there are 4 PLAG1 consensus binding sites in mouse beta-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.
Zhao
Xudong
X
Laboratory of Genetic Engineering, Department of Medical Genetics, Institute of Health Science, Shanghai Institutes for Biologic Sciences of Chinese Academy of Sciences and Shanghai Second Medical University, Shanghai, China.
Ren
Weihua
W
Yang
Wenjun
W
Wang
Yi
Y
Kong
Hui
H
Wang
Long
L
Yan
Lanzhen
L
Xu
Guojiang
G
Fei
Jian
J
Fu
Jiliang
J
Zhang
Chenping
C
Wang
Zhugang
Z
D016475:3T3 Cells; D008949:Adenoma, Pleomorphic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D012468:Salivary Gland Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D004268:DNA-Binding Proteins; C489428:Myc protein, mouse; C104382:PLAG1 protein, human; D016271:Proto-Oncogene Proteins c-myc; D051153:Wnt Proteins; D051176:beta Catenin