Abstract
Purpose
JF1/Ms mice, an inbred strain derived from Japanese wild mice, carry a germline hypomorphic mutation in the endothelin receptor type B gene (Ednrb). We observed that the JF1/Ms mice develop various spontaneous tumors at a high incidence late in life. The aim of this study was to elucidate the mechanism responsible for spontaneous tumors in these mice. Possible relevance of milk-borne mammary tumor virus and gene alterations in Ednrb to tumorigenesis was explored.
Methods
Expression and methylation status of Ednrb were quantitatively analyzed in normal and cancer tissues of mammary gland, liver, submandibular gland as well as in a cultured cell line, MW1, established from a submandibular gland adenocarcinoma. The biological effects of EDNRB were examined in the MW1 cells transfected with wild-type Ednrb.
Results
Transcripts of Ednrb were barely detectable, and the promoter region of Ednrb was hypermethylated in tumor tissues and the MW1 cells. In contrast, normal counterpart tissues showed positive expression of Ednrb transcripts and had unmethylated promoter regions. Treatment of the MW1 cells with 5-Aza-dC restored transcription of Ednrb to normal levels. Transfection of the MW1 cells with Ednrb1 (MW1-Ednrb1) resulted in lower growth rates and morphological changes compared with the mock-transfected MW1 cells (MW1-mock1). Furthermore, the MW1-Ednrb1 cells transplanted in syngeneic mice showed a lower proliferation rate than the MW1-mock1 cells.
Conclusions
Germline mutation and subsequent promoter methylation of Ednrb may be relevant to cancer susceptibility in the JF1/Ms mice. These data indicate that Ednrb acts as a tumor suppressor, as reported in human prostate, bladder, and clear cell renal carcinomas.
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Acknowledgments
We thank Dr. A. Tsubura for detecting MMTV infection in the JF1/Ms mice cancers. We thank Dr. H. Hiai and Dr. H. Shisa for helpful discussions. The authors would like to thank Enago for the English language review.
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We declare that we have no conflict of interest.
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Watanabe, J., Kaneko, Y., Kurosumi, M. et al. High-incidence spontaneous tumors in JF1/Ms mice: relevance of hypomorphic germline mutation and subsequent promoter methylation of Ednrb . J Cancer Res Clin Oncol 140, 99–107 (2014). https://doi.org/10.1007/s00432-013-1546-6
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DOI: https://doi.org/10.1007/s00432-013-1546-6