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Identification and Characterization of Metastatic Factors by Gene Transfer into the Novel RIP-Tag; RIP-tva Murine Model
Published on: October 16, 2017
Pulmonary tumors associated with the JC virus T-antigen in a transgenic mouse model
Akira Noguchi1, Keiji Kikuchi, Takashi Ohtsu
1Kanagawa Cancer Center Research Institute, Yokohama, Kanagawa 241-0815, Japan.
Abstract:
Many attempts to demonstrate the oncogenic role of the JC virus (JCV) have been partially successful in producing brain tumors, either by direct inoculation of JCV into the brain or in transgenic models in rodents. We previously reported the presence of JCV DNA with a relatively high incidence in pulmonary and digestive organs. However, we could not prove the oncogenic role of JCV. We prepared a transgene composed of the K19 promoter, specific to bronchial epithelium with the JCV T-antigen and established transgenic (TG) mice. Pulmonary tumors were detected without any metastasis in 2 out of 15 (13.3%) 16-month-old K19/JCV T-antigen TG mice. Using immunohistochemistry (IHC), these tumors showed JCV T-antigen, p53 and CK 19 expression, but not expression of nuclear and cytoplasmic β-catenin and insulin receptor substrate 1 (IRS1). IHC revealed the same expression pattern as in the bronchial epithelium of the TG mice. One tumor, which was examined with laser capture microdissection and molecular biological tools, demonstrated an EGFR mutation but not a K-ras mutation. We propose that the pulmonary tumors were derived from the JCV T-antigen in a TG mouse model. These findings shed light on pulmonary carcinogenesis.
Insights
JC virus (JCV) T-antigen expression in transgenic mice led to pulmonary tumors, suggesting a role for JCV in lung carcinogenesis. This study provides insights into the mechanisms of tumor development in the lungs.
Area of Science:
- Oncology
- Virology
- Genetics
Background:
- JC virus (JCV) has been investigated for its oncogenic potential, with some success in inducing brain tumors in animal models.
- Previous research indicated a high incidence of JCV DNA in pulmonary and digestive organs, but its oncogenic role remained unproven.
Purpose of the Study:
- To investigate the oncogenic role of JCV in pulmonary carcinogenesis using a novel transgenic mouse model.
- To establish a K19 promoter-driven JCV T-antigen transgene in mice to target bronchial epithelium.
Main Methods:
- Generation of transgenic (TG) mice expressing the JCV T-antigen under the control of the K19 promoter, specific to bronchial epithelium.
- Analysis of pulmonary tumors in 16-month-old TG mice using immunohistochemistry (IHC) for JCV T-antigen, p53, CK 19, β-catenin, and IRS1.
- Molecular analysis of tumor samples, including laser capture microdissection, to detect mutations such as EGFR and K-ras.
Main Results:
- Pulmonary tumors developed in 13.3% of K19/JCV T-antigen TG mice without metastasis.
- Tumors exhibited expression of JCV T-antigen, p53, and CK 19, consistent with bronchial epithelium.
- One tumor showed an EGFR mutation, suggesting a potential mechanism for tumor development.
Conclusions:
- The JCV T-antigen in the K19/JCV T-antigen TG mouse model is proposed to be the cause of pulmonary tumors.
- These findings contribute to understanding pulmonary carcinogenesis and the oncogenic potential of JCV.
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