Activation of hepatocyte growth factor/MET signaling initiates oncogenic transformation and enhances tumor aggressiveness in the murine prostate
| Autor: | Zijie Sun, Daniel T. Johnson, Dong Hoon Lee, Jiaqi Mi, Yongfeng He, Mark L. Gonzalgo, Eun Jeong Yu, Huiqing Wu, Erika Hooker, Vien Le, Hong Zeng, Joseph Aldahl, Steven Balog |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Tumor suppressor gene Mice Transgenic medicine.disease_cause Biochemistry Proto-Oncogene Mas Metastasis 03 medical and health sciences Prostate cancer Mice 0302 clinical medicine medicine PTEN Animals Epithelial–mesenchymal transition Molecular Biology biology Hepatocyte Growth Factor PTEN Phosphohydrolase Prostatic Neoplasms Molecular Bases of Disease Cell Biology Proto-Oncogene Proteins c-met medicine.disease 030104 developmental biology Cell Transformation Neoplastic Tumor progression 030220 oncology & carcinogenesis Cancer research biology.protein Hepatocyte growth factor Carcinogenesis medicine.drug Signal Transduction |
| Zdroj: | The Journal of biological chemistry. 293(52) |
| ISSN: | 1083-351X |
| Popis: | Emerging evidence has shown that the hepatocyte growth factor (HGF) and its receptor, MET proto-oncogene, receptor tyrosine kinase (MET), promote cell proliferation, motility, morphogenesis, and angiogenesis. Whereas up-regulation of MET expression has been observed in aggressive and metastatic prostate cancer, a clear understanding of MET function in prostate tumorigenesis remains elusive. Here, we developed a conditional Met transgenic mouse strain, H11(Met/+):PB-Cre4, to mimic human prostate cancer cells with increased MET expression in the prostatic luminal epithelium. We found that these mice develop prostatic intraepithelial neoplasia after HGF administration. To further assess the biological role of MET in prostate cancer progression, we bred H11(Met/+)/Pten(LoxP/LoxP):PBCre4 compound mice, in which transgenic Met expression and deletion of the tumor suppressor gene Pten occurred simultaneously only in prostatic epithelial cells. These compound mice exhibited accelerated prostate tumor formation and invasion as well as increased metastasis compared with Pten(LoxP/LoxP):PB-Cre4 mice. Moreover, prostatic sarcomatoid carcinomas and lesions resembling the epithelial-to-mesenchymal transition developed in tumor lesions of the compound mice. RNA-Seq and qRT-PCR analyses revealed a robust enrichment of known tumor progression and metastasis-promoting genes in samples isolated from H11(Met/+)/Pten(LoxP/LoxP):PB-Cre4 compound mice compared with those from Pten(LoxP/LoxP):PB-Cre4 littermate controls. HGF-induced cell proliferation and migration also increased in mouse embryonic fibroblasts (MEFs) from animals with both Met transgene expression and Pten deletion compared with Pten-null MEFs. The results from these newly developed mouse models indicate a role for MET in hastening tumorigenesis and metastasis when combined with the loss of tumor suppressors. |
| Databáze: | OpenAIRE |
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