Activation of hepatocyte growth factor/MET signaling initiates oncogenic transformation and enhances tumor aggressiveness in the murine prostate

• Published in: The Journal of biological chemistry Vol. 293; no. 52; pp. 20123 - 20136
• Main Authors: Mi, Jiaqi, Hooker, Erika, Balog, Steven, Zeng, Hong, Johnson, Daniel T., He, Yongfeng, Yu, Eun-Jeong, Wu, Huiqing, Le, Vien, Lee, Dong-Hoon, Aldahl, Joseph, Gonzalgo, Mark L., Sun, Zijie
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.12.2018; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Hepatocyte Growth Factor - genetics; Hepatocyte Growth Factor - metabolism; Male; Mice; Mice, Transgenic; Molecular Bases of Disease; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - metabolism; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; Signal Transduction; phosphatase and tensin homolog (PTEN); epithelial-to-mesenchymal transition; gene knockout; prostate cancer; prostatic intraepithelial neoplasia; androgen receptor; transgenic mice; PB-Cre4; metastasis; tumorigenesis; tumor cell biology; Met; hepatocyte growth factor/scatter factor (HGF/SF); HGF/SF
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA118.005395

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, H11Met/+: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 H11Met/+/PtenLoxP/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 PtenLoxP/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 H11Met/+/PtenLoxP/LoxP:PB-Cre4 compound mice compared with those from PtenLoxP/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.