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

Jiaqi Mi, Erika Hooker, Steven Balog, Hong Zeng, Daniel T. Johnson, Yongfeng He, Eun Jeong Yu, Huiqing Wu, Vien Le, Dong Hoon Lee, Joseph Aldahl, Mark L. Gonzalgo, Zijie Sun

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)20123-20136
Number of pages14
JournalJournal of Biological Chemistry
Volume293
Issue number52
DOIs
StatePublished - Jan 1 2018

Fingerprint

Hepatocyte Growth Factor
Tumors
Prostate
Chemical activation
Proto-Oncogene Proteins c-met
Cell proliferation
Fibroblasts
Neoplasms
Genes
Prostatic Neoplasms
Neoplasm Metastasis
Cell Movement
Carcinogenesis
Cell Proliferation
Animals
Prostatic Intraepithelial Neoplasia
Cells
RNA
Epithelial-Mesenchymal Transition
Tumor Suppressor Genes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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

In: Journal of Biological Chemistry, Vol. 293, No. 52, 01.01.2018, p. 20123-20136.

Research output: Contribution to journalArticle

Mi, J, Hooker, E, Balog, S, Zeng, H, Johnson, DT, He, Y, Yu, EJ, Wu, H, Le, V, Lee, DH, Aldahl, J, Gonzalgo, ML & Sun, Z 2018, 'Activation of hepatocyte growth factor/MET signaling initiates oncogenic transformation and enhances tumor aggressiveness in the murine prostate', Journal of Biological Chemistry, vol. 293, no. 52, pp. 20123-20136. https://doi.org/10.1074/jbc.RA118.005395
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. / Activation of hepatocyte growth factor/MET signaling initiates oncogenic transformation and enhances tumor aggressiveness in the murine prostate. In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 52. pp. 20123-20136.
@article{8bf7c1cbe1374cdc8799e34e49a76f69,
title = "Activation of hepatocyte growth factor/MET signaling initiates oncogenic transformation and enhances tumor aggressiveness in the murine prostate",
abstract = "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.",
author = "Jiaqi Mi and Erika Hooker and Steven Balog and Hong Zeng and Johnson, {Daniel T.} and Yongfeng He and Yu, {Eun Jeong} and Huiqing Wu and Vien Le and Lee, {Dong Hoon} and Joseph Aldahl and Gonzalgo, {Mark L.} and Zijie Sun",
year = "2018",
month = "1",
day = "1",
doi = "10.1074/jbc.RA118.005395",
language = "English (US)",
volume = "293",
pages = "20123--20136",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "52",

}

TY - JOUR

T1 - Activation of hepatocyte growth factor/MET signaling initiates oncogenic transformation and enhances tumor aggressiveness in the murine prostate

AU - Mi, Jiaqi

AU - Hooker, Erika

AU - Balog, Steven

AU - Zeng, Hong

AU - Johnson, Daniel T.

AU - He, Yongfeng

AU - Yu, Eun Jeong

AU - Wu, Huiqing

AU - Le, Vien

AU - Lee, Dong Hoon

AU - Aldahl, Joseph

AU - Gonzalgo, Mark L.

AU - Sun, Zijie

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85059241449&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85059241449&partnerID=8YFLogxK

U2 - 10.1074/jbc.RA118.005395

DO - 10.1074/jbc.RA118.005395

M3 - Article

C2 - 30401749

AN - SCOPUS:85059241449

VL - 293

SP - 20123

EP - 20136

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 52

ER -