title: Targeted overexpression of vav3 oncogene in prostatic epithelium induces nonbacterial prostatitis and prostate cancer.
abstract: Our previous study revealed that Vav3 oncogene is overexpressed in human prostate cancer, activates androgen receptor (AR), and stimulates growth in prostate cancer cells. The purpose of this study is to further determine the potential role of Vav3 in prostate cancer development in genetically engineered mouse model. We generated Vav3 transgenic mice by targeted overexpression of a constitutive active Vav3 in the prostatic epithelium. We found that overexpression of Vav3 led to development of mouse prostatic intraepithelial neoplasia and prostate cancer at the age of as early as 3 months. The AR signaling axis and phosphatidylinositol 3-kinase-Akt signaling were elevated in the prostate glands of Vav3 transgenic mice. In addition to prostate cancer, Vav3 transgenic mice developed significant nonbacterial chronic prostatitis in the prostate gland with notable infiltration of lymphomononuclear cells (monocytes, lymphocytes, and plasma cells), which was associated with elevated incidence of prostate cancer. DNA microarray and signaling pathway analysis revealed that the top diseases and disorders were inflammatory diseases and cancer of the prostate gland in Vav3 transgenic mice. In vitro analysis showed that overexpression of Vav3 in prostate cancer cells enhanced nuclear factor-kappaB (NF-kappaB) activity, implicating an underlying mechanism of innate inflammatory response induced by elevated Vav3 activity. These data showed that Vav3 overexpression in the prostate epithelium enhanced both the AR signaling axis and NF-kappaB-mediated pathway, which potentially contributed to the development of nonbacterial prostatitis and prostate cancer.
authors.affiliation: Departments of Pathology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45237-0507, USA.
authors.forename: Yin
authors.initials: Y
authors.lastname: Liu
authors.forename: Jun Qin
authors.initials: JQ
authors.lastname: Mo
authors.forename: Qiande
authors.initials: Q
authors.lastname: Hu
authors.forename: Gregory
authors.initials: G
authors.lastname: Boivin
authors.forename: Linda
authors.initials: L
authors.lastname: Levin
authors.forename: Shan
authors.initials: S
authors.lastname: Lu
authors.forename: Dianer
authors.initials: D
authors.lastname: Yang
authors.forename: Zhongyun
authors.initials: Z
authors.lastname: Dong
authors.forename: Shan
authors.initials: S
authors.lastname: Lu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004848:Epithelium / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011467:Prostate / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics*; D011472:Prostatitis / Q000201:enzymology / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D017931:DNA Primers; D051567:Proto-Oncogene Proteins c-vav; C496622:Vav3 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt