title: Suppression of Tak1 promotes prostate tumorigenesis.
abstract: More than 30% of primary prostate cancers contain a consensus deletion of an approximately 800 kb locus on chromosome 6q15.1. The MAP3K7 gene, which encodes TGF-β activated kinase-1 (Tak1), is a putative prostate tumor suppressor gene within this region whose precise function remains obscure. In this study, we investigated the role of Tak1 in human and murine prostate cancers. In 50 well-characterized human cancer specimens, we found that Tak1 expression was progressively lost with increasing Gleason grade, both within each cancer and across all cancers. In murine prostate stem cells and Tak1-deficient prostatic epithelial cells, Tak1 loss increased proliferation, migration, and invasion. When prostate stem cells attenuated for Tak1 were engrafted with fetal urogenital mesenchyme, the histopathology of the grafts reflected the natural history of prostate cancer leading from prostatic intraepithelial neoplasia to invasive carcinoma. In the grafts containing Tak1-suppressed prostate stem cells, p38 and c-jun-NH(2)-kinase activity was attenuated and proliferation was increased. Together, our findings functionally validate the proposed tumor suppressor role of Tak1 in prostate cancer.
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.forename: Lihong
authors.initials: L
authors.lastname: Shi
authors.forename: Adela
authors.initials: A
authors.lastname: Cimic
authors.forename: Lina
authors.initials: L
authors.lastname: Romero
authors.forename: Guangchao
authors.initials: G
authors.lastname: Sui
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Lees
authors.forename: J Mark
authors.initials: JM
authors.lastname: Cline
authors.forename: Darren F
authors.initials: DF
authors.lastname: Seals
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Sirintrapun
authors.forename: Thomas P
authors.initials: TP
authors.lastname: McCoy
authors.forename: Wennuan
authors.initials: W
authors.lastname: Liu
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Kim
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Hawkins
authors.forename: Donna M
authors.initials: DM
authors.lastname: Peehl
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
authors.forename: Scott D
authors.initials: SD
authors.lastname: Cramer
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D020930:MAP Kinase Kinase Kinases; D025521:Tumor Suppressor Proteins; D000099151:MAP Kinase Kinase Kinase 7