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.
Written by:
Wu M, Shi L, Cimic A, Romero L, Sui G, Lees CJ, Cline JM, Seals DF, Sirintrapun JS, McCoy TP, Liu W, Kim JW, Hawkins GA, Peehl DM, Xu J, Cramer SD Are you the author?
Department of Cancer Biology; Molecular Genetics & Genomics Graduate Program; Departments of Pathology and Biostatistical Sciences; Center for Cancer Genomics; Center for Genomics and Personalized Medicine Research, Wake Forest University School of Medicine, Winston-Salem, North Carolina; Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado; and Department of Urology, Stanford University School of Medicine, Stanford, California
Reference: Cancer Res. 2012 Jun 1;72(11):2833-43
doi: 10.1158/0008-5472.CAN-11-2724
PubMed Abstract
PMID: 22467172