Τίτλος:
Activation of β-catenin signaling in androgen receptor-negative prostate cancer cells
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Purpose: To study Wnt/β-catenin in castrate-resistant prostate cancer (CRPC) and understand its function independently of the β-catenin-androgen receptor (AR) interaction. Experimental Design: We carried out β-catenin immunocytochemical analysis, evaluated TOP-flash reporter activity (a reporter of β-catenin-mediated transcription), and sequenced the β-catenin gene inMDA prostate cancer 118a, MDA prostate cancer 118b, MDA prostate cancer 2b, and PC-3 prostate cancer cells. We knocked down β-catenin in AR-negative MDA prostate cancer 118b cells and carried out comparative gene-array analysis. We also immunohistochemically analyzed β-catenin and AR in 27 bone metastases of human CRPCs. Results: β-Catenin nuclear accumulation and TOP-flash reporter activity were high in MDA prostate cancer 118b but not in MDA prostate cancer 2b or PC-3 cells. MDA prostate cancer 118a and MDA prostate cancer 118b cells carry a mutated β-catenin at codon 32 (D32G). Ten genes were expressed differently (false discovery rate, 0.05) in MDA prostate cancer 118b cells with downregulated β-catenin. One such gene, hyaluronan synthase 2 (HAS2), synthesizes hyaluronan, a core component of the extracellular matrix. We confirmed HAS2 upregulation in PC-3 cells transfected with D32G-mutant β-catenin. Finally, we found nuclear localization of β-catenin in 10 of 27 human tissue specimens; this localization was inversely associated with AR expression (P=0.056, Fisher's exact test), suggesting that reduced AR expression enables Wnt/β-catenin signaling. Conclusion: We identified a previously unknown downstream target of β-catenin, HAS2, in prostate cancer, and found that high β-catenin nuclear localization and low or no AR expression may define a subpopulation of men with bone metastatic prostate cancer. These findings may guide physicians in managing these patients. ©2011 AACR.
Συγγραφείς:
Wan, X.
Liu, J.
Lu, J.-F.
Tzelepi, V.
Yang, J.
Starbuck, M.W.
Diao, L.
Wang, J.
Efstathiou, E.
Vazquez, E.S.
Troncoso, P.
Maity, S.N.
Navone, N.M.
Περιοδικό:
Clinical Cancer Research
Λέξεις-κλειδιά:
androgen receptor; beta catenin; hyaluronic acid; Wnt protein, animal cell; animal experiment; animal model; animal tissue; article; bone metastasis; cancer cell; clinical article; codon; controlled study; enzyme activation; enzyme activity; enzyme synthesis; gene sequence; gene silencing; Has2 gene; human; human cell; human tissue; immunocytochemistry; male; mouse; nonhuman; oncogene; priority journal; prostate cancer; protein function; protein localization; protein protein interaction; signal transduction, Animals; beta Catenin; Blotting, Western; Bone Neoplasms; Gene Expression Profiling; Glucuronosyltransferase; Humans; Immunohistochemistry; Male; Mice; Mice, SCID; Mutation; Prostatic Neoplasms; Real-Time Polymerase Chain Reaction; Receptors, Androgen; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Transplantation, Heterologous
DOI:
10.1158/1078-0432.CCR-11-2521
