RT Journal Article
SR Electronic
T1 <em>FZD4</em> as a Mediator of <em>ERG</em> Oncogene–Induced WNT Signaling and Epithelial-to-Mesenchymal Transition in Human Prostate Cancer Cells
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 6735
OP 6745
DO 10.1158/0008-5472.CAN-10-0244
VO 70
IS 17
A1 Gupta, Santosh
A1 Iljin, Kristiina
A1 Sara, Henri
A1 Mpindi, John Patrick
A1 Mirtti, Tuomas
A1 Vainio, Paula
A1 Rantala, Juha
A1 Alanen, Kalle
A1 Nees, Matthias
A1 Kallioniemi, Olli
YR 2010
UL http://cancerres.aacrjournals.org/content/70/17/6735.abstract
AB TMPRSS2-ERG and other gene fusions involving ETS factors and genes with strong promoter elements are common in prostate cancer. Although ERG activation has been linked to invasive properties of prostate cancers, the precise mechanisms and pathways of ERG-mediated oncogenesis remain poorly understood. Here, we show that ERG knockdown in VCaP prostate cancer cells causes an activation of cell adhesion, resulting in strongly induced active β1-integrin and E-cadherin expression as well as changes in WNT signaling. These observations were corroborated by data from ERG-overexpressing nontransformed prostate epithelial cells as well as gene expression data from clinical prostate cancer samples, which both indicated a link between ERG and epithelial-to-mesenchymal transition (EMT). Upregulation of several WNT pathway members was seen in ERG-positive prostate cancers, with frizzled-4 (FZD4) showing the strongest overexpression as verified by both reverse transcription-PCR and immunostaining. Both ERG knockin and knockdown modulated the levels of FZD4 expression. FZD4 silencing could mimic the ERG knockdown phenotype by inducing active β1-integrin and E-cadherin expression, whereas FZD4 overexpression reversed the phenotypic effects seen with ERG knockdown. Taken together, our results provide mechanistic insights to ERG oncogenesis in prostate cancer, involving activation of WNT signaling through FZD4, leading to cancer-promoting phenotypic effects, including EMT and loss of cell adhesion. Cancer Res; 70(17); 6735–45. ©2010 AACR.