FZD4 as a mediator of ERG oncogene-induced WNT signaling and epithelial-to-mesenchymal transition in human prostate cancer cells

Santosh Gupta, Kristiina Iljin, Henri Sara, John Mpindi, Tuomas Mirtti, Paula Vainio, Juha K. Rantala, Kalle Alanen, Matthias Nees, Olli Kallioniemi (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

166 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)6735-6745
Number of pages11
JournalCancer Research
Volume70
Issue number17
DOIs
Publication statusPublished - 2010
MoE publication typeA1 Journal article-refereed

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Epithelial-Mesenchymal Transition
Oncogenes
Prostatic Neoplasms
Cadherins
Cell Adhesion
Integrins
Carcinogenesis
Gene Fusion
Reverse Transcription
Prostate
Up-Regulation
Epithelial Cells
Phenotype
Gene Expression
Polymerase Chain Reaction
Genes
Neoplasms

Cite this

Gupta, Santosh ; Iljin, Kristiina ; Sara, Henri ; Mpindi, John ; Mirtti, Tuomas ; Vainio, Paula ; Rantala, Juha K. ; Alanen, Kalle ; Nees, Matthias ; Kallioniemi, Olli. / FZD4 as a mediator of ERG oncogene-induced WNT signaling and epithelial-to-mesenchymal transition in human prostate cancer cells. In: Cancer Research. 2010 ; Vol. 70, No. 17. pp. 6735-6745.
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title = "FZD4 as a mediator of ERG oncogene-induced WNT signaling and epithelial-to-mesenchymal transition in human prostate cancer cells",
abstract = "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.",
author = "Santosh Gupta and Kristiina Iljin and Henri Sara and John Mpindi and Tuomas Mirtti and Paula Vainio and Rantala, {Juha K.} and Kalle Alanen and Matthias Nees and Olli Kallioniemi",
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Gupta, S, Iljin, K, Sara, H, Mpindi, J, Mirtti, T, Vainio, P, Rantala, JK, Alanen, K, Nees, M & Kallioniemi, O 2010, 'FZD4 as a mediator of ERG oncogene-induced WNT signaling and epithelial-to-mesenchymal transition in human prostate cancer cells', Cancer Research, vol. 70, no. 17, pp. 6735-6745. https://doi.org/10.1158/0008-5472.CAN-10-0244

FZD4 as a mediator of ERG oncogene-induced WNT signaling and epithelial-to-mesenchymal transition in human prostate cancer cells. / Gupta, Santosh; Iljin, Kristiina; Sara, Henri; Mpindi, John; Mirtti, Tuomas; Vainio, Paula; Rantala, Juha K.; Alanen, Kalle; Nees, Matthias; Kallioniemi, Olli (Corresponding Author).

In: Cancer Research, Vol. 70, No. 17, 2010, p. 6735-6745.

Research output: Contribution to journalArticleScientificpeer-review

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T1 - FZD4 as a mediator of ERG oncogene-induced WNT signaling and epithelial-to-mesenchymal transition in human prostate cancer cells

AU - Gupta, Santosh

AU - Iljin, Kristiina

AU - Sara, Henri

AU - Mpindi, John

AU - Mirtti, Tuomas

AU - Vainio, Paula

AU - Rantala, Juha K.

AU - Alanen, Kalle

AU - Nees, Matthias

AU - Kallioniemi, Olli

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N2 - 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.

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.

U2 - 10.1158/0008-5472.CAN-10-0244

DO - 10.1158/0008-5472.CAN-10-0244

M3 - Article

VL - 70

SP - 6735

EP - 6745

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 17

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