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miRNA Expression Analyses in Prostate Cancer Clinical Tissues
Published on: September 8, 2015
Protective effect of stromal Dickkopf-3 in prostate cancer: opposing roles for TGFBI and ECM-1
Zainab Al Shareef1, Hoda Kardooni1, Virginia Murillo-Garzón2
1Department of Surgery and Cancer, Imperial College London, London, UK.
Abstract:
Aberrant transforming growth factor-β (TGF-β) signaling is a hallmark of the stromal microenvironment in cancer. Dickkopf-3 (Dkk-3), shown to inhibit TGF-β signaling, is downregulated in prostate cancer and upregulated in the stroma in benign prostatic hyperplasia, but the function of stromal Dkk-3 is unclear. Here we show that DKK3 silencing in WPMY-1 prostate stromal cells increases TGF-β signaling activity and that stromal cell-conditioned media inhibit prostate cancer cell invasion in a Dkk-3-dependent manner. DKK3 silencing increased the level of the cell-adhesion regulator TGF-β-induced protein (TGFBI) in stromal and epithelial cell-conditioned media, and recombinant TGFBI increased prostate cancer cell invasion. Reduced expression of Dkk-3 in patient tumors was associated with increased expression of TGFBI. DKK3 silencing reduced the level of extracellular matrix protein-1 (ECM-1) in prostate stromal cell-conditioned media but increased it in epithelial cell-conditioned media, and recombinant ECM-1 inhibited TGFBI-induced prostate cancer cell invasion. Increased ECM1 and DKK3 mRNA expression in prostate tumors was associated with increased relapse-free survival. These observations are consistent with a model in which the loss of Dkk-3 in prostate cancer leads to increased secretion of TGFBI and ECM-1, which have tumor-promoting and tumor-protective roles, respectively. Determining how the balance between the opposing roles of extracellular factors influences prostate carcinogenesis will be key to developing therapies that target the tumor microenvironment.
Insights
Loss of Dickkopf-3 (Dkk-3) in prostate cancer promotes tumor growth by increasing TGF-β signaling and TGFBI secretion, while also altering ECM-1 levels. This highlights Dkk-3
Area of Science:
- Oncology
- Cell Biology
- Cancer Microenvironment Research
Background:
- Aberrant transforming growth factor-β (TGF-β) signaling is characteristic of the cancer stroma.
- Dickkopf-3 (Dkk-3) inhibits TGF-β signaling but its role in prostate cancer stroma is not well understood.
- Dkk-3 is downregulated in prostate cancer and upregulated in benign prostatic hyperplasia stroma.
Purpose of the Study:
- To investigate the function of stromal Dickkopf-3 (Dkk-3) in prostate cancer.
- To elucidate the mechanisms by which Dkk-3 influences prostate cancer cell invasion and the tumor microenvironment.
- To determine the relationship between Dkk-3, TGF-β signaling, TGFBI, and ECM-1 in prostate cancer.
Main Methods:
- Silencing of DKK3 gene in WPMY-1 prostate stromal cells.
- Analysis of TGF-β signaling activity.
- Assessment of prostate cancer cell invasion using conditioned media.
- Measurement of TGF-β-induced protein (TGFBI) and extracellular matrix protein-1 (ECM-1) levels.
- Correlation analysis of gene expression in patient tumors.
Main Results:
- DKK3 silencing in stromal cells increased TGF-β signaling and prostate cancer cell invasion.
- DKK3 silencing led to increased TGFBI levels and decreased ECM-1 levels in stromal cell-conditioned media.
- Reduced Dkk-3 expression in tumors correlated with increased TGFBI expression.
- Increased ECM-1 in epithelial cell-conditioned media, and recombinant ECM-1 inhibited TGFBI-induced invasion.
- Increased ECM1 and DKK3 mRNA expression in tumors correlated with better relapse-free survival.
Conclusions:
- Loss of Dkk-3 in prostate cancer stroma promotes tumor progression via increased TGFBI and altered ECM-1.
- TGFBI and ECM-1 play opposing roles in prostate cancer, with TGFBI promoting invasion and ECM-1 inhibiting it.
- Targeting the balance of these extracellular factors in the tumor microenvironment is a potential therapeutic strategy.
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