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The type III transforming growth factor-beta receptor as a novel tumor suppressor gene in prostate cancer
Ryan S Turley1, Elizabeth C Finger, Nadine Hempel
1Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Abstract:
The transforming growth factor-beta (TGF-beta) signaling pathway has an important role in regulating normal prostate epithelium, inhibiting proliferation, differentiation, and both androgen deprivation-induced and androgen-independent apoptosis. During prostate cancer formation, most prostate cancer cells become resistant to these homeostatic effects of TGF-beta. Although the loss of expression of either the type I (TbetaRI) or type II (TbetaRII) TGF-beta receptor has been documented in approximately 30% of prostate cancers, most prostate cancers become TGF-beta resistant without mutation or deletion of TbetaRI, TbetaRII, or Smads2, 3, and 4, and thus, the mechanism of resistance remains to be defined. Here, we show that type III TGF-beta receptor (TbetaRIII or betaglycan) expression is decreased or lost in the majority of human prostate cancers as compared with benign prostate tissue at both the mRNA and protein level. Loss of TbetaRIII expression correlates with advancing tumor stage and a higher probability of prostate-specific antigen (PSA) recurrence, suggesting a role in prostate cancer progression. The loss of TbetaRIII expression is mediated by the loss of heterozygosity at the TGFBR3 genomic locus and epigenetic regulation of the TbetaRIII promoter. Functionally, restoring TbetaRIII expression in prostate cancer cells potently decreases cell motility and cell invasion through Matrigel in vitro and prostate tumorigenicity in vivo. Taken together, these studies define the loss of TbetaRIII expression as a common event in human prostate cancer and suggest that this loss is important for prostate cancer progression through effects on cell motility, invasiveness, and tumorigenicity.
Insights
The type III TGF-beta receptor (TbetaRIII) is often lost in prostate cancer, contributing to tumor progression. Restoring TbetaRIII expression reduces cancer cell motility, invasion, and tumorigenicity.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Transforming growth factor-beta (TGF-beta) signaling regulates normal prostate epithelium.
- Prostate cancer cells often develop resistance to TGF-beta's homeostatic effects.
- Mechanisms of TGF-beta resistance in prostate cancer, beyond receptor or Smad mutations, are not fully defined.
Purpose of the Study:
- To investigate the role of the type III TGF-beta receptor (TbetaRIII) in prostate cancer.
- To determine the frequency and mechanisms of TbetaRIII loss in prostate cancer.
- To evaluate the functional impact of TbetaRIII loss on prostate cancer progression.
Main Methods:
- Analysis of TbetaRIII mRNA and protein expression in human prostate cancer and benign tissues.
- Investigation of TbetaRIII gene locus (TGFBR3) for loss of heterozygosity.
- Assessment of TbetaRIII promoter methylation for epigenetic regulation.
- Functional studies involving restoration of TbetaRIII expression in prostate cancer cells.
- In vitro assays for cell motility and invasion (Matrigel assay).
- In vivo studies of prostate tumorigenicity.
Main Results:
- TbetaRIII expression is decreased or lost in the majority of human prostate cancers at both mRNA and protein levels.
- Loss of TbetaRIII expression correlates with advanced tumor stage and increased prostate-specific antigen (PSA) recurrence.
- Loss of TbetaRIII is mediated by loss of heterozygosity at the TGFBR3 locus and epigenetic promoter regulation.
- Restoring TbetaRIII expression significantly reduces prostate cancer cell motility, invasion, and in vivo tumorigenicity.
Conclusions:
- Loss of TbetaRIII expression is a common event in human prostate cancer.
- Decreased TbetaRIII contributes to prostate cancer progression by enhancing cell motility, invasiveness, and tumorigenicity.
- TbetaRIII represents a potential therapeutic target for prostate cancer treatment.
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