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Updated: May 11, 2026
An Orthotopic Murine Model of Human Prostate Cancer Metastasis
Published on: September 18, 2013
Identification of novel TMPRSS2:ERG mechanisms in prostate cancer metastasis: involvement of MMP9 and PLXNA2
11] Institut de Biologie de Lille, CNRS UMR8161, Lille, France [2] Institut Pasteur de Lille/IFR142, Lille, France [3] Université de Lille Nord de France, Lille, France [4] Faculté de Médecine Henri Warembourg, Université du Droit et de la Santé Lille II, Lille, France.
Abstract:
Prostate cancer (PCa) is one of the major public health problems in Western countries. Recently, the TMPRSS2:ERG gene fusion, which results in the aberrant expression of the transcription factor ERG, has been shown to be the most common gene rearrangement in PCa. Previous studies have determined the contributions of this fusion in PCa disease initiation and/or progression in vitro and in vivo. In this study on TMPRSS2:ERG regulation in PCa, we used an androgen receptor and TMPRSS2:ERG fusion double-negative PCa cell model: PC3c. In three cell clones with different TMPRSS2:ERG expression levels, ectopic expression of the fusion resulted in significant induction of cell migration and invasion in a dose-dependent manner. In agreement with this phenotype, high-throughput microarray analysis revealed that a set of genes, functionally associated with cell motility and invasiveness, were deregulated in a dose-dependent manner in TMPRSS2:ERG-expressing cells. Importantly, we identified increased MMP9 (Metalloproteinase 9) and PLXNA2 (Plexin A2) expression in TMPRSS2:ERG-positive PCa samples, and their expression levels were significantly correlated with ERG expression in a PCa cohort. In line with these findings, there was evidence that TMPRSS2:ERG directly and positively regulates MMP9 and PLXNA2 expression in PC3c cells. Moreover, PLXNA2 upregulation contributed to TMPRSS2:ERG-mediated enhancements of PC3c cell migration and invasion. Furthermore, and importantly, PLXNA2 expression was upregulated in metastatic PCa tumors compared with localized primary PCa tumors. This study provides novel insights into the role of the TMPRSS2:ERG fusion in PCa metastasis.
Insights
The TMPRSS2:ERG gene fusion promotes prostate cancer (PCa) metastasis by upregulating genes like PLXNA2, which enhances cell migration and invasion. This finding offers new insights into PCa progression.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Prostate cancer (PCa) is a significant public health concern.
- The TMPRSS2:ERG gene fusion is the most common genetic alteration in PCa, leading to aberrant ERG expression.
- Previous research established the role of this fusion in PCa initiation and progression.
Purpose of the Study:
- To investigate the regulatory mechanisms of the TMPRSS2:ERG fusion in PCa.
- To identify genes and pathways influenced by TMPRSS2:ERG expression.
- To elucidate the role of TMPRSS2:ERG in PCa metastasis.
Main Methods:
- Utilized a PC3c cell model lacking androgen receptor and TMPRSS2:ERG fusion.
- Ectopically expressed TMPRSS2:ERG in PC3c cell clones at varying levels.
- Performed high-throughput microarray analysis to identify deregulated genes.
- Correlated gene expression in PCa samples with ERG expression.
- Investigated the direct regulation of MMP9 and PLXNA2 by TMPRSS2:ERG.
Main Results:
- Ectopic TMPRSS2:ERG expression dose-dependently increased PC3c cell migration and invasion.
- Microarray analysis revealed deregulation of cell motility and invasiveness genes.
- MMP9 and PLXNA2 expression were elevated in TMPRSS2:ERG-positive PCa samples and correlated with ERG levels.
- TMPRSS2:ERG directly and positively regulated MMP9 and PLXNA2 expression in PC3c cells.
- PLXNA2 upregulation mediated TMPRSS2:ERG-driven increases in cell migration and invasion.
- PLXNA2 was upregulated in metastatic PCa compared to primary tumors.
Conclusions:
- The TMPRSS2:ERG fusion drives PCa cell migration and invasion.
- TMPRSS2:ERG directly upregulates MMP9 and PLXNA2.
- PLXNA2 plays a crucial role in TMPRSS2:ERG-mediated metastasis.
- These findings highlight the significance of the TMPRSS2:ERG fusion and PLXNA2 in PCa metastasis.
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