Identification of novel TMPRSS2:ERG mechanisms in prostate cancer metastasis: involvement of MMP9 and PLXNA2

• Published in: Oncogene Vol. 33; no. 17; pp. 2204 - 2214
• Main Authors: Tian, T V, Tomavo, N, Huot, L, Flourens, A, Bonnelye, E, Flajollet, S, Hot, D, Leroy, X, de Launoit, Y, Duterque-Coquillaud, M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.04.2014; Nature Publishing Group; Nature Publishing Group [1987-....]
• Subjects: 631/67/68; 692/420/755; 692/699/67/322; 692/699/67/589/466; Androgen receptors; Apoptosis; Biochemistry, Molecular Biology; Cancer; Cell adhesion & migration; Cell Biology; Cell fusion; Cell Line, Tumor; Cell migration; Cell Movement; Cell Proliferation; DNA microarrays; Ectopic expression; ERG gene; Gelatinase B; Gene Expression Regulation; Gene fusion; Gene rearrangement; Genetic aspects; Genomics; Human Genetics; Human health and pathology; Humans; Identification and classification; Internal Medicine; Invasiveness; Life Sciences; Lymphatic Metastasis; Male; Matrix Metalloproteinase 9 - metabolism; Medicine; Medicine & Public Health; Metalloproteinase; Metastases; Metastasis; Nerve Tissue Proteins - metabolism; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Oncogenes; Oncology; Oncology, Experimental; original-article; Phenotype; Phenotypes; Prostate cancer; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Public health; Receptors, Cell Surface - metabolism; Transcriptome; Tumors; Urology and Nephrology; fusion; migration; PLXNA2; prostate cancer; invasion; MMP9; TMPRSS2:ERG fusion
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/onc.2013.176

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.