Tian T V, Tomavo N, Huot L, Flourens A, Bonnelye E, Flajollet S, Hot D, Leroy X, de Launoit Y, Duterque-Coquillaud M
1] 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.
1] 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.
Oncogene. 2014 Apr 24;33(17):2204-14. doi: 10.1038/onc.2013.176. Epub 2013 May 27.
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.
前列腺癌（PCa）是西方国家主要的公共卫生问题之一。最近，导致转录因子ERG异常表达的TMPRSS2:ERG基因融合已被证明是PCa中最常见的基因重排。先前的研究已经确定了这种融合在体外和体内PCa疾病起始和/或进展中的作用。在这项关于PCa中TMPRSS2:ERG调控的研究中，我们使用了雄激素受体和TMPRSS2:ERG融合双阴性PCa细胞模型：PC3c。在三个具有不同TMPRSS2:ERG表达水平的细胞克隆中，融合基因的异位表达导致细胞迁移和侵袭以剂量依赖的方式显著诱导。与这种表型一致，高通量微阵列分析显示，一组与细胞运动性和侵袭性功能相关的基因在表达TMPRSS2:ERG的细胞中以剂量依赖的方式失调。重要的是，我们在TMPRSS2:ERG阳性PCa样本中鉴定出MMP9（基质金属蛋白酶9）和PLXNA2（丛状蛋白A2）表达增加，并且它们的表达水平在一个PCa队列中与ERG表达显著相关。与这些发现一致，有证据表明TMPRSS2:ERG在PC3c细胞中直接且正向调节MMP9和PLXNA2的表达。此外，PLXNA2的上调促成了TMPRSS2:ERG介导的PC3c细胞迁移和侵袭增强。此外，重要的是，与局限性原发性PCa肿瘤相比，转移性PCa肿瘤中PLXNA2表达上调。这项研究为TMPRSS2:ERG融合在PCa转移中的作用提供了新的见解。
