Hermans Karin G, van der Korput Hetty A, van Marion Ronald, van de Wijngaart Dennis J, Ziel-van der Made Angelique, Dits Natasja F, Boormans Joost L, van der Kwast Theo H, van Dekken Herman, Bangma Chris H, Korsten Hanneke, Kraaij Robert, Jenster Guido, Trapman Jan
Department of Pathology, Josephine Nefkens Institute, Erasmus University Medical Center, Rotterdam, the Netherlands.
Cancer Res. 2008 Sep 15;68(18):7541-9. doi: 10.1158/0008-5472.CAN-07-5930.
In this study, we describe the properties of novel ETV1 fusion genes, encoding N-truncated ETV1 (dETV1), and of full-length ETV1, overexpressed in clinical prostate cancer. We detected overexpression of novel ETV1 fusion genes or of full-length ETV1 in 10% of prostate cancers. Novel ETV1 fusion partners included FOXP1, an EST (EST14), and an endogenous retroviral repeat sequence (HERVK17). Like TMPRSS2, EST14 and HERVK17 were prostate-specific and androgen-regulated expressed. This unique expression pattern of most ETV1 fusion partners seems an important determinant in prostate cancer development. In transient reporter assays, full-length ETV1 was a strong transactivator, whereas dETV1 was not. However, several of the biological properties of dETV1 and full-length ETV1 were identical. On stable overexpression, both induced migration and invasion of immortalized nontumorigenic PNT2C2 prostate epithelial cells. In contrast to dETV1, full-length ETV1 also induced anchorage-independent growth of these cells. PNT2C2 cells stably transfected with dETV1 or full-length ETV1 expression constructs showed small differences in induced expression of target genes. Many genes involved in tumor invasion/metastasis, including uPA/uPAR and MMPs, were up-regulated in both cell types. Integrin beta3 (ITGB3) was clearly up-regulated by full-length ETV1 but much less by dETV1. Based on the present data and on previous findings, a novel concept of the role of dETV1 and of full-length ETV1 overexpression in prostate cancer is proposed.
在本研究中，我们描述了编码N端截短型ETV1（dETV1）的新型ETV1融合基因以及在临床前列腺癌中过表达的全长ETV1的特性。我们在10%的前列腺癌中检测到新型ETV1融合基因或全长ETV1的过表达。新型ETV1融合伴侣包括FOXP1、一个EST（EST14）和一个内源性逆转录病毒重复序列（HERVK17）。与TMPRSS2一样，EST14和HERVK17具有前列腺特异性且受雄激素调节表达。大多数ETV1融合伴侣的这种独特表达模式似乎是前列腺癌发展的一个重要决定因素。在瞬时报告基因检测中，全长ETV1是一种强转录激活因子，而dETV1不是。然而，dETV1和全长ETV1的一些生物学特性是相同的。在稳定过表达时，二者均诱导永生化的非致瘤性PNT2C2前列腺上皮细胞迁移和侵袭。与dETV1不同，全长ETV1还诱导这些细胞的非锚定依赖性生长。用dETV1或全长ETV1表达构建体稳定转染的PNT2C2细胞在靶基因的诱导表达上显示出微小差异。许多参与肿瘤侵袭/转移的基因，包括uPA/uPAR和基质金属蛋白酶（MMPs），在两种细胞类型中均上调。整合素β3（ITGB3）明显被全长ETV1上调，但被dETV1上调的程度要小得多。基于目前的数据和先前的研究结果，提出了dETV1和全长ETV1过表达在前列腺癌中作用的新概念。
