Role of the TMPRSS2-ERG gene fusion in prostate cancer
Role of the TMPRSS2-ERG gene fusion in prostate cancer
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DOI：
10.1593/neo.07822
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发表时间：
2008-02-01
期刊：
影响因子：
4.8
通讯作者：
Chinnaiyan, Arul M.
中科院分区：
文献类型：
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作者：
Chinnaiyan, Arul M.
TMPRSS2-ERG 基因融合是前列腺癌的主要分子亚型。在这里，我们利用体外和体内模型系统探索了 TMPRSS2-ERG 基因融合产物的作用。在雄激素调节下表达 ERG 基因融合产物的转基因小鼠会出现小鼠前列腺上皮内瘤变 (PIN)，这是前列腺癌的前兆病变。将ERG基因融合产物引入原代或永生化良性前列腺上皮细胞中，诱导了与侵袭相关的转录程序，但并没有增加细胞增殖或不依赖锚定的生长。这些结果表明，在没有继发性分子损伤的情况下，TMPRSS2-ERG 可能不足以进行转化。 TMPPRSS2-ERG 阳性前列腺癌细胞系 VCaP 中 ERG 敲低的转录谱显示，除了抑制侵袭之外，与 PIN 相比，前列腺癌中过表达的基因表达量也有所减少，ETS 阳性与阴性前列腺癌中过表达的基因表达量也有所减少。 VCaP 细胞中 ERG 的敲低也诱导了与前列腺分化一致的转录程序。重要的是，过表达 ERG 的 VCaP 细胞和良性前列腺细胞直接参与纤溶酶原激活途径的成分来介导细胞侵袭，可能代表易受治疗干预的下游 ETS 靶点。我们的结果支持之前的研究，表明 TMPRSS2-ERG 融合介导侵袭，与 PIN 和前列腺癌之间的组织学区别一致。
TMPRSS2-ERG gene fusions are the predominant molecular subtype of prostate cancer. Here, we explored the role of TMPRSS2-ERG gene fusion product using in vitro and in vivo model systems. Transgenic mice expressing the ERG gene fusion product under androgen-regulation develop mouse prostatic intraepithelial neoplasia ( PIN), a precursor lesion of prostate cancer. Introduction of the ERG gene fusion product into primary or immortalized benign prostate epithelial cells induced an invasion-associated transcriptional program but did not increase cellular proliferation or anchorage-independent growth. These results suggest that TMPRSS2-ERG may not be sufficient for transformation in the absence of secondary molecular lesions. Transcriptional profiling of ERG knockdown in the TMPPRSS2-ERG-positive prostate cancer cell line VCaP revealed decreased expression of genes over-expressed in prostate cancer versus PIN and genes overexpressed in ETS-positive versus -negative prostate cancers in addition to inhibiting invasion. ERG knockdown in VCaP cells also induced a transcriptional program consistent with prostate differentiation. Importantly, VCaP cells and benign prostate cells overexpressing ERG directly engage components of the plasminogen activation pathway to mediate cellular invasion, potentially representing a downstream ETS target susceptible to therapeutic intervention. Our results support previous work suggesting that TMPRSS2-ERG fusions mediate invasion, consistent with the defining histologic distinction between PIN and prostate cancer.