A causal role for ERG in neoplastic transformation of prostate epithelium
A causal role for ERG in neoplastic transformation of prostate epithelium
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DOI：
10.1073/pnas.0711711105
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发表时间：
2008-02-12
影响因子：
11.1
通讯作者：
Vasioukhin, Valeri
中科院分区：
文献类型：
--
作者：
Klezovitch, Olga;Risk, Michael;Vasioukhin, Valeri
相当比例的人前列腺癌携带染色体重排，导致ETS转录因子ERG的过表达;然而，对该事件的功能意义知之甚少。我们在这里报告，ERG转录的上调是足够的前列腺肿瘤的启动。与ERG转录本的测量结果一致，我们发现ERG蛋白在肿瘤性人前列腺上皮中表达。ERG在前列腺细胞系中的过表达增加细胞侵袭。此外，该转录物在转基因小鼠的管腔前列腺上皮细胞中的体内靶向表达导致前列腺瘤形成的开始，观察到作为局灶性癌前前列腺上皮内瘤形成（PIN）的发展。与人类癌症相似，这些PIN病变中的管腔上皮细胞取代数量减少的基底上皮细胞，并与基质细胞区室建立直接接触。基底细胞的丧失被认为是人类前列腺癌的关键标志之一;然而，导致这一事件的机制尚不清楚。我们认为，在人类前列腺癌中，ERG的上调激活了细胞侵袭程序，随后由肿瘤上皮取代基底细胞。我们的数据表明，视网膜电图在前列腺上皮细胞的转化中起着重要的因果作用，应被视为预防或早期治疗干预的目标。
A significant proportion of human prostate cancers carry a chromosomal rearrangement resulting in the overexpression of the ETS transcription factor, ERG; however, the functional significance of this event is poorly understood. We report here that up-regulation of ERG transcript is sufficient for the initiation of prostate neoplasia. In agreement with measurements of ERG transcripts, we found that ERG protein is expressed in neoplastic human prostate epithelium. Overexpression of ERG in prostate cell lines increased cell invasion. Moreover, targeted expression of this transcript in vivo in luminal prostate epithelial cells of transgenic mice results in initiation of prostate neoplasia observed as the development of focal precancerous prostatic intraepithelial neoplasia (PIN). Similar to human cancers, luminal epithelial cells in these PIN lesions displace diminishing in numbers basal epithelial cells and establish direct contact with the stromal cell compartment. Loss of basal cells is considered to be one of the critical hallmarks of human prostate cancer; however, the mechanisms responsible for this event were unknown. We propose that up-regulation of ERG in human prostate cancer activates cell invasion programs that subsequently displace basal cells by neoplastic epithelium. Our data demonstrate that ERG plays an important causal role in the transformation of prostate epithelium and should be considered as a target for prevention or early therapeutic intervention.