Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland.
Cancer Res. 2013 Jul 15;73(14):4533-47. doi: 10.1158/0008-5472.CAN-12-4537. Epub 2013 May 16.
Chromosomal translocations leading to deregulated expression of ETS transcription factors are frequent in prostate tumors. Here, we report a novel mechanism leading to oncogenic activation of the ETS factor ESE1/ELF3 in prostate tumors. ESE1/ELF3 was overexpressed in human primary and metastatic tumors. It mediated transforming phenotypes in vitro and in vivo and induced an inflammatory transcriptome with changes in relevant oncogenic pathways. ESE1/ELF3 was induced by interleukin (IL)-1β through NF-κB and was a crucial mediator of the phenotypic and transcriptional changes induced by IL-1β in prostate cancer cells. This linkage was mediated by interaction of ESE1/ELF3 with the NF-κB subunits p65 and p50, acting by enhancing their nuclear translocation and transcriptional activity and by inducing p50 transcription. Supporting these findings, gene expression profiling revealed an enrichment of NF-κB effector functions in prostate cancer cells or tumors expressing high levels of ESE1/ELF3. We observed concordant upregulation of ESE1/ELF3 and NF-κB in human prostate tumors that was associated with adverse prognosis. Collectively, our results define an important new mechanistic link between inflammatory signaling and the progression of prostate cancer.
导致 ETS 转录因子表达失调的染色体易位在前列腺肿瘤中很常见。在这里，我们报告了一种导致前列腺肿瘤中 ETS 因子 ESE1/ELF3 致癌激活的新机制。ESE1/ELF3 在人原发性和转移性肿瘤中过表达。它介导体外和体内的转化表型，并诱导具有相关致癌途径变化的炎症转录组。ESE1/ELF3 被白细胞介素（IL）-1β 通过 NF-κB 诱导，并且是 IL-1β 在前列腺癌细胞中诱导表型和转录变化的关键介质。这种联系是通过 ESE1/ELF3 与 NF-κB 亚基 p65 和 p50 的相互作用介导的，通过增强它们的核易位和转录活性以及诱导 p50 转录来实现的。支持这些发现，基因表达谱分析显示，在表达高水平 ESE1/ELF3 的前列腺癌细胞或肿瘤中，NF-κB 效应功能富集。我们观察到人类前列腺肿瘤中 ESE1/ELF3 和 NF-κB 的一致性上调，这与不良预后相关。总之，我们的结果定义了炎症信号与前列腺癌进展之间的一个重要的新的机制联系。
