Qi Mei, Liu Zhiyan, Shen Chengwu, Wang Lin, Zeng Jiping, Wang Chunni, Li Congcong, Fu Weiwei, Sun Yi, Han Bo
Department of Pathology, Shandong University Medical School, Jinan, 250012, China.
Tumour Biol. 2015 May;36(5):3565-72. doi: 10.1007/s13277-014-2993-7. Epub 2014 Dec 28.
ETS gene fusions involving ERG, ETV1, ETV4, ETV5, and FLI1 define a distinct class of prostate cancer (PCa), and this might have a bearing on diagnosis, prognosis, and rational therapeutic targeting. In the current study, we focused on the clinicopathological significance of ETV4 in Chinese PCa patients and the mechanisms whereby ETV4 overexpression mediates tumor invasion in the prostate. Overall, ETV4 overexpression was identified in 30.4 % (45/148) of PCa cases by immunohistochemistry. Accordingly, ETV4 was rearranged in only 1.6 % (2/128) of PCa patients. Clinically, ETV4 overexpression was significantly correlated with Gleason score (P = 0.045) and pathological tumor stage (P = 0.041). Multivariate Cox regression analysis indicated that ETV4 is an unfavorable independent prognostic factor (P = 0.040). Functional studies further showed that small interfering RNA (siRNA) knockdown of ETV4 significantly decreases proliferation and invasion of PC-3 cell and partially reverses epithelial-mesenchymal transition in vitro. Notably, ETV4 knockdown significantly downregulated expression of urokinase plasminogen activator (uPA) and its receptor (uPAR) at messenger RNA (mRNA) and protein levels. Chromatin immunoprecipitation assay demonstrated that ETV4 regulates uPA expression through direct binding to its promoter region. Additionally, ETV4 knockdown was also observed to significantly inhibit expression of matrix metalloproteinase (MMP)-2 and MMP-9. In conclusion, for the first time, our study suggested that ETV4 is an independent poor prognostic factor in Chinese PCa patients. Silencing of ETV4 suppresses invasion of PCa cells by inhibiting the expression of uPA/uPAR as well as MMPs. Further studies will be needed to determine whether ETV4 could be regarded as a potential target for the management and prevention of PCa.
涉及ERG、ETV1、ETV4、ETV5和FLI1的ETS基因融合定义了一种独特的前列腺癌（PCa）类型，这可能与诊断、预后及合理的治疗靶点有关。在本研究中，我们聚焦于ETV4在中国PCa患者中的临床病理意义以及ETV4过表达介导前列腺肿瘤侵袭的机制。总体而言，通过免疫组化在30.4%（45/148）的PCa病例中鉴定出ETV4过表达。相应地，仅1.6%（2/128）的PCa患者中存在ETV4重排。临床上，ETV4过表达与Gleason评分（P = 0.045）和病理肿瘤分期（P = 0.041）显著相关。多因素Cox回归分析表明ETV4是一个不良的独立预后因素（P = 0.040）。功能研究进一步显示，小干扰RNA（siRNA）敲低ETV4可显著降低PC-3细胞的增殖和侵袭，并在体外部分逆转上皮-间质转化。值得注意的是，ETV4敲低在信使核糖核酸（mRNA）和蛋白质水平显著下调尿激酶型纤溶酶原激活剂（uPA）及其受体（uPAR）的表达。染色质免疫沉淀试验表明ETV4通过直接结合其启动子区域来调节uPA表达。此外，还观察到ETV4敲低显著抑制基质金属蛋白酶（MMP）-2和MMP-9的表达。总之，我们的研究首次表明ETV4是中国PCa患者的一个独立不良预后因素。沉默ETV4通过抑制uPA/uPAR以及MMPs的表达来抑制PCa细胞的侵袭。还需要进一步研究以确定ETV是否可被视为PCa管理和预防的潜在靶点。
