Tsui Ke-Hung, Lin Yu-Hsiang, Chung Li-Chuan, Chuang Sung-Ting, Feng Tsui-Hsia, Chiang Kun-Chun, Chang Phei-Lang, Yeh Chi-Ju, Juang Horng-Heng
Department of Urology, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan, Taiwan; Department of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan.
Department of Urology, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan, Taiwan; Graduate Institute of Clinical Medical Science, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan.
Cancer Lett. 2016 May 28;375(1):142-151. doi: 10.1016/j.canlet.2016.02.056. Epub 2016 Mar 7.
Prostate-derived Ets (E-twenty six) factor (PDEF), an epithelium-specific member of the Ets family of transcription factors, has been shown to play a role in suppressing the development of many epithelium-derived cancers such as prostate and breast cancer. It is not clear, however, whether PDEF is involved in the development or progression of bladder cancer. In a comparison between normal urothelium and bladder tumor tissue, we identified significant decreases of PDEF in the tumor tissue. Further, the immunohistochemistry assays indicated a significantly higher immunostaining of PDEF in low-grade bladder tumors. Additionally, the highly differentiated transitional-cell bladder carcinoma RT-4 cells expressed significantly more PDEF levels than the bladder carcinoma HT1376 and the T24 cells. Ectopic overexpression of PDEF attenuated proliferation, invasion, and tumorigenesis of bladder carcinoma cells in vitro and in vivo. PDEF enhanced the expression levels of mammary serine protease inhibitor (MASPIN), N-myc downstream regulated gene 1 (NDRG1), KAI1, and B-cell translocation gene 2 (BTG2). PDEF modulated epithelial-mesenchymal-transition (EMT) by upregulating E-cadherin expression and downregulating the expression of N-cadherin, SNAIL, SLUG, and vimentin, leading to lower migration and invasion abilities of bladder carcinoma cells. Filamentous actin (F-actin) polarization and remodeling were observed in PDEF-knockdown RT-4 cells. Our results suggest that PDEF gene expression is associated with the extent of bladder neoplasia and PDEF modulated the expressions of EMT-related genes. The induction of BTG2, NDRG1, MASPIN, and KAI1 gene expressions by PDEF may explain the inhibitory functions of PDEF on the proliferation, invasion, and tumorigenesis in bladder carcinoma cells.
前列腺源Ets（E-26）因子（PDEF）是Ets转录因子家族的上皮特异性成员，已被证明在抑制许多上皮源性癌症（如前列腺癌和乳腺癌）的发展中发挥作用。然而，尚不清楚PDEF是否参与膀胱癌的发生或进展。在正常尿路上皮与膀胱肿瘤组织的比较中，我们发现肿瘤组织中PDEF显著降低。此外，免疫组化分析表明，低级别膀胱肿瘤中PDEF的免疫染色明显更高。此外，高分化的移行细胞膀胱癌RT-4细胞表达的PDEF水平明显高于膀胱癌细胞HT1376和T24细胞。PDEF的异位过表达在体外和体内均减弱了膀胱癌细胞的增殖、侵袭和肿瘤发生。PDEF增强了乳腺丝氨酸蛋白酶抑制剂（MASPIN）、N-myc下游调控基因1（NDRG1）、KAI1和B细胞易位基因2（BTG2）的表达水平。PDEF通过上调E-钙黏蛋白的表达并下调N-钙黏蛋白、SNAIL、SLUG和波形蛋白的表达来调节上皮-间质转化（EMT），导致膀胱癌细胞的迁移和侵袭能力降低。在PDEF敲低的RT-4细胞中观察到丝状肌动蛋白（F-肌动蛋白）的极化和重塑。我们的结果表明，PDEF基因表达与膀胱肿瘤的程度相关，并且PDEF调节EMT相关基因的表达。PDEF对BTG2、NDRG1、MASPIN和KAI1基因表达的诱导可能解释了PDEF对膀胱癌细胞增殖、侵袭和肿瘤发生的抑制作用。
