Darby S, Sahadevan K, Khan M M, Robson C N, Leung H Y, Gnanapragasam V J
Urology Research Group, Northern Institute for Cancer Research, Medical School, University of Newcastle Upon Tyne, Framlington Place, Newcastle Upon Tyne, UK.
Oncogene. 2006 Jul 6;25(29):4122-7. doi: 10.1038/sj.onc.1209428. Epub 2006 Feb 13.
Fibroblast growth factors (FGF), and in particular FGF8, have been strongly implicated in prostate carcinogenesis. This study investigated the expression of Sef, a key inhibitory regulator of FGF signalling, in prostate cancer. In a panel of cell lines, hSef was detected in both androgen-dependent and independent cells but was significantly reduced in highly metastatic derivative clones. hSef expression was not influenced by androgenic stimulation. Forced downregulation of hSef by siRNA increased FGF8b induced cell migration (P=0.02) and invasion (P=0.007). Reduced hSef levels also enhanced FGF8b stimulated expression of MMP9 (P=0.005). mRNA in situ hybridization revealed hSef expression in 80% (8/10) of benign biopsies but in only 69% (23/33) of Gleason sum 4-7 and 35% (10/28) of Gleason sum 8-10 cancer biopsies (P=0.004). Quantitative PCR of microdissected glands confirmed this trend (P=0.001). hSef was expressed in 69% (27/39) of non-metastatic tumours but in only 18% (2/11) of metastatic tumours (P=0.004, n=50). hSef expression was next correlated with earlier data on FGF8b expression in a subgroup of cancers. In this cohort, 86% (19/22) of high-grade cancers expressed FGF8 but only 31% (7/22) expressed hSef. Positive FGF8 expression but a loss of hSef was observed in 88% (7/8) of metastatic tumours. In contrast, metastasis was evident in only 10% (1/10) of tumours, which co-expressed both FGF8 and hSef (P<0.001). These results suggest evidence that hSef is downregulated in advanced prostate cancer and might facilitate an enhanced tumorigenic response to FGFs. Further research into the role of hSef in cancer cell signalling and the mechanism of its downregulation may contribute to more effective targeting of growth factors in prostate cancer.
成纤维细胞生长因子（FGF），尤其是FGF8，与前列腺癌发生密切相关。本研究调查了FGF信号关键抑制调节因子Sef在前列腺癌中的表达情况。在一组细胞系中，雄激素依赖和非依赖细胞中均检测到hSef，但在高转移衍生克隆中显著降低。hSef表达不受雄激素刺激影响。通过小干扰RNA（siRNA）强制下调hSef可增加FGF8b诱导的细胞迁移（P = 0.02）和侵袭（P = 0.007）。hSef水平降低还增强了FGF8b刺激的基质金属蛋白酶9（MMP9）表达（P = 0.005）。mRNA原位杂交显示，80%（8/10）的良性活检组织中有hSef表达，但在Gleason评分4 - 7的癌组织活检中只有69%（23/33）有表达，在Gleason评分8 - 10的癌组织活检中仅有35%（10/28）有表达（P = 0.004）。对显微切割腺体进行定量PCR证实了这一趋势（P = 0.001）。hSef在69%（27/39）的非转移性肿瘤中表达，但在转移性肿瘤中只有18%（2/11）有表达（P = 0.004，n = 50）。接下来，在一组癌症亚组中，将hSef表达与FGF8b表达的早期数据进行关联分析。在该队列中，86%（19/22）的高级别癌症表达FGF8，但只有31%（7/22）表达hSef。在88%（7/8）的转移性肿瘤中观察到FGF8表达阳性但hSef缺失。相反，在同时表达FGF8和hSef的肿瘤中，只有10%（1/10）发生转移（P < 0.001）。这些结果表明，在晚期前列腺癌中hSef下调，可能促进肿瘤对FGFs产生更强的致瘤反应。进一步研究hSef在癌细胞信号传导中的作用及其下调机制，可能有助于更有效地靶向前列腺癌中的生长因子。
