Dai Lan, Gu Liying, Ding Chuanwei, Qiu Lihua, Di Wen
Department of OB/GYN, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
Cancer Lett. 2009 Oct 8;283(2):159-67. doi: 10.1016/j.canlet.2009.03.036. Epub 2009 Apr 23.
The poor prognosis of human ovarian cancer is partly due to its metastasis and recurrence. It has been demonstrated that tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK)-fibroblast growth factor inducible-14 (Fn14) signaling system may be a potential regulator of human tumorigenesis. The objective of this study was to understand the effect of TWEAK on ovarian cancer metastasis. We recently showed that activation of Fn14 signaling by TWEAK promoted cell migration and invasion in human HO-8910PM cells. Treating HO-8910PM cells with TWEAK resulted in the activation of nuclear factor-kappa B (NF-kappaB) and subsequently the translocation of NF-kappaB from cytoplasm to nucleus. In addition, TWEAK promoted vascular endothelial growth factor (VEGF) protein expression, and this effect was dependent upon NF-kappaB transcriptional activity. Blocking the NF-kappaB pathway with PDTC suppressed TWEAK-induced up-regulation of VEGF protein expression and cell metastasis. Our results suggest that TWEAK-Fn14 functions, in part, through the NF-kappaB signaling pathway to up-regulate VEGF expression to foster ovarian cancer cell metastasis. Targeted therapy against TWEAK-Fn14 signaling system as an adjuvant to surgery may improve clinical management of invasive ovarian cancer cells and advance the outcome of this devastating cancer.
人类卵巢癌预后较差，部分原因在于其转移和复发。已有研究表明，肿瘤坏死因子（TNF）样凋亡微弱诱导剂（TWEAK）-成纤维细胞生长因子诱导14（Fn14）信号系统可能是人类肿瘤发生的潜在调节因子。本研究的目的是了解TWEAK对卵巢癌转移的影响。我们最近发现，TWEAK激活Fn14信号可促进人HO-8910PM细胞的迁移和侵袭。用TWEAK处理HO-8910PM细胞会导致核因子κB（NF-κB）激活，随后NF-κB从细胞质转位至细胞核。此外，TWEAK促进血管内皮生长因子（VEGF）蛋白表达，且这种作用依赖于NF-κB转录活性。用PDTC阻断NF-κB途径可抑制TWEAK诱导的VEGF蛋白表达上调和细胞转移。我们的结果表明，TWEAK-Fn14部分通过NF-κB信号通路发挥作用，上调VEGF表达以促进卵巢癌细胞转移。针对TWEAK-Fn14信号系统的靶向治疗作为手术辅助手段，可能改善侵袭性卵巢癌细胞的临床管理，并改善这种毁灭性癌症的治疗结果。
