Overexpression of Fn14 promotes androgen-independent prostate cancer progression through MMP-9 and correlates with poor treatment outcome
Overexpression of Fn14 promotes androgen-independent prostate cancer progression through MMP-9 and correlates with poor treatment outcome
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DOI：
10.1093/carcin/bgr182
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发表时间：
2011-11-01
期刊：
影响因子：
4.7
通讯作者：
Habuchi, Tomonori
中科院分区：
文献类型：
--
作者：
Huang, Mingguo;Narita, Shintaro;Habuchi, Tomonori
成纤维细胞生长因子诱导型14（Fn 14）是一种跨膜受体，与多功能细胞因子肿瘤坏死因子样弱凋亡诱导因子（TWEAK）结合，可调节多种细胞活性，包括肿瘤进展。在这里，我们证明了Fn 14在雄激素非依赖性前列腺癌（AIPC）细胞的侵袭，迁移和增殖中的重要作用。Fn 14及其配体TWEAK在两种AIPC细胞系DU 145和PC-3中高度表达，而在雄激素敏感的LNCaP细胞中表达较弱。使用小干扰RNA敲低Fn 14可减弱AIPC细胞系的迁移、侵袭和增殖，并增强凋亡。通过稳定的Fn 14互补DNA转染PC-3细胞（PC-3/Fn 14）强制Fn 14过表达和通过重组TWEAK在PC-3细胞中激活配体增强侵袭。Fn 14可调节PC-3细胞基质金属蛋白酶（MMP）-9的表达，MMP-9介导Fn 14对PC-3细胞侵袭能力的影响。在体内，PC-3/Fn 14的皮下异种移植物的生长显著快于PC-3/Mock的异种移植物，并且如在隔膜的侵袭模型中评估的，发现PC-3/Fn 14的侵袭能力高于PC-3/Mock的侵袭能力。PC-3/Fn 14移植瘤组织中MMP-9 mRNA的表达明显高于PC-3/Mock移植瘤组织。在临床上，Fn 14的高表达与接受根治性前列腺切除术的患者中较高的前列腺特异性抗原复发率显著相关。总之，Fn 14的过表达可能部分通过MMP-9导致与前列腺癌（PCa）进展相关的多种恶性细胞表型。TWEAK-Fn 14信号通路可能是前列腺癌治疗的新靶点。
Fibroblast growth factor-inducible 14 (Fn14), a transmembrane receptor binding to the multifunctional cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK), is known to modulate many cellular activities including cancer progression. Here, we demonstrated the significant role of Fn14 in invasion, migration and proliferation of androgen-independent prostate cancer (AIPC) cells. Fn14 and its ligand TWEAK were highly expressed in two AIPC cell lines, DU 145 and PC-3, whereas expression was weak in androgen-sensitive LNCaP cells. Fn14 knockdown using small-interfering RNAs attenuated migration, invasion and proliferation and enhanced apoptosis in the AIPC cell lines. Both forced overexpression of Fn14 by stable Fn14 complementary DNA transfection to PC-3 cells (PC-3/Fn14) and ligand activation by recombinant TWEAK in PC-3 cells enhanced invasion. Fn14 was shown to modulate expression of matrix metalloproteinase (MMP)-9, and MMP-9 mediated the invasive potential influenced by Fn14 in PC-3 cells. In vivo, subcutaneous xenografts of PC-3/Fn14 grew significantly faster than xenograft of PC-3/Mock, and the invasive capacity in PC-3/Fn14 was found to be higher than that of PC-3/Mock as evaluated in an invasion model of the diaphragm. Furthermore, the messenger RNA expressions of MMP-9 in PC-3/Fn14 xenografts were significantly higher than those in PC-3/Mock xenografts. Clinically, high expression of Fn14 was significantly associated with higher prostate-specific antigen recurrence rate in patients who underwent radical prostatectomy. In conclusion, the overexpression of Fn14 may contribute to multiple malignant cellular phenotypes associated with prostate cancer (PCa) progression, in part via MMP-9. TWEAK-Fn14 signaling may be a novel therapeutic target of PCa.