title: Overexpression of Fn14 promotes androgen-independent prostate cancer progression through MMP-9 and correlates with poor treatment outcome.
abstract: 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.
authors.affiliation: Department of Urology, Akita University Graduate School of Medicine, Akita 010-8543, Japan.
authors.forename: Mingguo
authors.initials: M
authors.lastname: Huang
authors.forename: Shintaro
authors.initials: S
authors.lastname: Narita
authors.forename: Norihiko
authors.initials: N
authors.lastname: Tsuchiya
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Ma
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Numakura
authors.forename: Takashi
authors.initials: T
authors.lastname: Obara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsuruta
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Saito
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Inoue
authors.forename: Yohei
authors.initials: Y
authors.lastname: Horikawa
authors.forename: Shigeru
authors.initials: S
authors.lastname: Satoh
authors.forename: Tomonori
authors.initials: T
authors.lastname: Habuchi
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D000074049:Cytokine TWEAK; D018450:Disease Progression; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000074049:Cytokine TWEAK; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; D048069:Tumor Necrosis Factors; D020780:Matrix Metalloproteinase 9