Overexpression of Fn14 promotes androgen independent prostate cancer progression through MMP-9 and correlates with poor treatment outcome - Abstract

Department of Urology, Akita University Graduate School of Medicine, Akita, Japan.

 

Fibroblast growth factor-inducible 14 (Fn14), a transmembrane receptor binding to the multifunctional cytokine 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, DU145 and PC-3, while expression was weak in androgen sensitive LNCaP cells. Fn14 knockdown using siRNAs attenuated migration, invasion, and proliferation, and enhanced apoptosis in the AIPC cell lines. Both forced overexpression of Fn14 by stable Fn14 cDNA 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-9 (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 mRNA 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 PSA 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 progression, in part via MMP-9. TWEAK-Fn14 signaling may be a novel therapeutic target of prostate cancer.

Written by:
Huang M, Narita S, Tsuchiya N, Ma Z, Numakura K, Obara T, Tsuruta H, Saito M, Inoue T, Horikawa Y, Satoh S, Habuchi T.   Are you the author?

Reference: Carcinogenesis. 2011 Aug 8. Epub ahead of print.
doi: 10.1093/carcin/bgr182

PubMed Abstract
PMID: 21828059

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