title: Inhibition of MMP-9 using a pyrrole-imidazole polyamide reduces cell invasion in renal cell carcinoma.
abstract: We investigated the clinical significance of the expression levels of matrix metalloproteinase 9 (MMP-9) in renal cell carcinoma (RCC). In addition, we validated the efficacy of pyrrole imidazole polyamide (PIP) targeting MMP-9 on inhibiting proliferation and invasion of RCC. We evaluated the expression levels of MMP-9 in 249 RCC specimens by immunostaining and analyzed the association between MMP-9 expression levels and cancer-specific survival. Furthermore, in a human RCC cell line, Caki-2, we tested the effect of a couple of PIPs targeting MMP-9 one recognizing an NF-κB binding site (MMP-9-NF-κB PIP) and another for the AP-1 binding site (MMP-9-AP-1 PIP) in the MMP-9 promoter. The expression levels of MMP-9, proliferative activity and invasive capability were tested by quantitative PCR, WST8 assay and Matrigel invasion assay, respectively. By immunostaining of the clinical specimens, strong MMP-9 staining was proven to be a significant predictor of poor prognosis for cancer-specific survival (P<0.01). In Caki-2 cells, MMP-9-NF-κB PIP significantly reduced the expression levels of MMP-9 mRNA and inhibited cell invasion, but did not affect the cell proliferation activity. On the other hand, no effect was found in MMP-9-AP-1 PIP on MMP-9 mRNA expression, cell proliferation and invasion. We confirmed the inhibitory effects of MMP-9-NF-κB PIP on the expression of MMP-9 and subsequent invasion of Caki-2 cells. Since it was clearly shown that high MMP-9 expression levels were associated with poor prognosis of RCC, MMP-9 is a potential candidate target for RCC treatment. Transcription therapy using a minor groove binder, such as NF-κB PIP, may be a potential therapeutic agent for RCC, although further investigation is required.
authors: Department of Urology, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan.
authors: Aya
authors: A
authors: Sato
authors: Hiroki
authors: H
authors: Nagase
authors: Daisuke
authors: D
authors: Obinata
authors: Kyoko
authors: K
authors: Fujiwara
authors: Noboru
authors: N
authors: Fukuda
authors: Masayoshi
authors: M
authors: Soma
authors: Kenya
authors: K
authors: Yamaguchi
authors: Nozomu
authors: N
authors: Kawata
authors: Satoru
authors: S
authors: Takahashi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009757:Nylons / Q000494:pharmacology*; D011379:Prognosis; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D007093:Imidazoles; D061965:Matrix Metalloproteinase Inhibitors; D009757:Nylons; D011758:Pyrroles; D012333:RNA, Messenger; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9