Inhibition of MMP-9 using a pyrrole-imidazole polyamide reduces cell invasion in renal cell carcinoma

Sato,Aya; Nagase,Hiroki; Obinata,Daisuke; Fujiwara,Kyoko; Fukuda,Noboru; Soma,Masayoshi; Yamaguchi,Kenya; Kawata,Nozomu; Takahashi,Satoru

doi:10.3892/ijo.2013.2073

Inhibition of MMP-9 using a pyrrole-imidazole polyamide reduces cell invasion in renal cell carcinoma

Authors:
- Aya Sato
- Hiroki Nagase
- Daisuke Obinata
- Kyoko Fujiwara
- Noboru Fukuda
- Masayoshi Soma
- Kenya Yamaguchi
- Nozomu Kawata
- Satoru Takahashi
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Affiliations: Department of Urology, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan, Department of Cancer Genetics, Chiba Cancer Center Research Institute, Chuo-Ku, Chiba 260-8717, Japan, Department of General Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
Published online on: August 21, 2013 https://doi.org/10.3892/ijo.2013.2073
Pages: 1441-1446

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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.

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