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Inhibition of peritoneal dissemination in human gastric cancer by MMP-7-specific antisense oligonucleotide
1Second Dept. of Surgery, School of Medicine, Kanazawa University, Japan. yonemu@med.kanazawa-u.ac.jp
Abstract:
MMP-7 is a matrix-degrading enzyme that is mainly produced from cancer cells, and has a great role in the invasion and metastasis of cancer. We have established a highly metastatic cell line (MKN-45-P) on the peritoneum of nude mice from MKN-45 by repeated intraperitoneal inoculation of intraperitoneal free cancer cells. By the precise screening of metastasis-related genes using reverse transcriptase-polymerase chain reaction (RT-PCR), MKN-45-P characteristically expressed more MMP-7 than the original cell line of MKN-45. In this study, we studied the effects of antisense oligonucleotides complementary to exon 3 of MMP-7 mRNA on the expression of MMP-7 and metastatic potential of MKN-45-P by using in vitro and in vivo experiments. RT-PCR and western blot analysis demonstrated that 10 microM antisense oligonucleotides suppressed MMP-7 expression at both the mRNA level (84%) and protein level (56%). Antisense oligonucleotides, specific for MMP-7 suppressed invasion by MKN-45-P cells without influencing proliferation. On the other hand, scrambling sequence control oligonucleotides did not show any inhibitory effects. In addition, survival of MKN-45-P bearing mice, which had been treated for 48 hrs with antisense oligonucleotides before intraperitoneal injection, was significantly better than that of control mice. In contrast, control oligonucleotides did not influence the survival of mice with the peritoneal dissemination model. These results strongly suggest that MMP-7 may have a great role in the formation of peritoneal dissemination in gastric cancer, and the molecular control of MMP-7 using antisense oligonucleotides may be a hopeful treatment modality for peritoneal dissemination.
Insights
Matrix metalloproteinase-7 (MMP-7) fuels cancer invasion. Antisense oligonucleotides targeting MMP-7 reduced gastric cancer cell metastasis and improved survival in mice, suggesting a potential therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis Research
Background:
- Matrix metalloproteinase-7 (MMP-7) is a key enzyme in cancer invasion and metastasis.
- A highly metastatic gastric cancer cell line (MKN-45-P) was established in nude mice.
- MKN-45-P cells exhibited significantly higher MMP-7 expression compared to the parent MKN-45 cell line.
Purpose of the Study:
- To investigate the role of MMP-7 in gastric cancer peritoneal dissemination.
- To evaluate the efficacy of antisense oligonucleotides targeting MMP-7 in inhibiting cancer cell metastasis and improving survival.
Main Methods:
- Utilized reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot to assess MMP-7 expression at mRNA and protein levels.
- Employed in vitro and in vivo experiments to test the effects of MMP-7-specific antisense oligonucleotides on cancer cell invasion, proliferation, and mouse survival.
- Used scrambled sequence oligonucleotides as a control.
Main Results:
- Antisense oligonucleotides significantly suppressed MMP-7 expression by 84% at the mRNA level and 56% at the protein level.
- MMP-7 inhibition reduced the invasive potential of MKN-45-P cells without affecting proliferation.
- Mice treated with MMP-7 antisense oligonucleotides showed significantly improved survival rates compared to control groups.
Conclusions:
- MMP-7 plays a critical role in the formation of peritoneal dissemination in gastric cancer.
- Targeting MMP-7 with antisense oligonucleotides represents a promising therapeutic approach for managing peritoneal metastasis.
