Inhibition of peritoneal dissemination in human gastric cancer by MMP-7-specific antisense oligonucleotide

MMP-7 is a matrix-degrading enzyme that is mainly produced from cancer cell s, and has a great role in the invasion and metastasis of cancer. We have e stablished a highly metastatic cell line (MKN-45-P) on the peritoneum of nu de mice from MKN-45 by repeated intraperitoneal inoculation of intraperiton eal free cancer cells. By the precise screening of metastasis-related genes using reverse transcriptase-polymerase chain reaction (RT-PCR), MKN-45-P c haracteristically expressed more MMP-7 than the original cell line of MKN-4 5. In this study, we studied the effects of antisense oligonucleotides comp lementary 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 an d western blot analysis demonstrated that 10 muM 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, scr ambling sequence control oligonucleotides did not show any inhibitory effec ts. 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.