EFFECT OF MATRILYSIN ANTISENSE OLIGONUCLEOTIDES ON METASTASIS AND INVASION OF COLON CANCER.

基质溶素（Matrilysin，MMP-7）是基质金属蛋白酶（matrix metalloproteinase，MMP）家族中最小的成员，通常由人结肠癌细胞产生，并被认为与这种类型癌症的进展和转移有关。在本研究中，我们测试了基质溶解素特异性反义硫代磷酸寡核苷酸对裸鼠中人结肠癌细胞系WiDr肝转移的影响。反义寡核苷酸适度抑制WiDr细胞分泌基质溶解素，将WiDr细胞注射到裸鼠脾脏中，在肝脏中产生许多转移性肿瘤结节。小鼠11天，转移性肿瘤结节的形成以剂量依赖性方式被强烈抑制。在每只小鼠120 μ g寡核苷酸的剂量下，获得了超过70%的肝转移抑制。反义寡核苷酸在脾和肝中不抑制肿瘤生长。乱序对照寡核苷酸对WiDr细胞的肝转移没有影响。我们的研究结果表明，在人类结肠癌肝转移的基质溶解素和治疗潜力的基质溶解素反义寡核苷酸的预防转移的重要作用。

Matrilysin (MMP-7), the smallest member of the matrix metalloproteinase (MMP) family, is commonly produced by human colon carcinoma cells and has been suggested to be involved in the progression and metastasis of this type of cancer. In the present study, we tested the effect of a matrilysin specific antisense phosphorothioate oligonucleotide on liver metastasis of the human colon carcinoma cell line WiDr in nude mice.In culture, the antisense oligonucleotide moderately inhibited the secretion of matrilysin by WiDr cells.Injection of WiDr cells into the spleen of nude mice produced many metastatic tumor nodules in the liver.When the antisense oligonucleotide was injected daily into the mice for 11 days, the formation of the metastatic tumor nodules was strongly inhibited in a dose dependent manner. An inhibition of liver metastasis of over 70 % was obtained at a dose of 120 ug of the oligonucleotide per mouse. The antisense oligonucleotides did not inhibit tumor growth in spleen and in liver. A scrambled control oligonucleotide has no effect on liver metrastasis of WiDr cells. Our results demonstrate an important role of matrilysin in liver metastasis of human colon cancer and the therapeutic potential of matrilysin antisense oligonucleotides for the prevention of metastasis.