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

基质溶素(MMP7)是基质金属蛋白酶(MMPs)家族中最小的成员，通常由人结肠癌细胞产生，并被认为与结肠癌的进展和转移有关。在本研究中，我们测试了一种针对基质溶素的反义硫代寡核苷酸对裸鼠体内人结肠癌细胞株WiDR肝转移的影响。在培养中，该反义寡核苷酸适度地抑制了WiDR细胞分泌基质溶素。将该反义寡核苷酸注射到裸鼠的脾中，在裸鼠的肝脏中产生了大量的转移瘤结节。当反义寡核苷酸每天注射到小鼠体内11d时，转移瘤结节的形成被强烈地抑制，并呈剂量依赖关系。对肝转移的抑制率在每只小鼠120微克时达到70%以上。反义寡核苷酸对小鼠脾、肝肿瘤生长无明显抑制作用。杂乱无章的对照寡核苷酸对WiDR细胞的肝脏代谢没有影响。我们的结果证实了基质溶素在结肠癌肝转移中的重要作用，以及基质溶素反义寡核苷酸预防转移的治疗潜力。

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.