Abrogation of lung metastasis of human fibrosarcoma cells by ribozyme-mediated suppression of integrin α6 subunit expression

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Abstract
The interaction of tumor cells with the basement membrane plays a crucial role in tumor metastasis. VLA‐6 (α6β1) integrin is one of the major surface receptors for the basement membrane, specifically recognizing laminin. To study the role of VLA‐6 integrin in tumor invasion and metastasis, we synthesized a ribozyme that selectively degrades the integrin α6 subunit mRNA. The catalytic activity of the ribozyme was verified by in vitro cleavage of α6 subunit mRNA. Introduction of the anti‐α6 ribozyme gene into the human fibrosarcoma cell line HT1080 yielded stable transfectants, which expressed a significantly reduced level of integrin α6 mRNA. Flow cytometric analysis showed that the surface expression of VLA‐6, but not other integrins, was reduced by approximately 70% in transfected cells. Ribozyme‐transfected cells were less adherent to laminin‐coated substrata and less invasive into reconstituted basement membrane than mock‐transfected cells. When injected i.v. into nude mice, ribozyme‐transfected cells produced no lung metastasis in all except 1 of 35 mice, though mock‐transfected cells produced multiple lung metastases in 22 of 29 mice. Our results indicate that VLA‐6 integrin plays a critical role in tumor invasion and metastasis and may serve as a potential target for eradication of tumor metastasis in the lung.