Adenovirus-mediated NK4 gene therapy suppresses hepatocellular carcinoma.

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Hepatocyte growth factor(HGF) is involved in malignant behavior of cancers as a mediator in tumor-stromal interaction, enhancing invasion and metastasis. NK4, is an internal fragment of HGF, acts as an angiogenesis inhibitor as well as an HGP antagonist. This study was designed to assess a potential of NK4 gene therapy for hepatocellular carcinoma(HCC) that is one of the most common malignant neoplasm worldwide. Human HCC cells(Huh7) were used for this study. NK4 gene transduction was mediated by recombinant adenovirus(Ad-NK4). To assess a function of NK4 as an HGF antagonist, the effects of Ad-NK4 on the biological behavior of HCC cells were studied in vitro. Huh7 cells were subcutaneously injected in nude mice to establish s.c.tumors. Ten days after tumor inoculation, the animals were injected Ad-NK4 into tumor 2 consecutive days. Control animals were received ph osphate-buffered saline(PBS) or Ad-LacZ. Next, HuH7 cells were injected into the portal vein in severe combined immunodeficiency(SCID) mice to establish a hepatic tumor. Two days after tumor inoculation, Ad-NK4 or Ad-LacZ was injected intraveneouly. Histological examination of liver tumor was performed at 30 days after tumor inoculation. NK4 inhibited HGF-induced phosphorylation of c-Met in Huh7 cells whereas NK4 did not affect on cell growth. On the contrary, invasion and migration induced by HGF were inhibited by NK4. NK4 transfection markedly suppressed growth of s.c.tumors, and apoptosis was recognized in the tumor. As the result of immunohistochemical staining of CD31, angiogenesis was obviously inhibited in the tumor that was transfected NK4. In liver tumor model, NK4 transfection significantly inhibited the growth of tumors in the liver and improved survival. Inhibition of angiogenesis was also seen in the liver tumor that was transfected NK4. NK4 gene therapy markedly suppressed tumor growth by inhibiting angiogenesis. This therapy seems to have great potential for the treatment of HCC.