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Up-Regulation of c-met Protooncogene Product Expression through Hypoxia-Inducible Factor-1 Is Involved in Trophoblast Invasion under Low-Oxygen Tension

Department of Obstetrics and Gynecology (M.H., M.S., M.T., Y.O., R.M., A.I., M.O., K.T., Y.M.), Osaka University Faculty of Medicine, Suita, Osaka 565-0871, Japan; Osaka Medical Center for Cancer and Cardiovascular Diseases (T.T.), Higashinari-ku, Osaka 537-8511, Japan; and Sakai Municipal Hospital (T.Y.), Sakai, Osaka 590-0064, Japan

Address all correspondence and requests for reprints to: Masami Hayashi, M.D., Ph.D., Department of Obstetrics and Gynecology, Osaka University Faculty of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail: masami{at}gyne.med.osaka-u.ac.jp.

During early pregnancy, the invasion of trophoblast cells into the decidua of the uterus is one of the essential steps in appropriate placentation. In this period, trophoblast cells are exposed to a relatively low-oxygen environment. The c-met protooncogene product (Met), which is a high-affinity receptor for hepatocyte growth factor, plays an important role in controlling the invasion of many types of cells. The present study was designed to investigate the effect of low-oxygen tension on Met expression and the invasiveness of trophoblast cells isolated from early-stage human placenta and trophoblast-derived BeWo cells and JEG-3 cells. RT-PCR and immunoblot analyses demonstrated that low-oxygen tension (1% O₂) stimulated the expression of Met mRNA and protein, respectively. Hepatocyte growth factor production in the cells was not affected by oxygen tension. Transient transfection of BeWo cells with a hypoxia-inducible factor (HIF)-1 expression vector to induce exogenous expression of HIF-1 significantly increased the level of Met mRNA and protein, compared with transfection of a control vector. To examine whether this up-regulation of Met was directly induced by HIF-1, we performed the chromatin immunoprecipitation assay, which revealed that HIF-1 binds to the promoter region of the Met gene under low-oxygen tension. JEG-3 cells cultured under 1% O₂ showed a more invasive character than those cultured under 20% O₂, whereas inhibition of Met expression by small interfering RNAs prevented the low-oxygen, tension-induced invasiveness. These results suggest that the induction of Met expression by low-oxygen tension may play an important role in the physiology of early pregnancy by promoting the invasion of trophoblast cells into the decidua of the uterus.

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