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Interruption of Activin A Autocrine Regulation by Antisense Oligodeoxynucleotides Accelerates Liver Tumor Cell Proliferation¹

The Clayton Foundation Laboratories for Peptide Biology (K.T., J.-J.L., W.V.), The Salk Institute, La Jolla, California 92037; Second Department of Surgery (K.T., Y.I., N.M., T.I.) and Department of Pathology (Y.N.), Yokohama City University School of Medicine, 3–9 Fukuura Kanazawa-ku Yokohama 236-0004, Japan; and Medical Science Division (M.M.), Hitachi Chemical Research Center, Irvine, California 92715

Address all correspondence and requests for reprints to: Wylie Vale, The Salk Institute, The Clayton Foundation for Peptide Biology, 10010 North Torrey Pines Road, La Jolla, California 92037.

Administration of activin A, a member of the transforming growth factor-ß superfamily inhibits hepatocyte proliferation in vitro and reduces liver mass in vivo. However, a role of endogenous activin A in local growth modulation has not been established in any system. The aim of this study was to examine the production of activin A in the human hepatoma cell line HLF and to explore a possible autocrine role of activin as a cell growth inhibitor by blocking production of endogenous activin using antisense oligodeoxynucleotides. Administration of exogenous activin A suppressed HLF cell growth, and immunoreactive activin A was shown to be produced in the cells at confluency by Western blotting analysis. Cells were exposed to phosphorothioate-modified oligodeoxynucleotides, synthesized with antisense or randomly shuffled base sequences of activin ßA subunit messenger RNA, under serum-free conditions. Uptake of the oligodeoxynucleotides into the cells was confirmed by use of fluorescein isothiocyanate-labeled oligodeoxynucleotides. Administration of antisense oligodeoxynucleotides reduced activin A production as confirmed by both competitive PCR and Western blotting. Activin ßA antisense oligodeoxynucleotides significantly increased cell proliferation compared with controls. These findings are consistent with the existence of an autocrine role of activin A as an inhibitor of hepatocyte proliferation.

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