title: Dual Therapeutic Effects of Interferon-α Gene Therapy in a Rat Hepatocellular Carcinoma Model With Liver Cirrhosis.
abstract: Human hepatocellular carcinoma (HCC) often arises from a background of liver cirrhosis. Therefore, in order to develop therapeutic strategies for HCC, an animal model bearing multifocal liver tumors accompanied by liver cirrhosis is a preferred experimental setting. In this study, we developed a rapid and reproducible method for generating such a model in rats by weekly administration of diethylnitrosamine (DEN) at doses based on body weight (BW). By adjusting the duration of administration of DEN, the animals could be induced to develop HCC alone, or HCC and liver cirrhosis simultaneously. The latter model was used for evaluating the therapeutic effects of adenoviral delivery of interferon-α (IFN-α). Our results demonstrated that targeting of IFN-α expression to the liver significantly reduced liver tumor volume and ameliorated liver cirrhosis. Mechanistic studies revealed that IFN-α gene therapy induced immunomodulatory, antiproliferative, and proapoptotic activities that were effective in the control of tumor growth, and reduced the expressions of transforming growth factor-β (TGF-β) and tissue inhibitor of metalloproteinase-1 (TIMP-1), leading to amelioration of liver cirrhosis. These results suggest that IFN-α gene therapy is a promising strategy to treat HCC patients who have concomitant liver cirrhosis.
authors.affiliation: Department of Surgery, National Taiwan University College of Medicine, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Kai-Wen
authors.initials: KW
authors.lastname: Huang
authors.affiliation: Graduate Institute of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Yung-Chi
authors.initials: YC
authors.lastname: Huang
authors.affiliation: Graduate Institute of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Kuo-Feng
authors.initials: KF
authors.lastname: Tai
authors.affiliation: Graduate Institute of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Bo-Hua
authors.initials: BH
authors.lastname: Chen
authors.affiliation: Department of Surgery, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Po-Huang
authors.initials: PH
authors.lastname: Lee
authors.affiliation: Graduate Institute of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address: lhhwang@ntu.edu.tw.
authors.forename: Lih-Hwa
authors.initials: LH
authors.lastname: Hwang