Abstract
We previously reported that the retroviral vector (LNAFW0.3TK) expressing the herpes simplex thymidine kinase (HSVtk) gene under the control of the 0.3 kb human α-fetoprotein (AFP) promoter provided the ganciclovir (GCV)-mediated cytotoxicity in the high AFP-producing (HuH-7) but not in the low AFP-producing (huH-1/cl.2) human hepatoma cells. In the present study, we constructed the retroviral vector (LNAFM0.3TK) in which the HSVtk gene expression is regulated by the variant-type of the 0.3 kb human AFP promoter with a G-to-A substitution at nucleotide −119, a point mutation responsible for hereditary persistence of human AFP and the vector was applied to three human hepatoma cell lines, HuH-7, huH-1/cl.2 and intermediate AFP-producing cells (PLC/PRF/5). By the reporter gene transfection assay, the activity of the variant-type of the promoter was much higher than that of the wild-type of the promoter in both HuH-7 and huH-1/cl.2 cells. Consistent with this, LNAFM0.3TK infection could sensitize huH-1/cl.2 cells, as well as HuH-7 and PLC/PRF/5 cells to GCV, but did not affect cell growth of nonhepatoma cells (HeLa). In addition, the bystander effect was achieved more efficiently by LNAFM0.3TK infection than LNAFW0.3TK infection in HuH-7 cells. These results suggest that the variant-type of the human AFP promoter ensures the therapeutic gene expression in gene therapy particularly for the low AFP-producing hepatoma cells.
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References
Levin B, Amos C . Therapy of unresectable hepatocellular carcinoma New Engl J Med 1995 332: 1294–1296
Sato Y et al. Early recognition of hepatocellular carcinoma based on altered profiles of alpha-fetoprotein New Engl J Med 1993 328: 1802–1806
Liver Cancer Study Group of Japan . Primary liver cancer in Japan. Clinicopathologic features and results of surgical treatment Ann Surg 1990 211: 277–287
Huber BE, Richards CA, Krenitsky TA . Retrovirus-mediated gene therapy for the treatment of hepatocellular carcinoma: an innovative approach for cancer therapy Proc Natl Acad Sci USA 1991 88: 8039–8043
Ido A et al. Gene therapy for hepatoma cells using a retrovirus vector carrying herpes simplex virus thymidine kinase gene under the control of human alpha-fetoprotein gene promoter Cancer Res 1995 55: 3105–3109
Kuriyama S et al. Tissue-specific expression of HSVtk gene can induce efficient antitumor effect and protective immunity to wild-type hepatocellular carcinoma Int J Cancer 1997 71: 470–475
Miller DG, Adam MA, Miller AD . Gene transfer by retrovirus vectors occurs only in cells that are actively replicating at the time of infection Mol Cell Biol 1990 10: 4239–4242
Moolten FL . Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: paradigm for a prospective cancer control strategy Cancer Res 1986 46: 5276–5281
Paul S, Dummer S . Topics in clinical pharmacology: ganciclovir Am J Med Sci 1992 304: 272–277
McVey JH et al. A G→A substitution in an HNF I binding site in the human alpha-fetoprotein gene is associated with hereditary persistence of alpha-fetoprotein (HPAFP) Hum Mol Genet 1993 2: 379–384
Freeman SM et al. The ‘bystander effect’: tumor regression when a fraction of the tumor mass is genetically modified Cancer Res 1993 53: 5274–5283
Alpert ME, Uriel J, Nechaud Bd . Alpha-1 fetoglobulin in the diagnosis of human hepatoma New Engl J Med 1968 278: 984–986
Hatano M et al. Hepatocyte growth factor down-regulates the alpha-fetoprotein gene expression in PLC/PRF/5 human hepatoma cells Biochem Biophys Res Commun 1992 189: 385–391
Mitsuoka S et al. Inhibitory effect of prostaglandin delta 12-PGJ2 on cell proliferation and alpha-fetoprotein expression in HuH-7 human hepatoma cells Prostaglandins 1992 43: 189–197
Nakao K et al. Transforming growth factor beta 1 differentially regulates alpha-fetoprotein and albumin in HuH-7 human hepatoma cells Biochem Biophys Res Commun 1991 174: 1294–1299
Nakata K et al. A possible mechanism of inverse developmental regulation of alpha-fetoprotein and albumin genes. Studies with epidermal growth factor and phorbol ester J Biol Chem 1992 267: 1331–1334
Tsutsumi T et al. Regulation of albumin and alpha-fetoprotein gene expression by colloid osmotic pressure in human hepatoma cells Gastroenterology 1993 104: 256–262
Nakabayashi H et al. A position-dependent silencer plays a major role in repressing alpha-fetoprotein expression in human hepatoma Mol Cell Biol 1991 11: 5885–5893
Vacher J, Tilghman SM . Dominant negative regulation of the mouse alpha-fetoprotein gene in adult liver Science 1990 250: 1732–1735
Nahon JL et al. The rat alpha-fetoprotein and albumin genes. Transcriptional control and comparison of the sequence organization and promoter region J Biol Chem 1987 262: 12479–12487
Sawadaishi K, Morinaga T, Tamaoki T . Interaction of a hepatoma-specific nuclear factor with transcription-regulatory sequences of the human alpha-fetoprotein and albumin genes Mol Cell Biol 1988 8: 5179–5187
Bois-Joyeux B, Danan JL . Members of the CAAT/enhancer-binding protein, hepatocyte nuclear factor-1 and nuclear factor-1 families can differentially modulate the activities of the rat alpha- fetoprotein promoter and enhancer Biochem J 1994 301: 49–55
Otsuru A et al. Analysis of alpha-fetoprotein gene expression in hepatocellular carcinoma and liver cirrhosis by in situ hybridization Cancer 1988 62: 1105–1112
Ng IO et al. Prognostic significance of proliferating cell nuclear antigen expression in hepatocellular carcinoma Cancer 1994 73: 2268–2274
Mawatari F et al. Retrovirus-mediated gene therapy for hepatocellular carcinoma: selective and enhanced suicide gene expression regulated by human a-fetoprotein enhancer directly linked to its promoter Cancer Gene Ther 1998 5: 301–306
Ueki T et al. Retrovirus-mediated gene therapy for human hepatocellular carcinoma transplanted in athymic mice Int J Mol Med 1998 1: 671–675
Kanai F et al. Gene therapy for alpha-fetoprotein-producing human hepatoma cells by adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene Hepatology 1996 23: 1359–1368
Wills KN et al. Gene therapy for hepatocellular carcinoma: chemosensitivity conferred by adenovirus-mediated transfer of the HSV-1 thymidine kinase gene Cancer Gene Ther 1995 2: 191–197
Nakabayashi H et al. Growth of human hepatoma cell lines with differentiated functions in chemically defined medium Cancer Res 1982 42: 3858–3863
Nakabayashi H et al. Phenotypical stability of a human hepatoma cell line, HuH- 7, in long-term culture with chemically defined medium Gann 1984 75: 151–158
Tsutsumi T et al. Reciprocal regulation of alpha-fetoprotein and albumin gene expression by butyrate in human hepatoma cells Gastroenterology 1994 107: 499–504
Felgner PL et al. Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure Proc Natl Acad Sci USA 1987 84: 7413–7417
Gorman CM, Moffat LF, Howard BH . Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells Mol Cell Biol 1982 2: 1044–1051
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Ishikawa, H., Nakata, K., Mawatari, F. et al. Utilization of variant-type of human α-fetoprotein promoter in gene therapy targeting for hepatocellular carcinoma. Gene Ther 6, 465–470 (1999). https://doi.org/10.1038/sj.gt.3300870
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DOI: https://doi.org/10.1038/sj.gt.3300870
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