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A novel approach for inducing enhanced and selective transgene expression in hepatocellular‐carcinoma cells
Author(s) -
Cao Guangwen,
Kuriyama Shigeki,
Tsujinoue Hirohisa,
Chen Qiuli,
Mitoro Akira,
Qi Zhongtian
Publication year - 2000
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/1097-0215(20000715)87:2<247::aid-ijc16>3.0.co;2-c
Subject(s) - hepatocellular carcinoma , transgene , cancer research , carcinoma , biology , computational biology , gene , genetics
Utility of the α‐fetoprotein ( afp ) promoter for gene therapy against hepatocellular carcinoma (HCC) is limited because of the weak promoter activity. To circumvent this, the 5.1‐kb 5`‐flanking sequence of the human afp gene including the entire enhancer and silencer regions as well as the promoter region was employed for achieving strong, HCC‐selective transgene expression. To thoroughly inhibit the promoter activity of the 5`‐flanking sequence of the human afp gene, the afp 5`‐flanking region was inserted downstream of the human interleukin‐2 ( il ‐2) gene controlled by the simian‐virus‐40 ( SV40 ) early promoter. il ‐2‐production ability of HCC cells transduced with the construct was significantly enhanced compared with that transduced with the same construct lacking the afp 5`‐flanking region. Importantly, il ‐2 production of non‐HCC cells was substantially inhibited by the addition of the afp 5`‐flanking region to the construct. When the afp 5`‐flanking region was inserted downstream of the human tumor‐necrosis‐factor‐α ( tnf ‐α) gene controlled by the retrovirus long‐terminal‐repeat ( LTR ) enhancer/promoter, tnf ‐α production ability of HCC cells was significantly enhanced and that of non‐HCC cells was significantly suppressed compared with that transduced with the same construct lacking the afp 5`‐flanking region. Our results indicated that the afp 5`‐flanking region gave the enhanced HCC‐selective activity to the non‐tissue specific SV40 early promoter and LTR enhancer/promoter. It is essential for successful gene therapy to induce strong, target‐cell‐selective transgene expression. This novel strategy, therefore, may contribute to the establishment of HCC‐selective cancer gene therapy. Int. J. Cancer 87:247–252, 2000. © 2000 Wiley‐Liss, Inc.