論文 - 詳細
| RRC ID | 2356 |
|---|---|
| 著者 | Shimura H, Suzuki H, Miyazaki A, Furuya F, Ohta K, Haraguchi K, Endo T, Onaya T. |
| タイトル | Transcriptional activation of the thyroglobulin promoter directing suicide gene expression by thyroid transcription factor-1 in thyroid cancer cells. |
| ジャーナル | Cancer Res |
| Abstract |
Gene therapy with thyroglobulin (TG) promoter and a prodrug/suicide gene combination may prove useful as a treatment for thyroid carcinoma. However, most poorly differentiated and anaplastic thyroid carcinomas have lost the ability to express the TG gene expression accompanied by loss of transcription factors [thyroid transcription factor-1 (TTF-1), TTF-2, or Pax-8] interacting with the TG promoter. In anticipation of developing transcriptionally targeted gene therapy of TG-nonproducing thyroid carcinomas, we investigated the effect of TTF-1 gene transfer on TG promoter activity and the cytotoxic effect obtained by the TG promoter-driven HSV-TK gene along with ganciclovir in thyroid carcinoma and nonthyroidal cells. Using a chimeric construct containing the 5'-flanking region of the rat TG gene between -826 and +39 bp and the luciferase gene, TG promoter activity was detected in a normal rat thyroid cell line (FRTL-5), but not in a dedifferentiated line of thyroid cells (FRT) expressing Pax-8 but not TTF-1, TTF-2, or TG [TTF-1(-)/TTF-2(-)/Pax-8(+)/TG(-)], or in a human papillary thyroid carcinoma cell line [BHP15-3; TTF-1(-)/TTF-2(-)/Pax-8(-)/TG(-)], a human pulmonary cell line [H441; TTF-1(+)/TTF-2(-)/Pax-8(-)/TG(-)], or a dog kidney epithelial cell line [MDCK; TTF-1(-)/TTF-2(-)/Pax-8(+)/TG(-)]. Cotransfection of the TTF-1 expression vector stimulated TG promoter activity in FRT and BHP15-3 dedifferentiated thyroid cells, but not in H441 pulmonary cells. Only weak activation was observed in MDCK kidney cells. We then constructed recombinant adenovirus vectors, AdTTF-1 and ADTGTK: AdTTF-1 contained cytomegalovirus promoter and rat TTF-1 cDNA; AdTGTK carried the TG promoter-driven HSV-TK gene. Infection with AdTGTK and combined with GCV treatment induced a cytotoxic effect in FRTL-5 cells but not in dedifferentiated thyroid or nonthyroid cells. Cotransduction of AdTTF-1 and AdTGTK permitted 90% cytotoxicity for BHP15-3 and >95% cytotoxicity for FRT, as well as for BHP7-13 and BHP18-21v thyroid cancer cell lines [both/TTF1(-)/TTF-2(-)/Pax-8(+)/TG(-)]. In contrast, little cytotoxicity was seen for H441 and MDCK cell lines even with 300 microg/ml of ganciclovir. These results suggest that cotransduction of a TG promoter-controlled suicide gene and the TTF-1 gene by adenoviral vectors confers transcriptionally targeted gene-mediated cytotoxicity in poorly differentiated thyroid carcinoma cells unable to express the TG gene. |
| 巻・号 | 61(9) |
| ページ | 3640-6 |
| 公開日 | 2001-5-1 |
| PMID | 11325833 |
| MeSH | Adenoviridae / genetics Animals Carcinoma, Papillary / drug therapy Carcinoma, Papillary / genetics* Carcinoma, Papillary / therapy Ganciclovir / pharmacokinetics Ganciclovir / pharmacology Gene Expression Regulation, Neoplastic Genetic Therapy / methods* Genetic Vectors / genetics HeLa Cells Humans Nuclear Proteins / genetics* Promoter Regions, Genetic Rats Simplexvirus / enzymology Simplexvirus / genetics Thymidine Kinase / genetics Thymidine Kinase / metabolism Thyroglobulin / biosynthesis Thyroglobulin / genetics* Thyroid Neoplasms / drug therapy Thyroid Neoplasms / genetics* Thyroid Neoplasms / therapy Thyroid Nuclear Factor 1 Transcription Factors / genetics* Transcriptional Activation* Transduction, Genetic Tumor Cells, Cultured |
| IF | 2.751 |
| 引用数 | 58 |
| WOS 分野 | GASTROENTEROLOGY & HEPATOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 各媒体での言及数の合計 | 0 |
| リソース情報 | |
| ヒト・動物細胞 | MDCK(RCB0995) |