title: Combining transfer of TTF-1 and Pax-8 gene: a potential strategy to promote radioiodine therapy of thyroid carcinoma.
abstract: Cotransfer of thyroid-specific transcription factor (TTF)-1 and Pax-8 gene to tumor cells, resulting in the re-expression of iodide metabolism-associated proteins, such as sodium iodide symporter (NIS), thyroglobulin (Tg), thyroperoxidase (TPO), offers the possibility of radioiodine therapy to non-iodide-concentrating tumor because the expression of iodide metabolism-associated proteins in thyroid are mediated by the thyroid transcription factor TTF-1 and Pax-8. The human TTF-1 and Pax-8 gene were transducted into the human thyroid carcinoma (K1 and F133) cells by the recombinant adenovirus, AdTTF-1 and AdPax-8. Re-expression of NIS mRNA and protein, but not TPO and Tg mRNA and protein, was detected in AdTTF-1-infected F133 cells, following with increasing radioiodine uptake (6.1-7.4 times), scarcely iodide organification and rapid iodide efflux (t(1/2) ≈ 8-min in vitro, t(1/2) ≈ 4.7-h in vivo). On contrast, all of the re-expression of NIS, TPO and Tg mRNA and proteins were detected in F133 cells coinfected with AdTTF-1 and AdPax-8. AdTTF-1- and AdPax-8-coinfected K1 and F133 cells could effectively accumulate radioiodine (6.6-7.5 times) and obviously retarded radioiodine retention (t(1/2) ≈ 25-30-min in vitro, t(1/2) ≈ 12-h in vivo) (P<0.05). Accordingly, the effect of radioiodine therapy of TTF-1 and Pax-8 cotransducted K1 and F133 cells (21-25% survival rate in vitro) was better than that of TTF-1-transducted cells (40% survival rate in vitro) (P<0.05). These results indicate that single TTF-1 gene transfer may have limited efficacy of radioiodine therapy because of rapid radioiodine efflux. The cotransduction of TTF-1 and Pax-8 gene, with resulting NIS-mediated radioiodine accumulation and TPO and Tg-mediated radioiodine organification and intracellular retention, may lead to effective radioiodine therapy of thyroid carcinoma.
authors.affiliation: Department of Nuclear Medicine, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: D
authors.initials: D
authors.lastname: Mu
authors.forename: R
authors.initials: R
authors.lastname: Huang
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.forename: X
authors.initials: X
authors.lastname: Ma
authors.forename: C
authors.initials: C
authors.lastname: Lou
authors.forename: A
authors.initials: A
authors.lastname: Kuang
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism; D002277:Carcinoma / Q000000981:diagnostic imaging / Q000378:metabolism / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism; D007457:Iodine Radioisotopes; D033862:Iron-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D011877:Radionuclide Imaging; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D013954:Thyroglobulin / Q000235:genetics / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000532:radiotherapy*; D014018:Tissue Distribution; D014157:Transcription Factors; D023041:Xenograft Model Antitumor Assays; D000099209:Sodium-Iodide Symporters
chemical_list: D001324:Autoantigens; D004268:DNA-Binding Proteins; D007453:Iodide Peroxidase; D007457:Iodine Radioisotopes; D033862:Iron-Binding Proteins; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; D011994:Recombinant Proteins; D027981:Symporters; D013954:Thyroglobulin; D014157:Transcription Factors; D000099209:Sodium-Iodide Symporters; C083325:PAX8 protein, human; C504003:TTF1 protein, human; C056658:TPO protein, human