Cancer cell targeting with mouse TERT-specific group I intron of Tetrahymena thermophila.
Telomerase reverse transcriptase (TERT), which prolongs the replicative life span of cells, is highly upregulated in 85-90% of human cancers, whereas most normal somatic tissues in humans express limited levels of the telomerase activity. Therefore, TERT has been a potential target for anticancer therapy. Recently, we described a new approach to human cancer gene therapy, which is based on the group I intron of Tetrahymena thermophila. This ribozyme can specifically mediate RNA replacement of human TERT (hTERT) transcript with a new transcript harboring anticancer activity through a trans-splicing reaction, resulting in selective regression of hTERT-positive cancer cells. However, to validate the therapeutic potential of the ribozyme in animal models, ribozymes targeting inherent transcripts of the animal should be developed. In this study, we developed a Tetrahymena-based trans-splicing ribozyme that can specifically target and replace the mouse TERT (mTERT) RNA. This ribozyme can trigger transgene activity not only also in mTERT-expressing cells but hTERT-positive cancer cells. Importantly, the ribozyme could selectively induce activity of the suicide gene, a herpes simplex virus thymidine kinase gene, in cancer cells expressing the TERT RNA and thereby specifically hamper the survival of these cells when treated with ganciclovir. The mTERT-targeting ribozyme will be useful for evaluation of the RNA replacement approach as a cancer gene therapeutic tool in the mouse model with syngeneic tumors.
Ban
Guyee
G
Department of Molecular Biology, BK21 Graduate Program for RNA Biology, Institute of Nanosensor and Biotechnology, Dankook University, Yongin 448-701, Korea.
Song
Min-Sun
MS
Lee
Seong-Wook
SW
D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor; D005091:Exons / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D041722:Genes, Transgenic, Suicide / Q000187:drug effects; D006801:Humans; D007438:Introns / Q000235:genetics*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics; D008168:Lung / Q000196:embryology; D051379:Mice; D019098:Telomerase / Q000235:genetics* / Q000627:therapeutic use*; D016808:Tetrahymena thermophila / Q000201:enzymology / Q000235:genetics*
D000970:Antineoplastic Agents; D019098:Telomerase