Gene expression responses in vivo by human telomerase reverse transcriptase (hTERT)-targeting trans-splicing ribozyme.
A trans-splicing ribozyme which can specifically reprogram human telomerase reverse transcriptase (hTERT) RNA was previously suggested as a useful agent for tumor-targeted gene therapy. In this study, we evaluated in vivo function of the hTERT-targeting trans-splicing ribozymes by employing the molecular analysis of expression level of genes affected by the ribozyme delivery into peritoneal carcinomatosis mice model. To this effect, we constructed adenoviral vector encoding the specific ribozyme. Noticeably, more than four-fold reduction in the level of hTERT RNA was observed in tumor nodules by the systemic infection of the ribozyme-encoding virus. Such hTERT RNA knockdown in vivo induced changes in the global gene expression profile, including the suppression of specific genes associated with anti-apoptosis including bcl2, and genes for angiogenesis and metastasis. In addition, specific trans-splicing reaction with the targeted hTERT RNA took place in the tumors established as peritoneal carcinomatosis in mice by systemic delivery of the ribozyme. In conclusion, this study demonstrates that an hTERT-specific RNA replacement approach using trans-splicing ribozyme represents a potential modality to treat cancer.
Song
Min-Sun
MS
Department of Molecular Biology, Institute of Nanosensor and Biotechnology, Dankook University, Yongin 448-701, Korea.
Jeong
Jin-Sook
JS
Cho
Kyung-Sook
KS
Lee
Seong Wook
SW
D000818:Animals; D002460:Cell Line; D015870:Gene Expression / Q000502:physiology*; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D016337:RNA, Catalytic / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020040:Trans-Splicing / Q000235:genetics*
D016337:RNA, Catalytic; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C509186:TERT protein, human; D019098:Telomerase