title: Targeted anticancer effect through microRNA-181a regulated tumor-specific hTERT replacement.
abstract: We previously generated a group I intron-based ribozyme that can reprogram human telomerase reverse transcriptase (hTERT) RNA to stimulate transgene activity in cancer cells expressing the target RNA via an accurate and specific trans-splicing reaction. One of the major concerns of the hTERT RNA targeting anti-cancer approach is the potential side effects to hTERT(+) hematopoietic stem cell-derived blood cells. Thus, here we modified the ribozyme by inserting target sites against microRNA-181a, which is a blood cell-specific microRNA, downstream of its 3' exon. The specificity of transgene induction and anticancer activity in hTERT(+) cancer cells improved significantly with the modified ribozyme, resulting in selective targeting of hTERT(+) cancer cells, but not hematopoietic cells even if they are hTERT-positive. Importantly, the trans-splicing reaction of the microRNA-regulated ribozyme worked equally well in a nude mouse model of hepatocarcinoma-derived intrasplenic carcinomatosis, inducing highly specific expression of a therapeutic transgene and efficiently regressing hTERT-positive liver tumors with minimal liver toxicity when systemically delivered with an adenoviral vector encoding the ribozyme. These results suggest that a combined approach of microRNA regulation with targeted RNA replacement is more useful for effective anti-cancer treatment.
authors.affiliation: Department of Molecular Biology, Institute of Nanosensor and Biotechnology, and Research Institute of Advanced Omics, Dankook University, Yongin, Republic of Korea.
authors.forename: You-Sub
authors.initials: YS
authors.lastname: Won
authors.affiliation: Department of Pathology and Medical Research Center for Cancer Molecular Therapy, Dong-A University College of Medicine, Busan, Republic of Korea.
authors.forename: Jin-Sook
authors.initials: JS
authors.lastname: Jeong
authors.affiliation: Department of Molecular Biology, Institute of Nanosensor and Biotechnology, and Research Institute of Advanced Omics, Dankook University, Yongin, Republic of Korea.
authors.forename: Sung Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Pathology and Medical Research Center for Cancer Molecular Therapy, Dong-A University College of Medicine, Busan, Republic of Korea.
authors.forename: Mi Ha
authors.initials: MH
authors.lastname: Ju
authors.affiliation: Department of Molecular Biology, Institute of Nanosensor and Biotechnology, and Research Institute of Advanced Omics, Dankook University, Yongin, Republic of Korea. Electronic address: swl0208@dankook.ac.kr.
authors.forename: Seong-Wook
authors.initials: SW
authors.lastname: Lee
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009369:Neoplasms; D016337:RNA, Catalytic / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D019076:Transgenes / Q000502:physiology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D016337:RNA, Catalytic; D012333:RNA, Messenger; C509186:TERT protein, human; D019098:Telomerase
keywords: Cancer gene therapy; RNA replacement; hTERT; microRNA-181a; trans-splicing ribozyme