title: Targeted Regression of Hepatocellular Carcinoma by Cancer-Specific RNA Replacement through MicroRNA Regulation.
abstract: Hepatocellular carcinoma (HCC) has a high fatality rate and limited therapeutic options with side effects and low efficacy. Here, we proposed a new anti-HCC approach based on cancer-specific post-transcriptional targeting. To this end, trans-splicing ribozymes from Tetrahymena group I intron were developed, which can specifically induce therapeutic gene activity through HCC-specific replacement of telomerase reverse transcriptase (TERT) RNA. To circumvent side effects due to TERT expression in regenerating liver tissue, liver-specific microRNA-regulated ribozymes were constructed by incorporating complementary binding sites for the hepatocyte-selective microRNA-122a (miR-122a), which is down-regulated in HCC. The ribozyme activity in vivo was assessed in mouse models orthotopically implanted with HCC. Systemic administration of adenovirus encoding the developed ribozymes caused efficient anti-cancer effect and the least hepatotoxicity with regulation of ribozyme expression by miR-122a in both xenografted and syngeneic orthotopic murine model of multifocal HCC. Of note, the ribozyme induced local and systemic antitumor immunity, thereby completely suppressing secondary tumor challenge in the syngeneic mouse. The cancer specific trans-splicing ribozyme system, which mediates tissue-specific microRNA-regulated RNA replacement, provides a clinically relevant, safe, and efficient strategy for HCC treatment.
authors.affiliation: Department of Molecular Biology, Institute of Nanosensor and Biotechnology, and Research Institute of Advanced Omics, Dankook University, Yongin 448-701, Republic of Korea.
authors.forename: Juhyun
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Molecular Biology, Institute of Nanosensor and Biotechnology, and Research Institute of Advanced Omics, Dankook University, Yongin 448-701, Republic of Korea.
authors.forename: Ranhui
authors.initials: R
authors.lastname: Won
authors.affiliation: Department of Molecular Biology, Institute of Nanosensor and Biotechnology, and Research Institute of Advanced Omics, Dankook University, Yongin 448-701, Republic of Korea.
authors.forename: Guyee
authors.initials: G
authors.lastname: Ban
authors.affiliation: Department of Pathology and Immune-network Pioneer Research Center, Dong-A University College of Medicine, Busan 602-714, Republic of Korea.
authors.forename: Mi Ha
authors.initials: MH
authors.lastname: Ju
authors.affiliation: Department of Pathology and Immune-network Pioneer Research Center, Dong-A University College of Medicine, Busan 602-714, Republic of Korea.
authors.forename: Kyung Sook
authors.initials: KS
authors.lastname: Cho
authors.affiliation: Department of Internal Medicine, Dong-A University College of Medicine, Busan 602-714, Republic of Korea.
authors.forename: Sang
authors.initials: S
authors.lastname: Young Han
authors.affiliation: Department of Pathology and Immune-network Pioneer Research Center, Dong-A University College of Medicine, Busan 602-714, 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 448-701, Republic of Korea.
authors.forename: Seong-Wook
authors.initials: SW
authors.lastname: Lee
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D012313:RNA / Q000235:genetics; D016337:RNA, Catalytic / Q000235:genetics*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D019076:Transgenes; D023041:Xenograft Model Antitumor Assays
chemical_list: D035683:MicroRNAs; D016337:RNA, Catalytic; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase