title: Selective regression of cancer cells expressing a splicing variant of AIMP2 through targeted RNA replacement by trans-splicing ribozyme.
abstract: AIMP2/p38 is a scaffolding protein critical for the assembly of the macromolecular tRNA synthetase complex. Moreover, AIMP2 harbors anti-proliferative activity and promotes cell death as a proapototic factor. A splicing variant of AIMP2 lacking exon 2 (AIMP2-DX2) is specifically generated by an alternative splicing process and is highly expressed in human lung cancer cells and the tissues of cancer patients. AIMP2-DX2 induces tumorigenesis by compromising the tumor suppressor function of normal AIMP2. Here, we describe a novel approach to cancer therapy that is based on trans-splicing ribozyme-mediated replacement of specific RNAs. We developed a specific ribozyme that can target and replace the splicing variant AIMP2-DX2 RNA with a new transcript selectively exerting therapeutic activity in AIMP2-DX2-expressing lung cancer cells. The RNA replacement was employed via a high-fidelity trans-splicing reaction with the targeted residue of the AIMP2-DX2 transcript, but not with normal AIMP2 RNA, in the cells. Noticeably, the ribozyme could selectively deliver the activity of a suicide gene into the AIMP2-DX2 RNA expressing lung cancer cells and thereby specifically and effectively retard the growth of the cancer cells with prodrug treatment. Therefore, the AIMP2-DX2 RNA-targeting trans-splicing ribozyme could be a useful genetic agent for efficient therapy targeting lung cancer.
authors.affiliation: Department of Molecular Biology, Institute of Nanosensor and Biotechnology, Dankook University, Yongin 448-701, Republic of Korea.
authors.forename: You-Sub
authors.initials: YS
authors.lastname: Won
authors.forename: Seong-Wook
authors.initials: SW
authors.lastname: Lee
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D017209:Apoptosis; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D041722:Genes, Transgenic, Suicide / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000628:therapy; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D016337:RNA, Catalytic / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020040:Trans-Splicing / Q000235:genetics*; D014162:Transfection
chemical_list: D016207:Cytokines; D009363:Neoplasm Proteins; D016337:RNA, Catalytic; D016601:RNA-Binding Proteins; C077219:small inducible cytokine subfamily E, member 1