title: Rational design of microRNA-siRNA chimeras for multifunctional target suppression.
abstract: MicroRNAs (miRNAs) are involved in a variety of human diseases by simultaneously suppressing many gene targets. Thus, the therapeutic value of miRNAs has been intensely studied. However, there are potential limitations with miRNA-based therapeutics such as a relatively moderate impact on gene target regulation and cellular phenotypic control. To address these issues, we proposed to design new chimeric small RNAs (aiRNAs) by incorporating sequences from both miRNAs and siRNAs. These aiRNAs not only inherited functions from natural miRNAs, but also gained new functions of gene knockdown in an siRNA-like fashion. The improved efficacy of multifunctional aiRNAs was demonstrated in our study by design and testing of an aiRNA that inherited the functions of both miR-200a and an AKT1-targeting siRNA for simultaneous suppression of cancer cell motility and proliferation. The general principles of aiRNA design were further validated by engineering new aiRNAs mimicking another miRNA, miR-9. By regulating multiple cellular functions, aiRNAs could be used as an improved tool over miRNAs to target disease-related genes, thus alleviating our dependency on a limited number of miRNAs for the development of RNAi-based therapeutics.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Jiang
authors.forename: Weijun
authors.initials: W
authors.lastname: Liu
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Gao
authors.forename: Ge
authors.initials: G
authors.lastname: Gao
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Wang
mesh_terms: D001483:Base Sequence; D016923:Cell Death; D002465:Cell Movement; D049109:Cell Proliferation; D003001:Cloning, Molecular; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques / Q000379:methods*; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics*; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C533896:MIRN200 microRNA, human; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: RNA interference; cancer therapy; microRNA; siRNA; target regulation