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Bioengineering Novel Chimeric microRNA-34a for Prodrug Cancer Therapy: High-Yield Expression and Purification, and Structural and Functional Characterization.
Wang, Wei-Peng; Ho, Pui Yan; Chen, Qiu-Xia; Addepalli, Balasubrahmanyam; Limbach, Patrick A; Li, Mei-Mei; Wu, Wen-Juan; Jilek, Joseph L; Qiu, Jing-Xin; Zhang, Hong-Jian; Li, Tianhong; Wun, Theodore; White, Ralph DeVere; Lam, Kit S; Yu, Ai-Ming.
Afiliación
  • Wang WP; Department of Biochemistry and Molecular Medicine (W.-P.W., P.Y.H., Q.-X.C., M.-M.L., W.-J.W., J.L.J., K.S.L., A.-M.Y.), Division of Hematology Oncology (T.L., T.W., K.S.L.) and Department of Urology (R.D.W.), School of Medicine, University of California-Davis, Sacramento, California; Rieveschl Labo
  • Ho PY; Department of Biochemistry and Molecular Medicine (W.-P.W., P.Y.H., Q.-X.C., M.-M.L., W.-J.W., J.L.J., K.S.L., A.-M.Y.), Division of Hematology Oncology (T.L., T.W., K.S.L.) and Department of Urology (R.D.W.), School of Medicine, University of California-Davis, Sacramento, California; Rieveschl Labo
  • Chen QX; Department of Biochemistry and Molecular Medicine (W.-P.W., P.Y.H., Q.-X.C., M.-M.L., W.-J.W., J.L.J., K.S.L., A.-M.Y.), Division of Hematology Oncology (T.L., T.W., K.S.L.) and Department of Urology (R.D.W.), School of Medicine, University of California-Davis, Sacramento, California; Rieveschl Labo
  • Addepalli B; Department of Biochemistry and Molecular Medicine (W.-P.W., P.Y.H., Q.-X.C., M.-M.L., W.-J.W., J.L.J., K.S.L., A.-M.Y.), Division of Hematology Oncology (T.L., T.W., K.S.L.) and Department of Urology (R.D.W.), School of Medicine, University of California-Davis, Sacramento, California; Rieveschl Labo
  • Limbach PA; Department of Biochemistry and Molecular Medicine (W.-P.W., P.Y.H., Q.-X.C., M.-M.L., W.-J.W., J.L.J., K.S.L., A.-M.Y.), Division of Hematology Oncology (T.L., T.W., K.S.L.) and Department of Urology (R.D.W.), School of Medicine, University of California-Davis, Sacramento, California; Rieveschl Labo
  • Li MM; Department of Biochemistry and Molecular Medicine (W.-P.W., P.Y.H., Q.-X.C., M.-M.L., W.-J.W., J.L.J., K.S.L., A.-M.Y.), Division of Hematology Oncology (T.L., T.W., K.S.L.) and Department of Urology (R.D.W.), School of Medicine, University of California-Davis, Sacramento, California; Rieveschl Labo
  • Wu WJ; Department of Biochemistry and Molecular Medicine (W.-P.W., P.Y.H., Q.-X.C., M.-M.L., W.-J.W., J.L.J., K.S.L., A.-M.Y.), Division of Hematology Oncology (T.L., T.W., K.S.L.) and Department of Urology (R.D.W.), School of Medicine, University of California-Davis, Sacramento, California; Rieveschl Labo
  • Jilek JL; Department of Biochemistry and Molecular Medicine (W.-P.W., P.Y.H., Q.-X.C., M.-M.L., W.-J.W., J.L.J., K.S.L., A.-M.Y.), Division of Hematology Oncology (T.L., T.W., K.S.L.) and Department of Urology (R.D.W.), School of Medicine, University of California-Davis, Sacramento, California; Rieveschl Labo
  • Qiu JX; Department of Biochemistry and Molecular Medicine (W.-P.W., P.Y.H., Q.-X.C., M.-M.L., W.-J.W., J.L.J., K.S.L., A.-M.Y.), Division of Hematology Oncology (T.L., T.W., K.S.L.) and Department of Urology (R.D.W.), School of Medicine, University of California-Davis, Sacramento, California; Rieveschl Labo
  • Zhang HJ; Department of Biochemistry and Molecular Medicine (W.-P.W., P.Y.H., Q.-X.C., M.-M.L., W.-J.W., J.L.J., K.S.L., A.-M.Y.), Division of Hematology Oncology (T.L., T.W., K.S.L.) and Department of Urology (R.D.W.), School of Medicine, University of California-Davis, Sacramento, California; Rieveschl Labo
  • Li T; Department of Biochemistry and Molecular Medicine (W.-P.W., P.Y.H., Q.-X.C., M.-M.L., W.-J.W., J.L.J., K.S.L., A.-M.Y.), Division of Hematology Oncology (T.L., T.W., K.S.L.) and Department of Urology (R.D.W.), School of Medicine, University of California-Davis, Sacramento, California; Rieveschl Labo
  • Wun T; Department of Biochemistry and Molecular Medicine (W.-P.W., P.Y.H., Q.-X.C., M.-M.L., W.-J.W., J.L.J., K.S.L., A.-M.Y.), Division of Hematology Oncology (T.L., T.W., K.S.L.) and Department of Urology (R.D.W.), School of Medicine, University of California-Davis, Sacramento, California; Rieveschl Labo
  • White RD; Department of Biochemistry and Molecular Medicine (W.-P.W., P.Y.H., Q.-X.C., M.-M.L., W.-J.W., J.L.J., K.S.L., A.-M.Y.), Division of Hematology Oncology (T.L., T.W., K.S.L.) and Department of Urology (R.D.W.), School of Medicine, University of California-Davis, Sacramento, California; Rieveschl Labo
  • Lam KS; Department of Biochemistry and Molecular Medicine (W.-P.W., P.Y.H., Q.-X.C., M.-M.L., W.-J.W., J.L.J., K.S.L., A.-M.Y.), Division of Hematology Oncology (T.L., T.W., K.S.L.) and Department of Urology (R.D.W.), School of Medicine, University of California-Davis, Sacramento, California; Rieveschl Labo
  • Yu AM; Department of Biochemistry and Molecular Medicine (W.-P.W., P.Y.H., Q.-X.C., M.-M.L., W.-J.W., J.L.J., K.S.L., A.-M.Y.), Division of Hematology Oncology (T.L., T.W., K.S.L.) and Department of Urology (R.D.W.), School of Medicine, University of California-Davis, Sacramento, California; Rieveschl Labo
J Pharmacol Exp Ther ; 354(2): 131-41, 2015 Aug.
Article en En | MEDLINE | ID: mdl-26022002
ABSTRACT
Development of anticancer treatments based on microRNA (miRNA/miR) such as miR-34a replacement therapy is limited to the use of synthetic RNAs with artificial modifications. Herein, we present a new approach to a high-yield and large-scale biosynthesis, in Escherichia coli using transfer RNA (tRNA) scaffold, of chimeric miR-34a agent, which may act as a prodrug for anticancer therapy. The recombinant tRNA fusion pre-miR-34a (tRNA/mir-34a) was quickly purified to a high degree of homogeneity (>98%) using anion-exchange fast protein liquid chromatography, whose primary sequence and post-transcriptional modifications were directly characterized by mass spectrometric analyses. Chimeric tRNA/mir-34a showed a favorable cellular stability while it was degradable by several ribonucleases. Deep sequencing and quantitative real-time polymerase chain reaction studies revealed that tRNA-carried pre-miR-34a was precisely processed to mature miR-34a within human carcinoma cells, and the same tRNA fragments were produced from tRNA/mir-34a and the control tRNA scaffold (tRNA/MSA). Consequently, tRNA/mir-34a inhibited the proliferation of various types of human carcinoma cells in a dose-dependent manner and to a much greater degree than the control tRNA/MSA, which was mechanistically attributable to the reduction of miR-34a target genes. Furthermore, tRNA/mir-34a significantly suppressed the growth of human non-small-cell lung cancer A549 and hepatocarcinoma HepG2 xenograft tumors in mice, compared with the same dose of tRNA/MSA. In addition, recombinant tRNA/mir-34a had no or minimal effect on blood chemistry and interleukin-6 level in mouse models, suggesting that recombinant RNAs were well tolerated. These findings provoke a conversation on producing biologic miRNAs to perform miRNA actions, and point toward a new direction in developing miRNA-based therapies.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Profármacos / Supervivencia Celular / MicroARNs / Bioingeniería / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Pharmacol Exp Ther Año: 2015 Tipo del documento: Article
Texto completo
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Profármacos / Supervivencia Celular / MicroARNs / Bioingeniería / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Pharmacol Exp Ther Año: 2015 Tipo del documento: Article