Silencing of human c-myc oncogene expression by poly-DNP-RNA.
Deregulation of c-myc oncogene expression drives the progression of many different types of cancer. Recent experimental data suggest that even brief inhibition of c-myc expression may be sufficient to permanently stop tumor growth and induce regression of tumors. Previous efforts in developing an inhibitor to silence the c-myc gene were hampered by low efficacy and lack of sequence specificity. Here, we report the synthesis of an antisense RNA inhibitor based on a new 21-nt sequence on a poly- DNP-RNA platform that can specifically inhibit cancer cell growth by silencing c-myc gene expression. Both c-myc mRNA and protein levels were significantly decreased in MCF-7 cells following treatment with this antisense DNP-RNA inhibitor. The control compounds with sense or mismatched sequence were inactive. When c-myc transgenic mice were each treated with a single dose of the antisense RNA inhibitor, in vivo silencing of c-myc gene expression was observed for up to 72 hours by real-time RT-PCR. Similar treatment of c-myc transgenic mice with unmodified (native) homologous small interfering RNA (siRNA) had no effect on the mRNA concentration of the c-myc gene. Injection of this short antisense poly-DNP-RNA into mice did not induce the synthesis of DNP-binding immunoglobulins in the host. The observed in vivo gene silencing by this antisense RNA inhibitor suggests its possible use as a therapeutic agent for cancers involving the deregulation of c-myc gene expression.
Shen
Long
L
Bioenergetics Laboratory, Natural Sciences Complex, University at Buffalo, Buffalo, NY 14260, USA.
Zhang
Chongjie
C
Ambrus
Julian L
JL
Wang
Jui H
JH
D019297:2,4-Dinitrophenol / Q000737:chemistry*; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018387:Codon, Initiator; D004247:DNA / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D020868:Gene Silencing; D016259:Genes, myc; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000737:chemistry; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D012313:RNA / Q000737:chemistry; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018387:Codon, Initiator; D007074:Immunoglobulin G; C489427:MYC protein, human; D016376:Oligonucleotides, Antisense; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012313:RNA; D004247:DNA; D019297:2,4-Dinitrophenol