Rational basis for oligodeoxynucleotides to inhibit collagen synthesis in lung fibroblasts and primary fibroblasts from liver granulomas of Schistosoma mansoni-infected mice.
Hepatocellular carcinoma is associated with liver fibrosis. Murine schistosomiasis infection offers a model to study hepatic fibrogenesis. Single-stranded phosphorothiate oligodeoxynucleotides containing the TGF-beta regulatory element have been shown to regulate the transcription of this gene and effectively inhibit collagen synthesis in primary fibroblasts isolated from schistosomiasis-induced hepatic granulomas. While the single-stranded oligos did not decrease collagen and non-collagen protein synthesis below control levels, their double-stranded modified and unmodified counterparts did. Competitive cold oligodeoxynucleotide gel mobility shift analysis using control fibroblast nuclear extract demonstrated that the single-stranded oligos diminished binding of the TGF-beta activator protein to the TGF-beta regulatory element while the double-stranded oligos totally inhibited this binding. TGF-beta element containing single-stranded phosphorothioate oligodeoxynucleotides and their double-stranded counterparts may be successful therapeutic agents to inhibit hepatic fibrogenesis and associated hepatocellular carcinoma.
Cutroneo
Kenneth R
KR
Department of Biochemistry, College of Medicine, University of Vermont, Burlington, VT 05405, USA. kenneth.cutroneo@uvm.edu
Boros
Dov L
DL
D000818:Animals; D003094:Collagen / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006099:Granuloma / Q000150:complications*; D008103:Liver Cirrhosis / Q000150:complications / Q000188:drug therapy*; D008107:Liver Diseases / Q000150:complications*; D008113:Liver Neoplasms / Q000209:etiology; D051379:Mice; D008808:Mice, Inbred CBA; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D012555:Schistosomiasis mansoni / Q000150:complications*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014945:Wound Healing
D009838:Oligodeoxyribonucleotides; D016212:Transforming Growth Factor beta; D003094:Collagen