Inhibitory Effect of Nuclear Factor-κB Decoy Oligodeoxynucleotide on Liver Fibrosis Through Regulation of the Epithelial–Mesenchymal Transition

Abstract

The epithelial-mesenchymal transition (EMT) has been recognized to occur during embryonic development, fibrosis, and tumor metastasis. Nuclear factor (NF)-jB plays a central role in mediating the inflammation and wound-healing responses during liver fibrogenesis. However, the involvement of NF-jB during EMT in liver cells remains unidentified. To develop a therapeutic approach to EMT during liver fibrosis, we examined the inhibition of transcription factor NF-jB, using a decoy oligodeoxynucleotide (ODN) strategy in liver fibrosis in vitro and in vivo. NF-jB decoy ODN contains consensus binding sequences of the NF-jB-binding site. NF-jB decoy ODN effectively suppresses transforming growth factor-b 1 -induced EMT in AML12 murine hepatocytes. Liver fibrosis induced by CCl 4 administration was suppressed by NF-jB decoy ODN. Furthermore, NF-jB decoy ODN was shown to inhibit the EMT process in fibrotic liver in vivo. This study demonstrates the feasibility of NF-jB decoy ODN treatment for preventing liver fibrosis via EMT processes.

Antifibrotic Effect of Smad Decoy Oligodeoxynucleotide in a CCl4-Induced Hepatic Fibrosis Animal Model

“…Following liver injury, hepatic stellate cells undergo phenotypic changes, which leads to increased deposition of ECM proteins, such as α-SMA, fibronectin, and type I collagen in the hepatic sinusoid [ 23 ]. Therefore, we investigated the effects of Smad decoy ODN on hepatic fibrogenesis and ECM accumulation by immunohistochemical and immunofluorescent staining in CCl 4 -induced hepatic fibrosis.…”

“…Some studies reported that the induction of synthetic decoy ODN with high attraction for their target transcription factors into peculiar cells. A previous study demonstrated that NF-κB decoy ODN inhibited the EMT process in mice of CCl 4 -induced hepatic fibrosis [ 23 ]. Park et al [ 29 ] reported the effect of ring-type decoy ODNs on CCl 4 -induced hepatic fibrosis.…”

“…We previously demonstrated that inhibition of Smad and Sp1 by the decoy ODN strategy prevented renal fibrosis in mice via inhibition of the production of cytokines related to fibrosis and EMT [ 22 ]. Additionally, we demonstrated the antifibrotic effect of the NF-κB decoy ODN in a hepatic fibrosis animal model [ 23 ]. However, the effect of Smad ODN on hepatic fibrosis in hepatocytes has not been reported.…”

Anti-fibrotic Effects of Synthetic Oligodeoxynucleotide for TGF-β1 and Smad in an Animal Model of Liver Cirrhosis

“…During liver fibrogenesis, hepatocytes lose their epithelial phenotype and acquire features of mesenchyme via EMT processes 42 . To induce EMT, AML12 cells were incubated for 48 hr with TGF-β1 (2 ng/mL), which is the key profibrogenic cytokine in the liver EMT process.…”

Beneficial Effects of SREBP Decoy Oligodeoxynucleotide in an Animal Model of Hyperlipidemia

“…This decoy ODN strategy is an effective approach for suppressing specific gene expression both in vitro and in vivo [24,25]. We previously demonstrated that the antifibrotic effect of the NF-κB decoy ODN in a hepatic fibrosis animal model [26]. Additionally, we demonstrated the effect of Smad ODN on hepatic fibrosis in hepatocytes and CCl 4 -induced hepatic fibrosis [27].…”